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Le Roux AB, Fung EK, Lee SG, Monette S, Xu H, Guo HF, Yang G, Ouerfelli O, Jungbluth A, Schöder H, Larson SM, Cheung NKV, Cheal SM, Veach DR. GPA33-pretargeted radioimmunotherapy with mono- and bivalent DOTA-based Lu-177-labeled radiohaptens in a mouse orthotopic liver xenograft model of metastatic human colorectal cancer. Theranostics 2025; 15:6274-6289. [PMID: 40521192 PMCID: PMC12159840 DOI: 10.7150/thno.107209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 04/04/2025] [Indexed: 06/18/2025] Open
Abstract
Rationale: Pretargeted radioimmunotherapy (PRIT), which combines systemic antibody-based targeting with ionizing radiation, is promising for treating liver metastases in patients with colorectal cancer (CRC). Previously, we established a three-step DOTA-PRIT regimen to deliver DOTA radiometal payloads to CRC using an anti-tumor/anti-DOTA bispecific antibody (BsAb) targeting cell surface glycoprotein A33 (GPA33), a tumor antigen target expressed on over 95% of primary and metastatic CRC; a clearing agent; and a monovalent 177Lu radiohapten called [177Lu]Lu-ABD. More recently, we developed a bivalent 177Lu radiohapten called [177Lu]Lu-Gemini to enhance tumor uptake and radiohapten retention. Here, we aimed to compare the efficacy and safety of bivalent vs. monovalent three-step DOTA-PRIT regimens in orthotopic CRC liver metastasis models, to mimic a clinical path forward. Methods: We established two orthotopic CRC liver metastasis models by inoculating either SW1222-luc (GPA33high) or LoVo (GPA33low) human CRC cells in athymic nude mice under ultrasonographic guidance. Tumor targeting efficacy and dosimetry of the radiohaptens were compared using ex vivo biodistribution studies, SPECT/CT, and quantitative autoradiography. We also performed a DOTA-PRIT experiment to compare the efficacy and safety profiles of bivalent (single-cycle [177Lu]Lu-Gemini, 48 h pretargeting interval) vs. monovalent (multicycle [177Lu]Lu-ABD, 24 h pretargeting interval) three-step DOTA-PRIT regimens, each designed to deliver comparable total radiation doses to tumors (around 50 Gy). Results: Both radiohaptens demonstrated efficient SW1222-luc tumor targeting, with [177Lu]Lu-Gemini showing superior targeting and tumor activity retention compared with [177Lu]Lu-ABD. In LoVo tumors, [177Lu]Lu-Gemini showed superior targeting, while [177Lu]Lu-ABD showed negligible targeting. Dosimetry estimates revealed higher SW1222-luc tumor mean absorbed doses for [177Lu]Lu-Gemini (119.88 cGy/MBq, 48 h pretargeting interval) compared with [177Lu]Lu-ABD (32.88 cGy/MBq, 24 h pretargeting interval), with more favorable blood and kidney therapeutic indices (50 and 9 for [177Lu]Lu-Gemini, and 15 and 5 for [177Lu]Lu-ABD, respectively). In the DOTA-PRIT experiment, both monovalent (injected activity: 3 × 44.4 MBq, 133.2 MBq total) and bivalent (injected activity: 44.4 MBq total) radiohapten regimens increased the median survival of treated mice compared with controls: 71 days for [177Lu]Lu-ABD-treated mice, 81 days for [177Lu]Lu-Gemini-treated mice, and 18 days for controls, without a statistical difference between treatment groups. Treatments were well tolerated, without significant weight loss or hematologic changes. Radiation-induced injuries were not identified histologically in the kidneys or bone marrow of mice submitted for necropsy. Conclusions: Our study demonstrates the exceptional benefit of a multivalent radiohapten strategy when treating an advanced model of CRC liver metastasis. Three-step GPA33 DOTA-PRIT with 177Lu-Gemini demonstrated that multivalency 1) improves PRIT therapeutic indices for blood and kidney and 2) has the potential to greatly reduce the administered activity without compromising the efficiency of the PRIT platform in clinically relevant models of target-rich and target-poor metastatic CRC.
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Affiliation(s)
| | - Edward K. Fung
- Department of Radiology, Weill Cornell Medicine, New York, NY
| | - Sang Gyu Lee
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sebastien Monette
- Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and Rockefeller University, New York, NY
| | - Hong Xu
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Hong-Fen Guo
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Guangbin Yang
- Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ouathek Ouerfelli
- Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Achim Jungbluth
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Heiko Schöder
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Radiology, Weill Cornell Medicine, New York, NY
| | - Steven M. Larson
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Radiology, Weill Cornell Medicine, New York, NY
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nai-Kong V. Cheung
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sarah M. Cheal
- Department of Radiology, Weill Cornell Medicine, New York, NY
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Darren R. Veach
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Radiology, Weill Cornell Medicine, New York, NY
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Rassouli FB, Matin MM, Hadizadeh F, Nejabat M, Allahverdizadeh H, Jamali H, Gharedaghi S, Hassanzadeh H. Exploring the anti-metastatic potential of sunitinib and novel analogs in colorectal cancer: insights into HIF-1α mediated metastasis. Front Pharmacol 2025; 16:1520881. [PMID: 39968177 PMCID: PMC11832664 DOI: 10.3389/fphar.2025.1520881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 01/10/2025] [Indexed: 02/20/2025] Open
Abstract
Introduction Colorectal cancer (CRC) is a prevalent malignancy worldwide with high mortality rate. Metastasis, the primary cause of cancer-related deaths, is attributed to various factors including tumor hypoxia. Due to the urgent demand for potent anti-metastatic agents, we aimed to determine the effects of sunitinib and novel analogs on the metastatic behavior of human CRC cells in hypoxic condition for the first time. Methods For in silico analyses, pathogenic targets of metastatic CRC were identified, PPI network was constructed and KEGG pathway enrichment analysis was conducted. The expression of HIF1A was evaluated in seven CRC cell lines, and computational modeling was carried out to define the interaction of sunitinib with HIF-1α. For in vitro studies, analogs of sunitinib were synthesized, and cells were assessed for viability, migration, invasion, MMPs activity and gene expression in hypoxic condition. Results and Discussion Computational analyses highlighted the importance of HIF-1α as a crucial mediator of metastasis in CRC. Molecular docking and dynamics simulations demonstrated favorable and stable interaction of sunitinib and three novel analogs with HIF-1α PAS-B domain. Volcano plots indicated upregulation of HIF1A in LoVo cells compared to six other CRC cell lines. Findings of in vitro studies revealed considerable inhibitory effects of sunitinib and analogs on LoVo cell migration and invasion in hypoxic condition. Gelatin zymography and qPCR analysis indicated decreased activity of MMP-2 and MMP-9, along with downregulation of EMT transcription factors in hypoxic condition. Current study reports promising anti-metastatic effects of sunitinib and novel analogs on CRC cells, providing foundation for further investigation to combat cancer metastasis.
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Affiliation(s)
- Fatemeh B. Rassouli
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Maryam M. Matin
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Farzin Hadizadeh
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Masoud Nejabat
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | | | - Hamidreza Jamali
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Shahin Gharedaghi
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Halimeh Hassanzadeh
- Stem Cell and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research (ACECR)-Khorasan Razavi, Mashhad, Iran
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Li Y, Cheng Z, Li S, Zhang J. Immunotherapy in colorectal cancer: Statuses and strategies. Heliyon 2025; 11:e41354. [PMID: 39811287 PMCID: PMC11731577 DOI: 10.1016/j.heliyon.2024.e41354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 12/10/2024] [Accepted: 12/18/2024] [Indexed: 01/16/2025] Open
Abstract
Colorectal cancer (CRC) is widely recognized as the third most prevalent malignancy globally and the second leading cause of cancer-related mortality. Traditional treatment modalities for CRC, including surgery, chemotherapy, and radiotherapy, can be utilized either individually or in combination. However, these treatments frequently result in significant side effects due to their non-specificity and cytotoxicity affecting all cells. Moreover, a considerable number of patients face relapses following these treatments. Consequently, it is imperative to explore more efficacious treatment interventions for CRC patients. Immunotherapy, an emerging frontier in oncology, represents a novel therapeutic approach that leverages the body's immune system to target cancer cells. The principal advantage of immunotherapy is its capacity to selectively target cancer cells while minimizing damage to healthy cells. Its recent adoption as a neoadjuvant therapy presents significant potential to transform the treatment landscape for both primary resectable and metastatic CRC. This review endeavors to offer a comprehensive overview of current strategies in CRC immunotherapy, critically analyze existing literature, underscore anticipated outcomes from ongoing clinical trials, and deliberate on the challenges and impediments encountered within the field of immunotherapy.
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Affiliation(s)
- Yuan Li
- Shanghai Key Laboratory of Compound Chinese Medicines, The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zewei Cheng
- Shanghai Key Laboratory of Compound Chinese Medicines, The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shengli Li
- Precision Research Center for Refractory Diseases and Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China
| | - Jiwei Zhang
- Shanghai Key Laboratory of Compound Chinese Medicines, The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
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Li Y, Chen J, Liang H, Du Q, Shen J, Wang X. Gasdermin D regulates the activation of EGFR in colorectal cancer. J Transl Med 2024; 22:1170. [PMID: 39741309 DOI: 10.1186/s12967-024-05984-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 12/13/2024] [Indexed: 01/02/2025] Open
Abstract
BACKGROUND Gasdermin D (GSDMD) is a key effector molecule that activates pyroptosis through its N terminal domain (GSDMD-NT). However, the roles of GSDMD in colorectal cancer (CRC) have not been fully explored. The role of the full-length GSDMD (GSDMD-FL) is also not clear. In this study, we observed that GSDMD modulates CRC progression through other mechanisms in addition to activating GSDMD-NT. METHODS Clinical CRC samples and human-derived CRC cell lines were used in this study. GSDMD expression was evaluated by RT-qPCR, Western blot and immunohistochemical (IHC) analysis. GSDMD knockdown and overexpression stable cell lines were established by Lentiviral transduction. CCK-8 assay, flow cytometry analysis for cell cycle, Transwell assay, and cell scratch assay were performed in vitro to explore the impact of GSDMD on CRC progression. Mouse subcutaneous transplantation tumor models were constructed to assess the role of GSDMD in vivo. Intestinal epithelial cell (IEC)-specific knockout of Gsdmd mice (GsdmdΔIEC) was used to evaluate the effect of GSDMD on intestinal adenoma formation in AOM-DSS and Apcmin/+ mouse models. RNA sequencing was performed to explore the regulatory pathways associated with the role of GSDMD in CRC cells. Co-Immunoprecipitation (CO-IP), Western blot and immunofluorescence (IF) were conducted to investigate the interactions between GSDMD and EGFR. Exogenous addition of Gefitinib was used to evaluate the effect of GSDMD on autophosphorylation of EGFR at the Tyr1068 site. RESULTS GSDMD was highly expressed in clinical CRC tissues and human-derived CRC cell lines. GSDMD knockdown inhibited the viability, cell cycle changes, invasion ability and migration ability of CRC cell lines in vitro and vivo, whereas GSDMD overexpression had the opposite effects. Intestinal adenoma development was reduced in GsdmdΔIEC mice in both AOM-DSS and Apcmin/+ mouse models. GSDMD-FL interacted with EGFR and promoted CRC progression by inducing autophosphorylation of EGFR at the Tyr1068 site, subsequently activating ERK1/2. Exogenous Gefitinib abrogated the tumorigenic properties of GSDMD. CONCLUSIONS GSDMD-FL promotes CRC progression by inducing EGFR autophosphorylation at the Tyr1068 site, subsequently activating the downstream ERK1/2. Inhibition of GSDMD is a potential strategy for the treatment of colorectal cancer.
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Affiliation(s)
- Ying Li
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Jiayao Chen
- Department of Oncology, Zhangjiagang Third People's Hospital, Suzhou, 215611, China
| | - Huijun Liang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Qindan Du
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Jingjie Shen
- The Ninth People's Hospital of Suzhou City, Suzhou, China
| | - Xiaoying Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China.
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of medicine, Jiangnan University, Wuxi, China.
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Maryam S, Krukiewicz K. Sweeten the pill: Multi-faceted polysaccharide-based carriers for colorectal cancer treatment. Int J Biol Macromol 2024; 282:136696. [PMID: 39437958 DOI: 10.1016/j.ijbiomac.2024.136696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 10/25/2024]
Abstract
Colorectal cancer (CRC) ranks as the second deadliest cancer globally and the third most common malignant tumor. While surgery remains the primary treatment for CRC, alternative therapies such as chemotherapy, molecular targeted therapy, and immunotherapy are also commonly used. The significant side effects and toxicity of conventional drugs drive the search for novel targeted therapies, including the design of advanced drug delivery systems. Polysaccharide-based biopolymers, with their low toxicity, non-immunogenic behavior, synergistic interactions with other biopolymers, and tissue and cell compatibility, emerge as excellent drug carriers for this application. This review aims to provide an in-depth overview of recent advancements in developing polysaccharide-based biopolymeric carriers for anticancer compounds in the treatment of CRC. We highlight the multifunctional nature of polysaccharides, showcasing their potential as standalone drug carriers or as integral components of intelligent robotic devices for biomedical therapeutic applications. In addition to exploring the opportunities for using carbohydrate polymers in CRC treatment, we address the challenges and failures that may limit their applicability in biomedical research, as well as summarize the recent preclinical and clinical trials, resulting in several commercialization attempts. This comprehensive overview critically summarizes the potential of polysaccharide-based biomaterials in CRC treatment.
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Affiliation(s)
- Sajida Maryam
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, Gliwice, Poland; Joint Doctoral School, Silesian University of Technology, Gliwice, Poland
| | - Katarzyna Krukiewicz
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, Gliwice, Poland; Centre for Organic and Nanohybrid Electronics, Silesian University of Technology, Gliwice, Poland.
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Sun W, Su Y, Zhang Z. Characterizing m6A modification factors and their interactions in colorectal cancer: implications for tumor subtypes and clinical outcomes. Discov Oncol 2024; 15:457. [PMID: 39292326 PMCID: PMC11411059 DOI: 10.1007/s12672-024-01298-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 09/02/2024] [Indexed: 09/19/2024] Open
Abstract
BACKGROUND The study aims to comprehensively combine colorectal cancer data cohorts in order to analyze the effects of various DNA methylation-coding genes on colorectal cancer patients. The annual incidence and mortality of colorectal cancer are very high, and there are no effective treatments for advanced colorectal cancer. DNA methylation is a method widely used to regulate epigenetics in the molecular mechanism study of tumors. METHOD Three single-cell cohorts GSE166555, GSE146771, and EMTAB8107, and five transcriptome cohorts GSE17536, GSE39582, GSE72970, and TCGA-CRC (TCGA-COAD and TCGA-READ) were applied in this study. 2 erasers (ALKBH5 and FTO), There are 7 writers (METTL3, METTL14, WTAP, VIRMA, RBM15, RBM15B, and ZC3H13) and 11 readers (YTHDC1, IGF2BP1, IGF2BP2, IGF2BP3, YTHDF1, YTHDF3, YTHDC2, and HNRNPA2B1, YTHDF2, HNRNPC and RBMX), a total of 20 M6A regulators, were used as the basis of the dataset in this study and were applied to the construction of molecular typing and prognostic models. Drugs that are differentially sensitive in methylation-regulated gene-related prognostic models were identified using the ConsensusClusterPlus package, which was also used to identify distinct methylation regulatory expression patterns in colorectal cancer and to model the relationship between tissue gene expression profiles and drug IC50 values. Finally, TISCH2 assessed which immune cells were significantly expressed with M6A scores. The immunosuppression of M6A methylation is spatially explained. RESULTS This study used data from 583 CRC patients in the TCGA-CRC cohort. Firstly, the mutation frequency and CNV variation frequency of 20 m6A modification-related factors were analyzed, and the corresponding histogram and heat map were drawn. The study next analyzed the expression variations between mutant and wild forms of the VIRMA gene and explored differences in the expression of these variables in tumor and normal tissues. In addition, the samples were divided into different subgroups by molecular clustering method based on m6A modification, and each subgroup's expression and clinicopathological characteristics were analyzed. Finally, we compared prognostic differences, tumor microenvironment (TME) characteristics, immune cell infiltration, and gene function enrichment among different subpopulations. We also developed a colorectal cancer m6A-associated gene signature and validated its prognostic effects across multiple cohorts. Finally, using single-cell RNA sequencing data, we confirmed that tumor cells show elevated expression of m6A-related gene signatures. DISCUSSION This study explored the mutation frequency, expression differences, interactions, molecular clustering, prognostic effect, and association with tumor characteristics of m6A modification-related factors in CRC and validated them at the single-cell level. These results clarify the association between m6A alteration and colorectal cancer (CRC) and offer important insights into the molecular recognition and management of cancer.
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Affiliation(s)
- Weidong Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China
| | - Yingchao Su
- Department of Neurology, Xinqiao Hospital, Army Medical University, No. 183 Xinqiao Road, Chongqing, 400037, China
| | - Zhiqiang Zhang
- Department of General Surgery, Xinqiao Hospital, Army Medical University, No. 183 Xinqiao Road, Chongqing, 400037, China.
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Paly VF, Dasari A, Hubbard J, Bekaii-Saab T, Padukkavidana T, Hernandez L. Adverse event costs of systemic therapies for metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy and biologics in the US. J Comp Eff Res 2024; 13:e240084. [PMID: 38976346 PMCID: PMC11284812 DOI: 10.57264/cer-2024-0084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 06/19/2024] [Indexed: 07/10/2024] Open
Abstract
Aim: The objective of this study was to compare adverse event (AE) management costs for fruquintinib, regorafenib, trifluridine/tipiracil (T/T) and trifluridine/tipiracil+bevacizumab (T/T+bev) for patients with metastatic colorectal cancer (mCRC) previously treated with at least two prior lines of therapy from the US commercial and Medicare payer perspectives. Materials & methods: A cost-consequence model was developed to calculate the per-patient and per-patient-per-month (PPPM) AE costs using rates of grade 3/4 AEs with incidence ≥5% in clinical trials, event-specific management costs and duration treatment. Anchored comparisons of AE costs were calculated using a difference-in-differences approach with best supportive care (BSC) as a common reference. AE rates and treatment duration were obtained from clinical trials: FRESCO and FRESCO-2 (fruquintinib), RECOURSE (T/T), CORRECT (regorafenib) and SUNLIGHT (T/T, T/T+bev). AE management costs for the commercial and Medicare perspectives were obtained from publicly available sources. Results: From the commercial perspective, the AE costs (presented as per-patient, PPPM) were: $4015, $1091 for fruquintinib (FRESCO); $4253, $1390 for fruquintinib (FRESCO-2); $17,110, $11,104 for T/T (RECOURSE); $9851, $4691 for T/T (SUNLIGHT); $8199, $4823 for regorafenib; and $11,620, $2324 for T/T+bev. These results were consistent in anchored comparisons: the difference-in-difference for fruquintinib based on FRESCO was -$1929 versus regorafenib and -$11,427 versus T/T; for fruquintinib based on FRESCO-2 was -$2257 versus regorafenib and -$11,756 versus T/T. Across all analyses, results were consistent from the Medicare perspective. Conclusion: Fruquintinib was associated with lower AE management costs compared with regorafenib, T/T and T/T+bev for patients with previously treated mCRC. This evidence has direct implications for treatment, formulary and pathways decision-making in this patient population.
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Affiliation(s)
- Victoria Federico Paly
- Global Pricing, Value & Access; Global Health Economics & US HEOR – Oncology, Takeda Pharmaceuticals America, Inc., Lexington, MA 02421, USA
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Joleen Hubbard
- Department of Hematology Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Thihan Padukkavidana
- US Medical Affairs – Oncology, Takeda Pharmaceuticals USA, Inc., Lexington, MA 02421, USA
| | - Luis Hernandez
- Global Pricing, Value & Access; Global Health Economics & US HEOR – Oncology, Takeda Pharmaceuticals America, Inc., Lexington, MA 02421, USA
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Fialková V, Ďúranová H, Borotová P, Klongová L, Grabacka M, Speváková I. Natural Stilbenes: Their Role in Colorectal Cancer Prevention, DNA Methylation, and Therapy. Nutr Cancer 2024; 76:760-788. [PMID: 38950568 DOI: 10.1080/01635581.2024.2364391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/29/2024] [Accepted: 05/31/2024] [Indexed: 07/03/2024]
Abstract
The resistance of colorectal cancer (CRC) to conventional therapeutic modalities, such as radiation therapy and chemotherapy, along with the associated side effects, significantly limits effective anticancer strategies. Numerous epigenetic investigations have unveiled that naturally occurring stilbenes can modify or reverse abnormal epigenetic alterations, particularly aberrant DNA methylation status, offering potential avenues for preventing or treating CRC. By modulating the activity of the DNA methylation machinery components, phytochemicals may influence the various stages of CRC carcinogenesis through multiple molecular mechanisms. Several epigenetic studies, especially preclinical research, have highlighted the effective DNA methylation modulatory effects of stilbenes with minimal adverse effects on organisms, particularly in combination therapies for CRC. However, the available preclinical and clinical data regarding the effects of commonly encountered stilbenes against CRC are currently limited. Therefore, additional epigenetic research is warranted to explore the preventive potential of these phytochemicals in CRC development and to validate their therapeutic application in the prevention and treatment of CRC. This review aims to provide an overview of selected bioactive stilbenes as potential chemopreventive agents for CRC with a focus on their modulatory mechanisms of action, especially in targeting alterations in DNA methylation machinery in CRC.
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Affiliation(s)
- Veronika Fialková
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Hana Ďúranová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Petra Borotová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Lucia Klongová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Maja Grabacka
- Department of Biotechnology and General Technology of Foods, Faculty of Food Technology, University of Agriculture, Cracow, Poland
| | - Ivana Speváková
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
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Mendoza-Rodríguez MG, Medina-Reyes D, Sánchez-Barrera CA, Fernández-Muñoz KV, García-Castillo V, Ledesma-Torres JL, González-González MI, Reyes JL, Pérez-Plascencia C, Rodríguez-Sosa M, Vaca-Paniagua F, Meraz MA, Terrazas LI. Helminth-derived molecules improve 5-fluorouracil treatment on experimental colon tumorigenesis. Biomed Pharmacother 2024; 175:116628. [PMID: 38663106 DOI: 10.1016/j.biopha.2024.116628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 04/10/2024] [Accepted: 04/17/2024] [Indexed: 06/03/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent fatal neoplasias worldwide. Despite efforts to improve the early diagnosis of CRC, the mortality rate of patients is still nearly 50%. The primary treatment strategy for CRC is surgery, which may be accompanied by chemotherapy and radiotherapy. The conventional and first-line chemotherapeutic agent utilized is 5-fluorouracil (5FU). However, it has low efficiency. Combination treatment with leucovorin and oxaliplatin or irinotecan improves the effectiveness of 5FU therapy. Unfortunately, most patients develop drug resistance, leading to disease progression. Here, we evaluated the effect of a potential alternative adjuvant treatment for 5FU, helminth-derived Taenia crassiceps (TcES) molecules, on treating advanced colitis-associated colon cancer. The use of TcES enhanced the effects of 5FU on established colonic tumors by downregulating the expression of the immunoregulatory cytokines, Il-10 and Tgf-β, and proinflammatory cytokines, Tnf-α and Il-17a, and reducing the levels of molecular markers associated with malignancy, cyclin D1, and Ki67, both involved in apoptosis inhibition and the signaling pathway of β-catenin. TcES+5FU therapy promoted NK cell recruitment and the release of Granzyme B1 at the tumor site, consequently inducing tumor cell death. Additionally, it restored P53 activity which relates to decreased Mdm2 expression. In vitro assays with human colon cancer cell lines showed that therapy with TcES+5FU significantly reduced cell proliferation and migration by modulating the P53 and P21 signaling pathways. Our findings demonstrate, for the first time in vivo, that helminth-derived excreted/secreted products may potentiate the effect of 5FU on established colon tumors.
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Affiliation(s)
- Mónica G Mendoza-Rodríguez
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico.
| | - Daniela Medina-Reyes
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico
| | - Cuauhtémoc A Sánchez-Barrera
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico
| | - Karen V Fernández-Muñoz
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico; Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional 2508, Ciudad de México 07360, Mexico
| | - Verónica García-Castillo
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico
| | - Jorge L Ledesma-Torres
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico
| | - Marisol I González-González
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico
| | - José L Reyes
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico
| | - Carlos Pérez-Plascencia
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico; Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, Mexico
| | - Miriam Rodríguez-Sosa
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico
| | - Felipe Vaca-Paniagua
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico; Laboratorio Nacional en Salud, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de Mexico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico
| | - Marco A Meraz
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional 2508, Ciudad de México 07360, Mexico
| | - Luis I Terrazas
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico; Laboratorio Nacional en Salud, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de Mexico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico.
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Hsu HC, Chung WH, Lin YC, Yang TS, Chang JWC, Hsieh CH, Hung SI, Lu CW, Chen JS, Chou WC, Wang CW. Clinical characteristics and genetic HLA marker for patients with oxaliplatin-induced adverse drug reactions. Allergol Int 2024:S1323-8930(24)00041-8. [PMID: 38594174 DOI: 10.1016/j.alit.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 03/03/2024] [Accepted: 03/07/2024] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND Oxaliplatin is commonly used to treat gastrointestinal malignancies. However, its applications are limited due to potential adverse drug reactions (ADRs), particularly severe anaphylactic shock. There is no method to predict or prevent ADRs caused by oxaliplatin. Therefore, we aimed to investigate the genetic HLA predisposition and immune mechanism of oxaliplatin-induced ADRs. METHODS A retrospective review was performed for 154 patients with ADRs induced by oxaliplatin during 2016-2021 recorded in our ADR notification system. HLA genotyping was conducted for 47 patients with oxaliplatin-induced ADRs, 1100 general population controls, and 34 oxaliplatin-tolerant controls in 2019-2023. The in vitro basophil activation test (BAT) was performed and oxaliplatin-specific IgE levels were determined. RESULTS The incidence of oxaliplatin-induced ADRs and anaphylactic shock in our cohort was 7.1% and 0.15%, respectively. Of the 154 patients, 67.5% suffered rash/eruption; 26.0% of the patients who could not undergo oxaliplatin rechallenge were considered to show oxaliplatin-induced immune-mediated hypersensitivity reactions (HRs). The genetic study found that the HLA-DRB∗12:01 allele was associated with oxaliplatin-induced HRs compared to the general population controls (sensitivity = 42.9%; odds ratio [OR] = 3.4; 95% CI = 1.4-8.2; P = 0.008) and tolerant controls (OR = 12; 95% CI = 2.3-63.7; P = 0.001). The in vitro BAT showed higher activation of CD63+ basophils in patients with oxaliplatin-induced HRs compared to the tolerant controls (P < 0.05). Only four patients (8.5%) with oxaliplatin-induced ADRs were positive for oxaliplatin-specific IgE. CONCLUSIONS This study found that 26.0% of patients with oxaliplatin-induced ADRs could not undergo oxaliplatin rechallenge. HLA-DRB∗12:01 is regarded as a genetic marker for oxaliplatin-induced hypersensitivity.
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Affiliation(s)
- Hung-Chih Hsu
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wen-Hung Chung
- College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and Keelung, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taiwan; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Linkou, Taiwan; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; Department of Dermatology, Beijing Tsinghua Chang Gung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China; Department of Dermatology, Ruijin Hospital, Shanghai, China; School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yung-Chang Lin
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tsai-Sheng Yang
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - John Wen-Cheng Chang
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Chia-Hsun Hsieh
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shuen-Iu Hung
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Linkou, Taiwan; Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taiwan
| | - Chun-Wei Lu
- College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and Keelung, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taiwan; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China
| | - Jen-Shi Chen
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wen-Chi Chou
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chuang-Wei Wang
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and Keelung, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Linkou, Taiwan.
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11
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Sharma S, Singh N, Turk AA, Wan I, Guttikonda A, Dong JL, Zhang X, Opyrchal M. Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions. World J Gastroenterol 2024; 30:1815-1835. [PMID: 38659481 PMCID: PMC11036501 DOI: 10.3748/wjg.v30.i13.1815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/22/2024] [Accepted: 03/13/2024] [Indexed: 04/03/2024] Open
Abstract
Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
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Affiliation(s)
- Samantha Sharma
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Naresh Singh
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Anita Ahmed Turk
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Isabella Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Akshay Guttikonda
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Julia Lily Dong
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Xinna Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Mateusz Opyrchal
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
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12
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Saadh MJ, Mohamed AH, Almoyad MAA, Allela OQB, Amin AH, Malquisto AA, Jin WT, Sârbu I, AlShamsi F, Elsaid FG, Akhavan-Sigari R. Dual role of mesenchymal stem/stromal cells and their cell-free extracellular vesicles in colorectal cancer. Cell Biochem Funct 2024; 42:e3962. [PMID: 38491792 DOI: 10.1002/cbf.3962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/13/2024] [Accepted: 02/19/2024] [Indexed: 03/18/2024]
Abstract
Colorectal cancer (CRC) is one of the main causes of cancer-related deaths. However, the surgical control of the CRC progression is difficult, and in most cases, the metastasis leads to cancer-related mortality. Mesenchymal stem/stromal cells (MSCs) with potential translational applications in regenerative medicine have been widely researched for several years. MSCs could affect tumor development through secreting exosomes. The beneficial properties of stem cells are attributed to their cell-cell interactions as well as the secretion of paracrine factors in the tissue microenvironment. For several years, exosomes have been used as a cell-free therapy to regulate the fate of tumor cells in a tumor microenvironment. This review discusses the recent advances and current understanding of assessing MSC-derived exosomes for possible cell-free therapy in CRC.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, Jordan
- Applied Science Research Center, Applied Science Private University, Amman, Jordan
| | - Asma'a H Mohamed
- Biomedical Engineering Department, College of Engineering and Technologies, Al-Mustaqbal University, Babil, Hilla, Iraq
| | - Muhammad Ali Abdullah Almoyad
- Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Mushait, Saudi Arabia
| | | | - Ali H Amin
- Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - April Ann Malquisto
- Abuyog Community College, Abuyog Leyte, Philippines
- ESL Science Teacher, Tacloban City, Tacloban, Philippines
- Department of Art Sciences and Education, Tacloban City, Philippines
| | - Wong Tze Jin
- Department of Science and Technology, Faculty of Humanities, Management and Science, Universiti Putra Malaysia Bintulu Campus, Sarawak, Malaysia
- Institute for Mathematical Research, Universiti Putra Malaysia, Selangor, Malaysia
| | - Ioan Sârbu
- 2nd Department of Surgery-Pediatric Surgery and Orthopedics, "Grigore T. Popa" University of Medicine and Pharmacy, Romania
| | - Faisal AlShamsi
- Dubai Health Authority, Primary Health Care Department, Dubai, United Arab Emirates
| | - Fahmy Gad Elsaid
- Biology Department, College of Science, King Khalid University, Asir, Abha, Al-Faraa, Saudi Arabia
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Tuebingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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13
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Saadh MJ, Allela OQB, Sattay ZJ, Al Zuhairi RAH, Ahmad H, Eldesoky GE, Adil M, Ali MS. Deciphering the functional landscape and therapeutic implications of noncoding RNAs in the TGF-β signaling pathway in colorectal cancer: A comprehensive review. Pathol Res Pract 2024; 255:155158. [PMID: 38320438 DOI: 10.1016/j.prp.2024.155158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 02/08/2024]
Abstract
Colorectal cancer (CRC) remains a major global health concern, necessitating an in-depth exploration of the intricate molecular mechanisms underlying its progression and potential therapeutic interventions. Transforming Growth Factor-β (TGF-β) signaling, a pivotal pathway implicated in CRC plays a dual role as a tumor suppressor in the early stages and a promoter of tumor progression in later stages. Recent research has shed light on the critical involvement of noncoding RNAs (ncRNAs) in modulating the TGF-β signaling pathway, introducing a new layer of complexity to our understanding of CRC pathogenesis. This comprehensive review synthesizes the current state of knowledge regarding the function and therapeutic potential of various classes of ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), in the context of TGF-β signaling in CRC. The intricate interplay between these ncRNAs and key components of the TGF-β pathway is dissected, revealing regulatory networks that contribute to the dynamic balance between tumor suppression and promotion. Emphasis is placed on how dysregulation of specific ncRNAs can disrupt this delicate equilibrium, fostering CRC initiation, progression, and metastasis. Moreover, the review provides a critical appraisal of the emerging therapeutic strategies targeting ncRNAs associated with TGF-β signaling in CRC. The potential of these ncRNAs as diagnostic and prognostic biomarkers is discussed, highlighting their clinical relevance. Additionally, the challenges and prospects of developing RNA-based therapeutics, such as RNA interference and CRISPR/Cas-based approaches, are explored in the context of modulating TGF-β signaling for CRC treatment. In conclusion, this review offers a comprehensive overview of the intricate interplay between ncRNAs and the TGF-β signaling pathway in CRC. By unraveling the functional significance of these regulatory elements, we gain valuable insights into the molecular landscape of CRC, paving the way for the development of novel and targeted therapeutic interventions aimed at modulating the TGF-β signaling cascade through the manipulation of ncRNAs.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan
| | | | - Zahraa Jasim Sattay
- Department of Medical Laboratory Technology l, University of imam Jaafar Al-Sadiq, Iraq
| | | | - Hijaz Ahmad
- Section of Mathematics, International Telematic University Uninettuno, Corso Vittorio Emanuele II, 39, Rome 00186, Italy; Center for Applied Mathematics and Bioinformatics, Gulf University for Science and Technology, Kuwait; Department of Computer Science and Mathematics, Lebanese American University, Beirut, Lebanon
| | - Gaber E Eldesoky
- Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
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Yadav R, Bhawale R, Srivastava V, Pardhi E, Bhalerao HA, Sonti R, Mehra NK. Innovative Nanoparticulate Strategies in Colon Cancer Treatment: A Paradigm Shift. AAPS PharmSciTech 2024; 25:52. [PMID: 38429601 DOI: 10.1208/s12249-024-02759-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 02/06/2024] [Indexed: 03/03/2024] Open
Abstract
As a major public health issue, colorectal cancer causes 9.4% of total cancer-related deaths and comprises 10% of new cancer diagnoses worldwide. In the year 2023, an estimated 153,020 people are expected to receive an identification of colorectal cancer (CRC), resulting in roughly 52,550 fatalities anticipated as a result of this illness. Among those impacted, approximately 19,550 cases and 3750 deaths are projected to occur in individuals under the age of 50. Irinotecan (IRN) is a compound derived from the chemical structure of camptothecin, a compound known for its action in inhibiting DNA topoisomerase I. It is employed in the treatment strategy for CRC therapies. Comprehensive in vivo and in vitro studies have robustly substantiated the anticancer efficacy of these compounds against colon cancer cell lines. Blending irinotecan in conjunction with other therapeutic cancer agents such as oxaliplatin, imiquimod, and 5 fluorouracil enhanced cytotoxicity and improved chemotherapeutic efficacy. Nevertheless, it is linked to certain serious complications and side effects. Utilizing nano-formulated prodrugs within "all-in-one" carrier-free self-assemblies presents an effective method to modify the pharmacokinetics and safety portfolio of cytotoxic chemotherapeutics. This review focuses on elucidating the mechanism of action, exploring synergistic effects, and innovating novel delivery approaches to enhance the therapeutic efficacy of irinotecan.
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Affiliation(s)
- Rati Yadav
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, 500 037, India
| | - Rohit Bhawale
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, 500 037, India
| | - Vaibhavi Srivastava
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, 500 037, India
| | - Ekta Pardhi
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, 500 037, India
| | - Harshada Anil Bhalerao
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Rajesh Sonti
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Neelesh Kumar Mehra
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, 500 037, India.
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15
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Marotta C, Cirri D, Kanavos I, Ronga L, Lobinski R, Funaioli T, Giacomelli C, Barresi E, Trincavelli ML, Marzo T, Pratesi A. Oxaliplatin(IV) Prodrugs Functionalized with Gemcitabine and Capecitabine Induce Blockage of Colorectal Cancer Cell Growth-An Investigation of the Activation Mechanism and Their Nanoformulation. Pharmaceutics 2024; 16:278. [PMID: 38399332 PMCID: PMC10892879 DOI: 10.3390/pharmaceutics16020278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 02/10/2024] [Indexed: 02/25/2024] Open
Abstract
The use of platinum-based anticancer drugs, such as cisplatin, oxaliplatin, and carboplatin, is a common frontline option in cancer management, but they have debilitating side effects and can lead to drug resistance. Combination therapy with other chemotherapeutic agents, such as capecitabine and gemcitabine, has been explored. One approach to overcome these limitations is the modification of traditional Pt(II) drugs to obtain new molecules with an improved pharmacological profile, such as Pt(IV) prodrugs. The design, synthesis, and characterization of two novel Pt(IV) prodrugs based on oxaliplatin bearing the anticancer drugs gemcitabine or capecitabine in the axial positions have been reported. These complexes were able to dissociate into their constituents to promote cell death and induce apoptosis and cell cycle blockade in a representative colorectal cancer cell model. Specifically, the complex bearing gemcitabine resulted in being the most active on the HCT116 colorectal cancer cell line with an IC50 value of 0.49 ± 0.04. A pilot study on the encapsulation of these complexes in biocompatible PLGA-PEG nanoparticles is also included to confirm the retention of the pharmacological properties and cellular drug uptake, opening up to the possible delivery of the studied complexes through their nanoformulation.
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Affiliation(s)
- Carlo Marotta
- Department of Chemistry and Industrial Chemistry, University of Pisa, 56124 Pisa, Italy; (C.M.); (T.F.)
| | - Damiano Cirri
- Department of Chemistry and Industrial Chemistry, University of Pisa, 56124 Pisa, Italy; (C.M.); (T.F.)
| | - Ioannis Kanavos
- Institute of Analytical and Physical Chemistry for the Environment and Materials (IPREM-UMR 5254), Pau University, E2S UPPA, CNRS, 64053 Pau, France; (I.K.); (L.R.); (R.L.)
| | - Luisa Ronga
- Institute of Analytical and Physical Chemistry for the Environment and Materials (IPREM-UMR 5254), Pau University, E2S UPPA, CNRS, 64053 Pau, France; (I.K.); (L.R.); (R.L.)
| | - Ryszard Lobinski
- Institute of Analytical and Physical Chemistry for the Environment and Materials (IPREM-UMR 5254), Pau University, E2S UPPA, CNRS, 64053 Pau, France; (I.K.); (L.R.); (R.L.)
| | - Tiziana Funaioli
- Department of Chemistry and Industrial Chemistry, University of Pisa, 56124 Pisa, Italy; (C.M.); (T.F.)
| | - Chiara Giacomelli
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (C.G.); (E.B.); (M.L.T.); (T.M.)
| | - Elisabetta Barresi
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (C.G.); (E.B.); (M.L.T.); (T.M.)
| | | | - Tiziano Marzo
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (C.G.); (E.B.); (M.L.T.); (T.M.)
| | - Alessandro Pratesi
- Department of Chemistry and Industrial Chemistry, University of Pisa, 56124 Pisa, Italy; (C.M.); (T.F.)
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16
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Alalikhan A, Ebrahimi S, Aliee A, Mirzavi F, Hashemy SI. The combined anti-tumor effects of 5-fluorouracil and neurokinin receptor inhibitor, aprepitant, against colorectal cancer: In vitro and in vivo study. Med Oncol 2024; 41:70. [PMID: 38340190 DOI: 10.1007/s12032-024-02312-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 01/23/2024] [Indexed: 02/12/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the world's largest health concerns with growing global incidence and mortality. The potential value of the neurokinin-1 receptor as a therapeutic target has been reported in several tumor types, including CRC. Here we examined the potential anti-tumor effects of a clinically approved neurokinin-1 receptor antagonist, aprepitant, alone and its combination with 5-Fluorouracil (5-FU) as a first choice CRC chemotherapeutic drug, in both in vitro and in vivo models of CRC. METHODS MTT assay was employed for assessing cell proliferation. mRNA expression levels were determined by quantitative real-time PCR (qRT-PCR). Flow cytometric analysis of apoptosis was performed using an Annexin-V/propidium iodide assay kit. We finally conducted an in vivo experiment in a mouse model of CRC to confirm the in vitro antiproliferative activity of aprepitant and 5-FU. RESULTS We found that aprepitant and 5-FU significantly reduced CRC cell viability. The combination of drugs exhibited potent synergistic growth inhibitory effects on CRC cells. Moreover, aprepitant and 5-FU induced apoptosis and altered the levels of apoptotic genes (up-regulation of Bax, and p53 along with downregulation of Bcl-2). Importantly, the aprepitant and 5-FU combination showed a more pronounced impact on apoptosis and associated genes than either of the agents alone. Furthermore, aprepitant reduced tumor growth in vivo and led to significantly longer survival time, and this effect was more prominent when using the aprepitant and 5-FU combination. CONCLUSIONS Collectively, combinatory treatment with aprepitant and 5-FU potentially exerts synergistic growth inhibition and apoptosis induction in CRC, deserving further consideration as a novel strategy for CRC patients.
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Affiliation(s)
- Abbas Alalikhan
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Safieh Ebrahimi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Aliee
- Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Farshad Mirzavi
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Szemitko M, Falkowski A, Modrzejewska M, Golubinska-Szemitko E. Efficacy and Safety of Liver Chemoembolization Procedures, Combined with FOLFIRI Chemotherapy, in First-Line Treatment of Metastatic Colorectal Cancer in Patients with Oncogene Mutations. Cancers (Basel) 2023; 16:71. [PMID: 38201500 PMCID: PMC10778126 DOI: 10.3390/cancers16010071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/08/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
PURPOSE The usual first- and second-line treatments for inoperable liver metastases from colorectal cancer (CRC) involve systemic chemotherapy, often with molecular targeted therapy. Chemoembolization, using microspheres loaded with irinotecan, has also been available as a treatment option for many years, used mainly in later lines of treatment when, due to increasing resistance, other chemotherapy regimens may have been exhausted. However, when there are contraindications to molecular therapies, the use of chemoembolization as first or second lines of treatment, in combination with FOLFIRI chemotherapy, may provide greater efficacy due to reduced irinotecan resistance. OBJECTIVE The aim of the study was to evaluate the efficacy and safety of transarterial chemoembolization (DEB-TACE) procedures for the treatment of metastatic liver lesions from CRC, using irinotecan-loaded microspheres as first-line treatment together with FOLFIRI chemotherapy. PATIENTS AND METHODS The analysis included 20 patients (12 females; 8 males) with unresectable liver metastases in the course of CRC with KRAS, NRAS and BRAF mutations, who underwent 73 chemoembolization procedures with microspheres loaded with 100 mg of irinotecan, in combination with interspersed FOLFIRI chemotherapy. Response to treatment was assessed through computed tomography according to the Modified Response Evaluation Criteria in Solid Tumors (mRECIST). Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Assessment of adverse events utilized the Cancer Therapy Evaluation Program's Common Terminology Criteria for Adverse Events (CTCAE; version 5.0). RESULTS Partial remission (PR) was observed in 11 (55%) patients while 5 (25%) patients showed stable disease (SD). Progression (PD) was observed in 4 (20%) patients. Median PFS was 9.1 months (95% CI: 7.2-10.1 months) and median OS was 20.7 months (95% CI: 18.2-23.3 months). The most common adverse events (AEs) resulting in treatment delay were hematological disorders, notably neutropenia (CTCAE grades 1-3). No deaths or AEs above grade 3 occurred during TACE. Continued FOLFIRI chemotherapy after TACE treatments resulted in grade 4 neutropenia in two patients, grade 3 in four patients and grade 2 thrombocytopenia in two patients. CONCLUSION Combining FOLFIRI chemotherapy with chemoembolization procedures for liver metastatic lesions from colorectal cancer may provide a valuable treatment option for patients not qualified for monoclonal antibody therapy.
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Affiliation(s)
- Marcin Szemitko
- Department of Interventional Radiology, Pomeranian Medical University, Al. Pow. Wielkopolskich 72, 70-111 Szczecin, Poland;
| | - Aleksander Falkowski
- Department of Interventional Radiology, Pomeranian Medical University, Al. Pow. Wielkopolskich 72, 70-111 Szczecin, Poland;
| | - Monika Modrzejewska
- II Department of Ophthalmology, Pomeranian Medical University, Al. Pow. Wielkopolskich 72, 70-111 Szczecin, Poland;
| | - Elzbieta Golubinska-Szemitko
- Department of General and Dental Diagnostic Imaging, Pomeranian Medical University, Al. Pow. Wielkopolskich 72, 70-111 Szczecin, Poland;
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18
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Deshmukh R, Prajapati M, Harwansh RK. A review on emerging targeted therapies for the management of metastatic colorectal cancers. Med Oncol 2023; 40:159. [PMID: 37097307 DOI: 10.1007/s12032-023-02020-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 04/08/2023] [Indexed: 04/26/2023]
Abstract
Colorectal cancers are among the most commonly found cancers over the world. In spite of the recent advancements in diagnosis and prognosis, the management of this metastatic condition remains a challenge. The utility of monoclonal antibodies in the healing of patients with colorectal cancer has opened a new chapter in the quest for newer therapies. The resistance to the standard treatment regimen made it mandatory to search for newer targets. Mutagenic alterations in the gene engaged in cellular differentiation and growth pathway have been the reason for resistance to treatment. The newer therapies target the various proteins and receptors involved in the signal transduction and down streaming pathways leading to cell proliferation. This review presents an insight into the newer targeted therapies for colorectal cancer involving tyrosine kinase blockers, epidermal growth factor receptors, vascular endothelial growth factor, immune checkpoint therapy, and BRAF inhibitors.
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Affiliation(s)
- Rohitas Deshmukh
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India.
| | - Mahendra Prajapati
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
| | - Ranjit K Harwansh
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
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19
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Karami Fath M, Moayedi Banan Z, Barati R, Mohammadrezakhani O, Ghaderi A, Hatami A, Ghiabi S, Zeidi N, Asgari K, Payandeh Z, Barati G. Recent advancements to engineer mesenchymal stem cells and their extracellular vesicles for targeting and destroying tumors. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 178:1-16. [PMID: 36781149 DOI: 10.1016/j.pbiomolbio.2023.02.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/24/2023] [Accepted: 02/10/2023] [Indexed: 02/13/2023]
Abstract
Mesenchymal stem cells (MSCs) have the ability to migrate into tumor sites and release growth factors to modulate the tumor microenvironment. MSC therapy have shown a dual role in cancers, promoting or inhibiting. However, MSCs could be used as a carrier of anticancer agents for targeted tumor therapy. Recent technical improvements also allow engineering MSCs to improve tumor-targeting properties, protect anticancer agents, and decrease the cytotoxicity of drugs. While some of MSC functions are mediated through their secretome, MSCs-derived extracellular vesicles (EVs) are also proposed as a possible viechle for cancer therapy. EVs allow efficient loading of anticancer agents and have an intrinsic ability to target tumor cells, making them suitable for targeted therapy of tumors. In addition, the specificity and selectivity of EVs to the tumor sites could be enhanced by surface modification. In this review, we addressed the current approaches used for engineering MSCs and EVs to effectively target tumor sites and deliver anticancer agents.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Zahra Moayedi Banan
- School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Barati
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Omid Mohammadrezakhani
- Faculty of Pharmacy, Ramsar Campus, Mazandaran University of Medical Sciences, Sari, Iran
| | - Aliasghar Ghaderi
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Hatami
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shamim Ghiabi
- Department of Medical Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nazanin Zeidi
- Division of Pharmaceutical Science, Long Island University, Brooklyn, NY, USA
| | - Katayoon Asgari
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
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20
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Haque E, Muhsen IN, Esmail A, Umoru G, Mylavarapu C, Ajewole VB, Abdelrahim M. Case report: Efficacy and safety of regorafenib plus fluorouracil combination therapy in the treatment of refractory metastatic colorectal cancer. Front Oncol 2022; 12:992455. [PMID: 36620581 PMCID: PMC9822717 DOI: 10.3389/fonc.2022.992455] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 11/18/2022] [Indexed: 12/23/2022] Open
Abstract
Background More than half of patients with colorectal cancer (CRC) present with metastatic disease or develop recurrent disease on first-line and second-line options. Treatment beyond the second line remains an area of unmet need for patients with progressive or recurrent disease. Methods We retrospectively reviewed data of adult (>18 years old) patients with mCRC who received regorafenib + 5FU combination therapy at Houston Methodist Hospital with outcomes of interest including response rate, discontinuation due to side effects, and overall survival. Results Seven patients received regorafenib + 5FU combination therapy for mCRC after receiving at least two other lines of therapy (including at least one fluorouracil-based therapy). Four patients (57%) achieved disease control in 7-12 weeks after therapy initiation while three patients developed recurrent disease. In patients who achieved disease control, no new adverse events were reported among patients with this combination. Conclusion Regorafenib and Fluorouracil combination could be considered an option beyond the second line for patients with treatment-refractory metastatic colorectal cancer. Further studies, including a prospective trial, are needed to investigate the efficacy and safety of regorafenib plus 5FU therapy compared to other limited available therapies.
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Affiliation(s)
- Emaan Haque
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Ibrahim N. Muhsen
- Department of Medicine, Houston Methodist Hospital, Houston, TX, United States
| | - Abdullah Esmail
- Section of Gastrointestinal Oncology, Houston Methodist Neal Cancer Center, Houston, TX, United States,*Correspondence: Maen Abdelrahim, ; Abdullah Esmail,
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, United States,College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, United States
| | - Charisma Mylavarapu
- Department of Medicine, Houston Methodist Hospital, Houston, TX, United States
| | - Veronica B. Ajewole
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, United States,College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, United States
| | - Maen Abdelrahim
- Section of Gastrointestinal Oncology, Houston Methodist Neal Cancer Center, Houston, TX, United States,Cockrell Center for Advanced Therapeutic Phase I program, Houston Methodist Research Institute, Houston, TX, United States,Department of Medicine, Weill Cornell Medical College, New York, NY, United States,*Correspondence: Maen Abdelrahim, ; Abdullah Esmail,
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21
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Knavel Koepsel EM, Smolock AR, Pinchot JW, Kim CY, Ahmed O, Chamarthy MRK, Hecht EM, Hwang GL, Kaplan DE, Luh JY, Marrero JA, Monroe EJ, Poultsides GA, Scheidt MJ, Hohenwalter EJ. ACR Appropriateness Criteria® Management of Liver Cancer: 2022 Update. J Am Coll Radiol 2022; 19:S390-S408. [PMID: 36436965 DOI: 10.1016/j.jacr.2022.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 11/27/2022]
Abstract
The treatment and management of hepatic malignancies can be complex because it encompasses a variety of primary and metastatic malignancies and an assortment of local and systemic treatment options. When to use each of these treatments is critical to ensure the most appropriate care for patients. Interventional radiologists have a key role to play in the delivery of a variety of liver directed treatments including percutaneous ablation, transarterial embolization with bland embolic particles alone, transarterial chemoembolization (TACE) with injection of a chemotherapeutic emulsion, and transarterial radioembolization (TARE). Based on 9 clinical variants, the appropriateness of each treatment is described in this document. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.
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Affiliation(s)
| | - Amanda R Smolock
- Froedtert & The Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Charles Y Kim
- Panel Vice-Chair, Duke University Medical Center, Durham, North Carolina
| | - Osmanuddin Ahmed
- Vice-Chair of Wellness, Director of Venous Interventions, University of Chicago, Chicago, Illinois
| | - Murthy R K Chamarthy
- Vascular Institute of North Texas, Dallas, Texas; Commission on Nuclear Medicine and Molecular Imaging
| | - Elizabeth M Hecht
- Vice-Chair of Academic Affairs, Professor of Radiology, Weill Cornell Medicine, New York, New York; RADS Committee; Member of Appropriateness Subcommittees on Hepatobiliary Topics; Member of LI-RADS
| | - Gloria L Hwang
- Associate Chair of Clinical Performance Improvement, Stanford Radiology, Stanford Medical Center, Stanford, California
| | - David E Kaplan
- Section Chief of Hepatology at the University of Pennsylvania Division of Gastroenterology and Hepatology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania; American Association for the Study of Liver Diseases
| | - Join Y Luh
- Providence Health Radiation Oncology Focus Group Chair, Providence St. Joseph Health, Eureka, California; Commission on Radiation Oncology; ACR CARROS President; ACR Council Steering Committee; California Radiological Society Councilor to ACR
| | - Jorge A Marrero
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; American Gastroenterological Association
| | | | - George A Poultsides
- Chief of Surgical Oncology and Professor of Surgery, Stanford University School of Medicine, Stanford, California; Society of Surgical Oncology
| | - Matthew J Scheidt
- Program Director of Independent IR Residency, Froedtert & The Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Eric J Hohenwalter
- Specialty Chair; Chief, MCW VIR, Froedtert & The Medical College of Wisconsin, Milwaukee, Wisconsin
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22
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Chen CI, Chuang FC, Li HJ, Chen YC, Chen HP, Liu KW, Su YC, Chen JH, Lee HM. The impact of a multispecialty operative team on colorectal cancer surgery: A retrospective study from a would-be medical center in Taiwan. Medicine (Baltimore) 2022; 101:e29863. [PMID: 35945804 PMCID: PMC9351883 DOI: 10.1097/md.0000000000029863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Some studies showed that when distant metastasis or locally advanced tumors were observed, the participation of 2 or more operating surgeons (combined surgery) in the operation could improve the prognosis of patients. The multispecialty operative team would perform combined surgery in colon cancer patients with some complications since 2015. The goal of this study is to confirm performing combined surgery would improve the outcomes of colon cancer patients. A retrospective observational study was conducted, which involved all colon cancer patients between November 2015 and December 2019 at one would-be medical center. Patients were divided into 3 cohorts: those with complicated cases and had combined surgery (C_2S), those with complicated cases and had surgery performed by a single surgeon (C_1S), and those with uncomplicated cases and had surgery performed by a single surgeon (NC_1S). Overall survival and disease-free survival were compared among the 3 groups. A total of 296 colon cancer patients during the study period. Among them, 35 were C_2S, 87 were C_1S, and 174 were NC_1S. Patients in the NC_1S group had significantly higher 12-, 24-, and 36-month OS rates compared to those in the C_1S group (P < .01). In contrast, there was no significant difference in overall survival among patients in the NC_1S and C_2S group (P =.15). The quality of surgery must be impact the prognosis, especially in the individual who was complicated case, the survival in patients who had surgery performed by multispecialty operative team would be improved.
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Affiliation(s)
- Chih-I Chen
- Division of Colon and Rectal Surgery, Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan
- Division of General Medicine Surgery, Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Department of Information Engineering, I-Shou University, Kaohsiung, Taiwan
- School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung, Taiwan
| | - Fu-Cheng Chuang
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Department of Radiation Oncology, E-Da Hospital, Kaohsiung, Taiwan
| | - Hung-Ju Li
- Division of Hematology-Oncology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Yu-Chi Chen
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Department of Urology, E-Da Cancer Hospital, Kaohsiung, Taiwan
| | - Hsin-Pao Chen
- Division of Colon and Rectal Surgery, Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Kuang-Wen Liu
- Division of Colon and Rectal Surgery, Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Yu-Chieh Su
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Division of Hematology-Oncology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Jian-Han Chen
- School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung, Taiwan
- Bariatric and Metabolic International Surgery Center, E-Da Hospital, Kaohsiung, Taiwan
- Division of General Surgery, Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan
| | - Hui-Ming Lee
- Division of General Surgery, Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan
- *Correspondence: Hui-Ming Lee, MD, E-Da Hospital, Kaohsiung, Taiwan (e-mail: )
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23
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Karami Fath M, Anjomrooz M, Taha SR, Shariat Zadeh M, Sahraei M, Atbaei R, Fazlollahpour Naghibi A, Payandeh Z, Rahmani Z, Barati G. The therapeutic effect of exosomes from mesenchymal stem cells on colorectal cancer: Toward cell-free therapy. Pathol Res Pract 2022; 237:154024. [PMID: 35905664 DOI: 10.1016/j.prp.2022.154024] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 06/30/2022] [Accepted: 07/12/2022] [Indexed: 12/01/2022]
Abstract
Colorectal cancer (CRC) is known for its high mortality rate and affects more men than women. The treatment requires invasive surgical interventions, however, the progression of CRC metastasis is difficult to control in most cases. Mesenchymal stem cells (MSCs) with their outstanding characteristics have been widely used in the treatment of degenerative diseases as well as cancers. They affect the tumor microenvironment through either cell-cell interactions or communications with their secretome. While stem cells may represent a dual role in tumor proliferation and progression, exosomes have attracted much attention as a cell-free therapy in CRC treatment. Exosomes derived from native or genetically modified MSCs, as well as exosomal microRNAs (miRNAs), have been evaluated on CRC progression. Moreover, MSC-derived exosomes have been used as a carrier to deliver anticancer agents in colorectal cancer. In this review, we overview and discuss the current knowledge in both stem cell-based and cell-free exosome therapy of CRC.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mehran Anjomrooz
- Department of Radiology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Reza Taha
- Faculty of Medicine, Islamic Azad University, Tehran Branch, Tehran, Iran
| | | | - Mahya Sahraei
- Department of Chemistry, Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Raihaneh Atbaei
- Faculty of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
| | | | - Zahra Payandeh
- Department of Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Sweden
| | - Zobeir Rahmani
- Faculty of Paramedical, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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A RAS-Independent Biomarker Panel to Reliably Predict Response to MEK Inhibition in Colorectal Cancer. Cancers (Basel) 2022; 14:cancers14133252. [PMID: 35805024 PMCID: PMC9265111 DOI: 10.3390/cancers14133252] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 06/27/2022] [Accepted: 06/29/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Today, clinical management for the majority of cancer patients is still based on a “one-size-fits-all” approach. To improve the outcomes in the era of personalized medicine, it is essential to stratify patients based on established and novel biomarkers. In the present study, we investigated a SMAD4 loss-of-function mutation, which is associated with chemoresistance and decreased overall survival in colorectal cancer (CRC). To investigate the molecular mechanism behind the impact on drug response, we used CRISPR technology on patient-derived organoid models (PDOs) of CRC. We showed that PDOs with loss-of-function SMAD4 mutations are sensitive to MEK-inhibitors. Using a novel four-gene signature reliably predicts sensitivity towards MEK-inhibitors, regardless of the RAS and BRAF status. The present study is a significant step towards personalized cancer therapy by identifying a new biomarker. Abstract Background: In colorectal cancer (CRC), mutations of genes associated with the TGF-β/BMP signaling pathway, particularly affecting SMAD4, are known to correlate with decreased overall survival and it is assumed that this signaling axis plays a key role in chemoresistance. Methods: Using CRISPR technology on syngeneic patient-derived organoids (PDOs), we investigated the role of a loss-of-function of SMAD4 in sensitivity to MEK-inhibitors. CRISPR-engineered SMAD4R361H PDOs were subjected to drug screening, RNA-Sequencing, and multiplex protein profiling (DigiWest®). Initial observations were validated on an additional set of 62 PDOs with known mutational status. Results: We show that loss-of-function of SMAD4 renders PDOs sensitive to MEK-inhibitors. Multiomics analyses indicate that disruption of the BMP branch within the TGF-β/BMP pathway is the pivotal mechanism of increased drug sensitivity. Further investigation led to the identification of the SFAB-signature (SMAD4, FBXW7, ARID1A, or BMPR2), coherently predicting sensitivity towards MEK-inhibitors, independent of both RAS and BRAF status. Conclusion: We identified a novel mutational signature that reliably predicts sensitivity towards MEK-inhibitors, regardless of the RAS and BRAF status. This finding poses a significant step towards better-tailored cancer therapies guided by the use of molecular biomarkers.
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Hsu HY, Chern YJ, Hsieh CT, Yeh TL, Tsai MC, Wang CC, Hsiao BY, Jhuang JR, Chiang CJ, Lee WC, Chien KL. Increased standardised incidence ratio of cardiovascular diseases among colorectal cancer patients. Int J Colorectal Dis 2022; 37:887-894. [PMID: 35301555 PMCID: PMC8976771 DOI: 10.1007/s00384-022-04129-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/07/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE Evidence regarding the relationship between colorectal cancer and the risk of cardiovascular disease (CVD) is limited. Thus, in this study, we aimed to determine the standardised incidence ratio (SIR) of CVDs in colorectal cancer patients in Taiwan. METHODS A population-based cohort study enrolling the incident colorectal cancer population based on the Cancer Registry Database from 2007 to 2016 was conducted (n = 94,233, mean age: 62.4 years, 43.0% women). New cases of CVD, including coronary heart disease and ischemic stroke, through 31 December 2018 were obtained from the National Health Insurance Research Database and National Death Registry. Compared with the general population (n = 1,977,659, mean age: 44.3 years, 49.6% women), age- and sex-specific SIRs for CVDs were calculated by the time since diagnosis. RESULTS A total of 6852 cardiovascular events occurred in colorectal cancer patients during a median follow-up of 4.4 years. The SIR of CVD was highest in the first year after diagnosis (SIR: 1.45, 95% confidence interval: 1.39-1.50); however, this decreased to the same value as that of the general population in later years. Similar patterns were observed for the SIR of coronary heart disease. However, the SIR of ischemic stroke among colorectal cancer patients was low from the second year following cancer diagnosis. CONCLUSIONS Colorectal cancer patients are at an increased risk of developing CVD, especially coronary heart disease, during the first 3 years following colorectal cancer diagnosis.
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Affiliation(s)
- Hsin-Yin Hsu
- Department of Family Medicine, Taipei MacKay Memorial Hospital, Taipei, Taiwan
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
| | - Yih-Jong Chern
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, TaoYuan, Taiwan
| | - Cheng-Tzu Hsieh
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Tzu-Lin Yeh
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
- Department of Family Medicine, Hsinchu MacKay Memorial Hospital, Hsinchu, Taiwan
| | - Ming-Chieh Tsai
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- Division of Endocrinology, Department of Internal Medicine, Tamsui Branch, MacKay Memorial Hospital, New Taipei City, Taiwan
| | - Chia-Chun Wang
- Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Bo-Yu Hsiao
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Jing-Rong Jhuang
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chun-Ju Chiang
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
- Taiwan Cancer Registry, Taipei, Taiwan
| | - Wen-Chung Lee
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
- Taiwan Cancer Registry, Taipei, Taiwan
- Innovation and Policy Center for Population Health and Sustainable Environment, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Kuo-Liong Chien
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
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Alrumaihi F, Khan MA, Babiker AY, Alsaweed M, Azam F, Allemailem KS, Almatroudi AA, Ahamad SR, Alsugoor MH, Alharbi KN, Almansour NM, Khan A. Lipid-Based Nanoparticle Formulation of Diallyl Trisulfide Chemosensitizes the Growth Inhibitory Activity of Doxorubicin in Colorectal Cancer Model: A Novel In Vitro, In Vivo and In Silico Analysis. Molecules 2022; 27:2192. [PMID: 35408590 PMCID: PMC9000458 DOI: 10.3390/molecules27072192] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/19/2022] [Accepted: 03/25/2022] [Indexed: 02/07/2023] Open
Abstract
Garlic's main bioactive organosulfur component, diallyl trisulfide (DATS), has been widely investigated in cancer models. However, DATS is not suitable for clinical use due to its low solubility. The current study seeks to improve DATS bioavailability and assess its chemopreventive and chemosensitizing properties in an AOM-induced colorectal cancer model. The polyethylene glycol coated Distearoylphosphatidylcholine/Cholesterol (DSPC/Chol) comprising DATS-loaded DATSL and doxorubicin (DOXO)-encapsulated DOXL liposomes was prepared and characterized. The changes in the sensitivity of DATS and DOXO by DATSL and DOXL were evaluated in RKO and HT-29 colon cancer cells. The synergistic effect of DATSL and DOXL was studied by cell proliferation assay in the combinations of IC10, IC25, and IC35 of DATSL with the IC10 of DOXL. AOM, DATSL, and DOXL were administered to different groups of mice for a period of 21 weeks. The data exhibited ~93% and ~46% entrapment efficiency of DATSL and DOXL, respectively. The size of sham liposomes was 110.5 nm, whereas DATSL and DOXL were 135.5 nm and 169 nm, respectively. DATSL and DOXL exhibited significant sensitivity in the cell proliferation experiment, lowering their IC50 doses by more than 8- and 14-fold, respectively. However, the DATSL IC10, IC25, and IC35 showed escalating chemosensitivity, and treated the cells in combination with DOXL IC10. Analysis of histopathological, cancer marker enzymes, and antioxidant enzymes revealed that the high dose of DATSL pretreatment and DOXL chemotherapy is highly effective in inhibiting AOM-induced colon cancer promotion. The combination of DATSL and DOXL indicated promise as a colorectal cancer treatment in this study. Intermolecular interactions of DATS and DOXO against numerous cancer targets by molecular docking indicated MMP-9 as the most favourable target for DATS exhibiting binding energy of -4.6 kcal/mol. So far, this is the first research to demonstrate the chemopreventive as well as chemosensitizing potential of DATSL in an animal model of colorectal cancer.
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Affiliation(s)
- Faris Alrumaihi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (F.A.); (A.Y.B.); (K.S.A.); (A.A.A.); (K.N.A.)
| | - Masood Alam Khan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia;
| | - Ali Yousif Babiker
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (F.A.); (A.Y.B.); (K.S.A.); (A.A.A.); (K.N.A.)
| | - Mohammed Alsaweed
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia;
| | - Faizul Azam
- Department of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Unaizah 51911, Saudi Arabia;
| | - Khaled S. Allemailem
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (F.A.); (A.Y.B.); (K.S.A.); (A.A.A.); (K.N.A.)
| | - Ahmad A. Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (F.A.); (A.Y.B.); (K.S.A.); (A.A.A.); (K.N.A.)
| | - Syed Rizwan Ahamad
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Mahdi H. Alsugoor
- Department of Emergency Medical Services, Faculty of Health Sciences, AlQunfudah, Umm Al-Qura University, Makkah 21912, Saudi Arabia;
| | - Khloud Nawaf Alharbi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (F.A.); (A.Y.B.); (K.S.A.); (A.A.A.); (K.N.A.)
| | - Nahlah Makki Almansour
- Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin 31991, Saudi Arabia;
| | - Arif Khan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia;
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Ebrahimpour M, Mohammadian M, Pourheydar B, Moradi Z, Behrouzkia Z. Effects of Radiotherapy in Combination With Irinotecan and 17-AAG on Bcl-2 and Caspase 3 Gene Expression in Colorectal Cancer Cells. J Lasers Med Sci 2022; 13:e9. [DOI: 10.34172/jlms.2022.09] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 11/14/2021] [Indexed: 12/24/2022]
Abstract
Introduction: In this study, the cytotoxic and anti-cancer effects of Irinotecan as a conventional chemotherapeutic agent compared to 17-(allyl amino)-17-demethoxygeldanamycin (17-AAG) as possible radiosensitizers in the HCT-116 cell line were investigated. Methods: HCT-116 cells were treated with various concentrations of irinotecan and 17-AAG and also irradiated with a 2-Gy of X-ray radiation. Then, the cell viability was examined by a water-soluble tetrazolium-1 assay after 24 hours. For single therapies and double and triple combination cases, IC50, 0.5×IC50 and 0.25×IC50 concentrations of each drug were selected respectively for a terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay and other tests. In treated and untreated cells, the caspase 3 and Bcl-2 gene expression ratios were evaluated by the real-time PCR method. Likewise, caspase 3 activity was detected with a colorimetric assay. Results: In all combined treatments, including 17-AAG- radiation, irinotecan - radiation, irinotecan -17-AAG, and irinotecan-17-AAG-radiation, decreased cellular viability and increased TUNEL positive cells were presented versus the control group (P<0.05). There were increased TUNEL positive cells in the triple combination, in concentrations of 0.25×IC50 of each drug, in comparison with single and double agent treatments. Moreover, in triple combination, the caspase 3 mRNA level and caspase 3 activity increased versus related single treatments. Likewise, in the irinotecan-17-AAG-radiation combined treatment and the 17-AAG-radiation double treatment, the Bcl-2 gene expression level decreased in comparison with single therapies. Conclusion: It can be indicated that the combination of chemo-radiotherapy versus single treatments has significant anti-cancer effects.
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Affiliation(s)
- Mahnaz Ebrahimpour
- Medical Physics Department, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mahshid Mohammadian
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Bagher Pourheydar
- Neurophysiology Research Center, Department of Anatomical Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Zhino Moradi
- Medical Physics Department, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Zhaleh Behrouzkia
- Medical Physics Department, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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Zhao Y, Roy S, Wang C, Goel A. A Combined Treatment with Berberine and Andrographis Exhibits Enhanced Anti-Cancer Activity through Suppression of DNA Replication in Colorectal Cancer. Pharmaceuticals (Basel) 2022; 15:262. [PMID: 35337060 PMCID: PMC8953248 DOI: 10.3390/ph15030262] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/18/2022] [Accepted: 02/19/2022] [Indexed: 12/13/2022] Open
Abstract
The high morbidity and mortality associated with colorectal cancer (CRC) are largely due to the invariable development of chemoresistance to classic chemotherapies, as well as intolerance to their significant toxicity. Many pharmaceutical formulations screened from natural plant extracts offer safe, inexpensive, and multi-target therapeutic options. In this study, we demonstrated that Berberis vulgaris L. (Berberine) and Andrographis paniculata (Burm. f.) Nees (Andrographis) extracts exerted their synergistic amplified anti-cancer effects by jointly inhibiting cell viability, suppressing colony formation, and inducing cell cycle arrest. Consistent with our in-vitro findings, the amplified synergistic anti-cancer effects were also observed in subcutaneous xenograft preclinical animal models, as well as patient-derived primary tumor organoids. To explore the molecular mechanisms underlying the amplified synergistic anti-cancer effects, RNA sequencing was performed to identify candidate pathways and genes. A transcriptome analysis revealed that DNA-replication-related genes, including FEN1, MCM7, PRIM1, MCM5, POLA1, MCM4, and PCNA, may be responsible for the enhanced anticancer effects of these two natural extracts. Taken together, our data revealed the powerful enhanced synergistic anti-CRC effects of berberine and Andrographis and provide evidence for the combinational targeting of DNA-replication-related genes as a promising new strategy for the therapeutic option in the management of CRC patients.
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Affiliation(s)
- Yinghui Zhao
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA 91010, USA; (Y.Z.); (S.R.)
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China;
| | - Souvick Roy
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA 91010, USA; (Y.Z.); (S.R.)
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China;
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, China
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA 91010, USA; (Y.Z.); (S.R.)
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
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The Effect of Liposomal Diallyl Disulfide and Oxaliplatin on Proliferation of Colorectal Cancer Cells: In Vitro and In Silico Analysis. Pharmaceutics 2022; 14:pharmaceutics14020236. [PMID: 35213970 PMCID: PMC8877238 DOI: 10.3390/pharmaceutics14020236] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/24/2021] [Accepted: 01/13/2022] [Indexed: 01/27/2023] Open
Abstract
Diallyl disulfide (DADS) is one of the main bioactive organosulfur compounds of garlic, and its potential against various cancer models has been demonstrated. The poor solubility of DADS in aqueous solutions limits its uses in clinical application. The present study aimed to develop a novel formulation of DADS to increase its bioavailability and therapeutic potential and evaluate its role in combination with oxaliplatin (OXA) in the colorectal cancer system. We prepared and characterized PEGylated, DADS (DCPDD), and OXA (DCPDO) liposomes. The anticancer potential of these formulations was then evaluated in HCT116 and RKO colon cancer cells by different cellular assays. Further, a molecular docking-based computational analysis was conducted to determine the probable binding interactions of DADS and OXA. The results revealed the size of the DCPDD and DCPDO to be 114.46 nm (95% EE) and 149.45 nm (54% EE), respectively. They increased the sensitivity of the cells and reduced the IC50 several folds, while the combinations of them showed a synergistic effect and induced apoptosis by 55% in the cells. The molecular docking data projected several possible targets of DADS and OXA that could be evaluated more precisely by these novel formulations in detail. This study will direct the usage of DCPDD to augment the therapeutic potential of DCPDO against colon cancer in clinical settings.
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Liu Z, Li Y, Zhu Y, Li N, Li W, Shang C, Song G, Li S, Cong J, Li T, Xiu Z, Lu J, Ge C, Yang X, Li Y, Sun L, Li X, Jin N. Apoptin induces pyroptosis of colorectal cancer cells via the GSDME-dependent pathway. Int J Biol Sci 2022; 18:717-730. [PMID: 35002520 PMCID: PMC8741846 DOI: 10.7150/ijbs.64350] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 10/25/2021] [Indexed: 12/24/2022] Open
Abstract
Apoptin is a small molecular weight protein encoded by the VP3 gene of chicken anemia virus (CAV). It can induce apoptosis of tumor cells and play anti-tumorigenic functions. In this study, we identified a time-dependent inhibitory role of apoptin on the viability of HCT116 cells. We also demonstrated that apoptin induces pyroptosis through cleaved caspase 3, and with a concomitant cleavage of gasdermin E (GSDME) rather than GSDMD. GSDME knockdown switched the apoptin-induced cell death from pyroptosis to apoptosis in vitro. Furthermore, we demonstrated that the effect of apoptin on GSDME-dependent pyroptosis could be mitigated by caspase-3 and caspase-9 siRNA knockdown. Additionally, apoptin enhanced the intracellular reactive oxygen species (ROS), causing aggregation of the mitochondrial membrane protein Tom20. Moreover, bax and cytochrome c were released to the activating caspase-9, eventually triggering pyroptosis. Therefore, GSDME mediates the apoptin-induced pyroptosis through the mitochondrial apoptotic pathway. Finally, using nude mice xenografted with HCT116 cells, we found that apoptin induces pyroptosis and significantly inhibits tumor growth. Based on this mechanism, apoptin may provide a new strategy for colorectal cancer therapy.
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Affiliation(s)
- Zirui Liu
- College of Veterinary Medicine, Jilin University, Changchun, 130062, China.,Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Yiquan Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Yilong Zhu
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Nan Li
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Wenjie Li
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Chao Shang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Gaojie Song
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Shanzhi Li
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Jianan Cong
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Tingyu Li
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Zhiru Xiu
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Jing Lu
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Chenchen Ge
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Xia Yang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Yaru Li
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China
| | - Lili Sun
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China.,Department of Head and Neck Surgery, Tumor Hospital of Jilin Province, Changchun, 130012, China
| | - Xiao Li
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China.,Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130021, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China
| | - Ningyi Jin
- College of Veterinary Medicine, Jilin University, Changchun, 130062, China.,Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China.,Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130021, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China
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31
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Passo MDS, Carvalho GGCD. In silico evaluation of potential drugs for the treatment of Colorectal Carcinoma. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e20343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
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Kraszkiewicz M, Napieralska A, Wydmański J, Suwiński R, Majewski W. Evaluation of Efficacy and Tolerance of Radical Radiotherapy and Radiochemotherapy in Treatment of Locally Advanced, Unresectable Rectal Cancer. Technol Cancer Res Treat 2022; 21:15330338221086085. [PMID: 35296187 PMCID: PMC9123928 DOI: 10.1177/15330338221086085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: A retrospective evaluation of tolerance and efficacy of
two schemes of neoadjuvant treatment in patients (pts) with unresectable rectal
cancer: radiochemotherapy (CRT) and radiotherapy (RT), including conventional
and accelerated hyperfractionation. Material and Method: A total of
145 consecutive pts with unresectable, locally advanced rectal cancer. The
schemes used are RT in 73 (50%) or CRT in 72 (50%). In CRT, 54 Gy in 1.8 Gy
fractions was given with chemotherapy, In the RT group, conventional
fractionation (CFRT) and hyperfractionated accelerated radiotherapy (HART). HART
was introduced at first as an alternative to CFRT, after radiobiological studies
suggesting a therapeutic gain of hyperfractionation in other cancers, and second
to administer relatively high dose needed in unresectable cancer, which is not
feasible in hypofractionation because of critical organs sensitivity to high
fraction doses (fd). HART was an alternative option in pts with medical
contraindications to chemotherapy and to shorten overall treatment time with
greater radiobiological effectiveness than CFRT. Results: Objective
response (OR) in the RT and CRT group was 60% versus 75%. Resection rate (RR) in
RT and CRT: 37% versus 65%. Tumor mobility and laparotomy-based unresectability
were significant factors for OR. Performance status (PS), tumor mobility, and
neoadjuvant treatment method were significant for RR.
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Affiliation(s)
- M Kraszkiewicz
- Maria Sklodowska-CUrie National Research Institute of Oncology Gliwice Branch, Radiotherapy Department, Gliwice, Poland
| | - A Napieralska
- Maria Sklodowska-CUrie National Research Institute of Oncology Gliwice Branch, Radiotherapy Department, Gliwice, Poland
| | - J Wydmański
- Maria Sklodowska-CUrie National Research Institute of Oncology Gliwice Branch, Radiotherapy Department, Gliwice, Poland
| | - R Suwiński
- Maria Sklodowska-CUrie National Research Institute of Oncology Gliwice Branch, II Radiotherapy and Chemotherapy Teaching Hospital, Gliwice, Poland
| | - W Majewski
- Maria Sklodowska-CUrie National Research Institute of Oncology Gliwice Branch, Radiotherapy Department, Gliwice, Poland
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Li J, Sun A, Zhong G, He Y, Xiong H, Yuan X. Mutation analysis of a 10-gene panel for colorectal cancer in Huizhou, Guangdong Province of China. J Int Med Res 2021; 49:3000605211061040. [PMID: 34851763 PMCID: PMC8647259 DOI: 10.1177/03000605211061040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Objective This study aimed to investigate the type and frequency of mutations in 10 genes in 85 colorectal cancer (CRC) patients in Huizhou and the guiding significance of targeted drug use. Methods The 10-gene panel next-generation sequencing (NGS) was used to assess genetic variants in 85 CRC patients from the Huizhou area combined with clinical information for a comprehensive analysis. Results Upon initial mutation testing, 68% (58/85) were positive. The mutation frequencies of these genes, including KRAS, PIK3CA, NRAS, ERBB2, BRAF, EGFR, and PDGFRA, were 51%, 20%, 5%, 4%, 4%, 1%, and 1%, respectively. Overall, 29 mutation types were detected from seven genes. More mutations were detected in more advanced cancers. There were three samples with multiple mutations of a single gene, including KRAS (n = 2) and ERBB2 (n = 2), 12 samples with multiple mutations of double genes, including KRAS/PIK3CA (n = 10), BRAF/PIK3CA (n = 1), and NRAS/PIK3CA (n = 1), and one sample with multiple mutations of three genes, including ERBB2/KRAS/PIK3CA (n = 1). Theoretically, 27 patients could receive targeted treatment. During the actual treatment, 10 patients received bevacizumab, cetuximab, or fruquintinib with no progression ranging from 12 to 24 months. Conclusion Gene mutations detected by a 10-gene panel were useful for targeting therapy of CRC in Huizhou.
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Affiliation(s)
- Jun Li
- Department of Medical Oncology, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Aihua Sun
- Department of Medical Oncology, Huizhou Municipal Center Hospital, Huizhou, Guangdong, China
| | - Guofang Zhong
- Department of Medical Oncology, Huizhou Municipal Center Hospital, Huizhou, Guangdong, China
| | - Ying He
- Department of Medical Oncology, Huizhou Municipal Center Hospital, Huizhou, Guangdong, China
| | - Hailin Xiong
- Department of Medical Oncology, Huizhou Municipal Center Hospital, Huizhou, Guangdong, China
| | - Xia Yuan
- Department of Medical Oncology, Huizhou First Hospital, Huizhou, Guangdong, China
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Ba L, Wang Q, Wang H, Zhu L, Zhang T, Ren J, Lin Z. Survival analysis and prognostic factors of palliative radiotherapy in patients with metastatic colorectal cancer: a propensity score analysis. J Gastrointest Oncol 2021; 12:2211-2222. [PMID: 34790386 DOI: 10.21037/jgo-21-540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/28/2021] [Indexed: 12/16/2022] Open
Abstract
Background Radiation therapy (RT) is known to have beneficial effects on the palliative treatment of patients with advanced cancer. However, valid data on this treatment method are limited, especially for patients with metastatic colorectal cancer (mCRC). This study aimed to identify prognostic factors and investigate the outcomes of mCRC patients who received palliative RT. Methods A total of 488 mCRC patients who underwent systemic therapy with or without palliative RT between 2014 and 2019 were included in the study. Of the 488 patients, 155 received systemic treatment combined with palliative RT (RT group), while 333 were only administered systemic treatment (non-RT group). Propensity score matching (PSM) was conducted to eliminate possible bias, and overall survival (OS) was calculated using the Kaplan-Meier (KM) method. A log-rank test was used to compare the survival outcomes of each group, and a multivariate analysis was conducted using a Cox proportional hazards model. Results The RT group had a higher OS than that of the non-RT group (P=0.001). After PSM, the median OS of the RT group was 50.8 months, and for the non-RT group it was 32.2 months (P=0.003). Subgroup analysis revealed that RT had a better effect on the OS of patients who had synchronous metastasis, or who didn't receive targeted therapy or local treatment (including surgery, ablation, and intervention). Multivariate analysis of the whole cohort showed that palliative RT was associated with improved OS. Moreover, multivariate analysis of the RT group showed that systemic therapy before RT, and the site of RT was in the liver and lung, were independent prognostic factors affecting survival time. Conclusions We demonstrated that systemic treatment followed by palliative RT led to a better OS for mCRC patients. This combination method can therefore be seen as a suitable treatment approach for patients with mCRC.
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Affiliation(s)
- Li Ba
- Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingrui Wang
- Department of Oncology, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), Jianghan University, Wuhan, China
| | - Haihong Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lisheng Zhu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinghua Ren
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenyu Lin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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The Role of Glycosyltransferases in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22115822. [PMID: 34070747 PMCID: PMC8198577 DOI: 10.3390/ijms22115822] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the main causes of cancer death in the world. Post-translational modifications (PTMs) have been extensively studied in malignancies due to its relevance in tumor pathogenesis and therapy. This review is focused on the dysregulation of glycosyltransferase expression in CRC and its impact in cell function and in several biological pathways associated with CRC pathogenesis, prognosis and therapeutic approaches. Glycan structures act as interface molecules between cells and their environment and in several cases facilitate molecule function. CRC tissue shows alterations in glycan structures decorating molecules, such as annexin-1, mucins, heat shock protein 90 (Hsp90), β1 integrin, carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), insulin-like growth factor-binding protein 3 (IGFBP3), transforming growth factor beta (TGF-β) receptors, Fas (CD95), PD-L1, decorin, sorbin and SH3 domain-containing protein 1 (SORBS1), CD147 and glycosphingolipids. All of these are described as key molecules in oncogenesis and metastasis. Therefore, glycosylation in CRC can affect cell migration, cell–cell adhesion, actin polymerization, mitosis, cell membrane repair, apoptosis, cell differentiation, stemness regulation, intestinal mucosal barrier integrity, immune system regulation, T cell polarization and gut microbiota composition; all such functions are associated with the prognosis and evolution of the disease. According to these findings, multiple strategies have been evaluated to alter oligosaccharide processing and to modify glycoconjugate structures in order to control CRC progression and prevent metastasis. Additionally, immunotherapy approaches have contemplated the use of neo-antigens, generated by altered glycosylation, as targets for tumor-specific T cells or engineered CAR (Chimeric antigen receptors) T cells.
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Chiang CT, Lau R, Ghaffarizadeh A, Brovold M, Vyas D, Juárez EF, Atala A, Agus DB, Soker S, Macklin P, Ruderman D, Mumenthaler SM. High-throughput microscopy reveals the impact of multifactorial environmental perturbations on colorectal cancer cell growth. Gigascience 2021; 10:giab026. [PMID: 33871006 PMCID: PMC8054261 DOI: 10.1093/gigascience/giab026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 11/21/2020] [Accepted: 03/15/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) mortality is principally due to metastatic disease, with the most frequent organ of metastasis being the liver. Biochemical and mechanical factors residing in the tumor microenvironment are considered to play a pivotal role in metastatic growth and response to therapy. However, it is difficult to study the tumor microenvironment systematically owing to a lack of fully controlled model systems that can be investigated in rigorous detail. RESULTS We present a quantitative imaging dataset of CRC cell growth dynamics influenced by in vivo-mimicking conditions. They consist of tumor cells grown in various biochemical and biomechanical microenvironmental contexts. These contexts include varying oxygen and drug concentrations, and growth on conventional stiff plastic, softer matrices, and bioengineered acellular liver extracellular matrix. Growth rate analyses under these conditions were performed via the cell phenotype digitizer (CellPD). CONCLUSIONS Our data indicate that the growth of highly aggressive HCT116 cells is affected by oxygen, substrate stiffness, and liver extracellular matrix. In addition, hypoxia has a protective effect against oxaliplatin-induced cytotoxicity on plastic and liver extracellular matrix. This expansive dataset of CRC cell growth measurements under in situ relevant environmental perturbations provides insights into critical tumor microenvironment features contributing to metastatic seeding and tumor growth. Such insights are essential to dynamical modeling and understanding the multicellular tumor-stroma dynamics that contribute to metastatic colonization. It also establishes a benchmark dataset for training and testing data-driven dynamical models of cancer cell lines and therapeutic response in a variety of microenvironmental conditions.
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Affiliation(s)
- Chun-Te Chiang
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90064, USA
| | - Roy Lau
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90064, USA
| | - Ahmadreza Ghaffarizadeh
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90064, USA
| | - Matthew Brovold
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27157, USA
| | - Dipen Vyas
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27157, USA
| | - Edwin F Juárez
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90064, USA
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27157, USA
| | - David B Agus
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90064, USA
| | - Shay Soker
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27157, USA
| | - Paul Macklin
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90064, USA
- Intelligent Systems Engineering, Indiana University, Bloomington, IN 47408, USA
| | - Daniel Ruderman
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90064, USA
| | - Shannon M Mumenthaler
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90064, USA
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Mostafa YS, Alamri SA, Alfaifi MY, Alrumman SA, Elbehairi SEI, Taha TH, Hashem M. L-Glutaminase Synthesis by Marine Halomonas meridiana Isolated from the Red Sea and Its Efficiency against Colorectal Cancer Cell Lines. Molecules 2021; 26:molecules26071963. [PMID: 33807313 PMCID: PMC8037810 DOI: 10.3390/molecules26071963] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 03/27/2021] [Accepted: 03/28/2021] [Indexed: 12/14/2022] Open
Abstract
L-glutaminase is an important anticancer agent that is used extensively worldwide by depriving cancer cells of L-glutamine. The marine bacterium, Halomonas meridian was isolated from the Red Sea and selected as the more active L-glutaminase-producing bacteria. L-glutaminase fermentation was optimized at 36 h, pH 8.0, 37 °C, and 3.0% NaCl, using glucose at 1.5% and soybean meal at 2%. The purified enzyme showed a specific activity of 36.08 U/mg, and the molecular weight was found to be 57 kDa by the SDS-PAGE analysis. The enzyme was highly active at pH 8.0 and 37 °C. The kinetics’ parameters of Km and Vmax were 12.2 × 10−6 M and 121.95 μmol/mL/min, respectively, which reflects a higher affinity for its substrate. The anticancer efficiency of the enzyme showed significant toxic activity toward colorectal adenocarcinoma cells; LS 174 T (IC50 7.0 μg/mL) and HCT 116 (IC50 13.2 μg/mL). A higher incidence of cell death was observed with early apoptosis in HCT 116 than in LS 174 T, whereas late apoptosis was observed in LS 174 T more than in HCT 116. Also, the L-glutaminase induction nuclear fragmentation in HCT 116 was more than that in the LS 174T cells. This is the first report on Halomonas meridiana as an L-glutaminase producer that is used as an anti-colorectal cancer agent.
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Affiliation(s)
- Yasser S. Mostafa
- Department of Biology, College of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia; (S.A.A.); (M.Y.A.); (S.A.A.); (S.E.I.E.); (M.H.)
- Correspondence:
| | - Saad A. Alamri
- Department of Biology, College of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia; (S.A.A.); (M.Y.A.); (S.A.A.); (S.E.I.E.); (M.H.)
- Prince Sultan Bin Abdulaziz Center for Environmental and Tourism Research and Studies, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia
| | - Mohammad Y. Alfaifi
- Department of Biology, College of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia; (S.A.A.); (M.Y.A.); (S.A.A.); (S.E.I.E.); (M.H.)
| | - Sulaiman A. Alrumman
- Department of Biology, College of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia; (S.A.A.); (M.Y.A.); (S.A.A.); (S.E.I.E.); (M.H.)
| | - Serag Eldin I. Elbehairi
- Department of Biology, College of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia; (S.A.A.); (M.Y.A.); (S.A.A.); (S.E.I.E.); (M.H.)
- Cell Culture Lab, Egyptian Organization for Biological Products and Vaccines, P.O. Box 12311, Giza, Egypt
| | - Tarek H. Taha
- Environmental Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research & Technological Applications, P.O. Box 21934, Alexandria, Egypt;
| | - Mohamed Hashem
- Department of Biology, College of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia; (S.A.A.); (M.Y.A.); (S.A.A.); (S.E.I.E.); (M.H.)
- Department of Botany and Microbiology, Faculty of Science, Assiut University, P.O. Box 61413, Assiut, Egypt
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Gholamzadeh Khoei S, Saidijam M, Amini R, Jalali A, Najafi R. Impact of PIN1 Inhibition on Tumor Progression and Chemotherapy Sensitivity in Colorectal Cancer. J Gastrointest Cancer 2021; 53:299-310. [PMID: 33580870 DOI: 10.1007/s12029-021-00600-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2021] [Indexed: 01/16/2023]
Abstract
BACKGROUND Deregulated PIN1 is associated with cancer development and progression. Herein, for the first time, we evaluate the roles that PIN1 in tumorigenic characteristics of colorectal cancer (CRC) cells. METHODS In this study, PIN1 expression was knocked down in SW-48 cells by synthetic small interfering RNA (siRNA). After confirming the knockdown of PIN1, cell viability, colony formation, apoptosis, autophagy, cancer stem cell (CSC)-related genes, CSC-related signaling pathways, cell migration, and 5-FU chemosensitivity were evaluated in vitro. RESULTS Transfection of PIN1 siRNA into SW-48 cells inhibited cancer cell proliferation, migration, and increased apoptosis and autophagy. Transfected SW-48 cells had lower properties of CSCs through the inhibition of β-catenin and Notch1 gene expression. Moreover, inhibition of PIN1 enhanced the inhibitory effect of 5-FU on SW-48 cell proliferation. CONCLUSION Our results indicated that targeting of PIN1 serves as a promising therapeutic solution for the suppression of tumor progression processes in CRC.
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Affiliation(s)
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Razieh Amini
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Akram Jalali
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rezvan Najafi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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Zengin M, Zergeroğlu S, Okcu O, Benek S. PD-1 and PD-L2 expression predict relapse risk and poor survival in patients with stage III colorectal cancer. Cell Oncol (Dordr) 2021; 44:423-432. [PMID: 33469839 DOI: 10.1007/s13402-020-00579-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/03/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Immune responses have long been an area of interest in cancer research. In this study, the effects of programmed cell death-1 (PD-1) and its ligand (PD-L2) on the prognosis of colorectal cancer (CRC) were investigated. METHODS Primary tumour specimens of stage III CRC patients operated between 2002 and 2013 were assessed for PD-1 and PD-L2 expression and various clinicopathological and prognostic factors. RESULTS We observed a significant relationship between poor prognostic factors and PD-1/PD-L2 expression. These biomarkers were also found to serve as independent risk factors for LIR and MSI. In univariate analysis, relapse-free survival (RFS) and overall survival (OS) rates were found to be poor in PD-1 and PD-L2 positive patients. In multivariate analysis, these biomarkers were found to serve as independent poor prognostic factors for RFS and OS. CONCLUSIONS Our data indicate that PD-1 and PD-L2 may serve as independent prognostic survival parameters for CRC patients and may be employed for the design of targeted therapies.
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Affiliation(s)
- Mehmet Zengin
- Department of Pathology, Kırıkkale University, Kırıkkale, Turkey.
| | - Sema Zergeroğlu
- Department of Pathology, Kırıkkale University, Kırıkkale, Turkey
| | - Oğuzhan Okcu
- Recep Tayyip Erdoğan University, Training and Research Hospital, Rize, Turkey
| | - Suat Benek
- Department of General Surgery, Tekirdağ Namık Kemal University, Tekirdağ, Turkey
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Ren T, Wang S, Shen Z, Xu C, Zhang Y, Hui F, Qi X, Zhao Q. Efficacy and Safety of Bevacizumab Plus Oxaliplatin- or Irinotecan-Based Doublet Backbone Chemotherapy as the First-Line Treatment of Metastatic Colorectal Cancer: A Systematic Review and Meta-analysis. Drug Saf 2021; 44:29-40. [PMID: 33180265 DOI: 10.1007/s40264-020-00997-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND OBJECTIVE Guidelines recommend combined doublet backbone chemotherapy based on 5-fluorouracil and oxaliplatin (OX) or irinotecan (IR) as the first-line treatment options for metastatic colorectal cancer. However, it is still unknown which is better when combined with bevacizumab (BEV). This systematic review and meta-analysis were performed to compare BEV-IR with BEV-OX regimens in terms of efficacy and safety. METHODS We searched studies from databases including MEDLINE, EMBASE, CENTRAL, and conference papers. The outcomes were overall response rate, overall survival, progression-free survival, and the incidence of the most common adverse events. The dichotomous data were reported as the risk ratio (RR) and the survival outcomes were extracted as the hazard ratio with 95% confidence interval (CI). RESULTS Eleven studies including 5632 patients were identified. No difference was found in overall survival or overall response rate between BEV-IR and BEV-OX regimens. The pooled progression-free survival was significantly longer in the BEV-IR group than the BEV-OX group (hazard ratio = 0.92, 95% CI 0.87-0.98, p = 0.08). Compared with the BEV-OX group, the BEV-IR group was related to a higher risk of bleeding events (RR = 0.80, 95% CI 0.64-0.98, p = 0.03), venous thromboembolism (RR = 0.60, 95% CI 0.46-0.79, p = 0.0002), and diarrhea (RR = 0.71, 95% CI 0.62-0.80, p < 0.00001). Conversely, the BEV-OX group was related to a higher risk of thrombocytopenia (RR 2.39, 95% CI 1.67-3.42, p < 0.00001) and neuropathy (RR 3.80, 95% CI 1.90-7.64, p = 0.0002). CONCLUSIONS The BEV-IR regimen was superior in improving progression-free survival as the first-line treatment for metastatic colorectal cancer. The two different doublet regimens combined with BEV had their specific features of adverse events.
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Affiliation(s)
- Tianshu Ren
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Shu Wang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Zexu Shen
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Chang Xu
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Yingshi Zhang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Fuhai Hui
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
| | - Qingchun Zhao
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China.
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China.
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Cai X, Wei B, Li L, Chen X, Yang J, Li X, Jiang X, Lv M, Li M, Lin Y, Xu Q, Guo W, Gu Y. Therapeutic Potential of Apatinib Against Colorectal Cancer by Inhibiting VEGFR2-Mediated Angiogenesis and β-Catenin Signaling. Onco Targets Ther 2020; 13:11031-11044. [PMID: 33154652 PMCID: PMC7606303 DOI: 10.2147/ott.s266549] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 10/05/2020] [Indexed: 01/05/2023] Open
Abstract
Purpose Apatinib is an inhibitor of VEGFR2 (vascular endothelial growth factor receptor 2) that has attracted a great deal of attention due to its promotion of anticancer activity. In the present study, we investigated the therapeutic effects of apatinib against colorectal cancer (CRC) and examined the underlying mechanism. Materials and Methods Both in vivo and in vitro assays were conducted to study the effect of apatinib on CRC. To elucidate the associated mechanism, RNA-seq (transcriptome) analysis was conducted on apatinib-treated HCT116 cells. Results Apatinib showed antiproliferative and proapoptotic effects, induced G0/G1 arrest and blocked cell migration and invasion in CRC. An analysis of the mechanism associated with apatinib activity demonstrated that by interacting with VEGFR2, apatinib decreased p-Src, p-Akt, and p-GSK3β levels, which further increased β-catenin ubiquitination and reduced the nuclear translocation of β-catenin. Furthermore, apatinib strongly suppressed CT26 cell growth in mouse xenograft models by inhibiting β-catenin signaling and angiogenesis. Conclusion Overall, the results of the present study here indicated that by inhibiting the VEGFR2-β-catenin-mediated malignant phenotype, apatinib significantly suppresses the growth of CRC, suggesting that the use of apatinib is a promising therapeutic strategy for CRC.
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Affiliation(s)
- Xiaomin Cai
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Bin Wei
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.,Department of Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an 223300, People's Republic of China
| | - Lele Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiaofeng Chen
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Jing Yang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiaofei Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiaozheng Jiang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Mu Lv
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Mingyang Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Yumeng Lin
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People's Republic of China
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People's Republic of China
| | - Wenjie Guo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People's Republic of China
| | - Yanhong Gu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
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Weakest-Link Dynamics Predict Apparent Antibiotic Interactions in a Model Cross-Feeding Community. Antimicrob Agents Chemother 2020; 64:AAC.00465-20. [PMID: 32778550 PMCID: PMC7577160 DOI: 10.1128/aac.00465-20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 07/31/2020] [Indexed: 12/17/2022] Open
Abstract
With the growing global threat of antimicrobial resistance, novel strategies are required for combatting resistant pathogens. Combination therapy, in which multiple drugs are used to treat an infection, has proven highly successful in the treatment of cancer and HIV. However, this practice has proven challenging for the treatment of bacterial infections due to difficulties in selecting the correct combinations and dosages. An additional challenge in infection treatment is the polymicrobial nature of many infections, which may respond to antibiotics differently than a monoculture pathogen. With the growing global threat of antimicrobial resistance, novel strategies are required for combatting resistant pathogens. Combination therapy, in which multiple drugs are used to treat an infection, has proven highly successful in the treatment of cancer and HIV. However, this practice has proven challenging for the treatment of bacterial infections due to difficulties in selecting the correct combinations and dosages. An additional challenge in infection treatment is the polymicrobial nature of many infections, which may respond to antibiotics differently than a monoculture pathogen. This study tests whether patterns of antibiotic interactions (synergy, antagonism, or independence/additivity) in monoculture can be used to predict antibiotic interactions in an obligate cross-feeding coculture. Using our previously described weakest-link hypothesis, we hypothesized antibiotic interactions in coculture based on the interactions we observed in monoculture. We then compared our predictions to observed antibiotic interactions in coculture. We tested the interactions between 10 previously identified antibiotic combinations using checkerboard assays. Although our antibiotic combinations interacted differently than predicted in our monocultures, our monoculture results were generally sufficient to predict coculture patterns based solely on the weakest-link hypothesis. These results suggest that combination therapy for cross-feeding multispecies infections may be successfully designed based on antibiotic interaction patterns for their component species.
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Cetuximab-Mediated Protection from Hypoxia- Induced Cell Death: Implications for Therapy Sequence in Colorectal Cancer. Cancers (Basel) 2020; 12:cancers12103050. [PMID: 33092032 PMCID: PMC7589936 DOI: 10.3390/cancers12103050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/14/2020] [Accepted: 10/16/2020] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Therapeutic antibodies are an integral part of treatment regimens for metastasized colorectal cancer. In KRAS wildtype tumors both bevacizumab and cetuximab are active. While bevacizumab has previously been shown to induce tumor hypoxia, we here report that EGFR inhibition by cetuximab protects colon cancer cells from hypoxia-induced cell death. This effect appears to be responsible for the inferior efficacy of a treatment sequence of bevacizumab followed by cetuximab versus an inverse sequence that we observed in a colorectal cancer mouse model. It also offers a mechanistic explanation for effects observed in clinical trials such as underadditive or even detrimental effects when combining bevacizumab and cetuximab (CAIRO2 trial) and the superior efficacy of first line cetuximab (FIRE-3 trial) under chemotherapy backbones in colorectal cancer. Abstract Monoclonal antibodies like cetuximab, targeting the epidermal growth factor receptor (EGFR), and bevacizumab, targeting the vascular endothelial growth factor (VEGF), are an integral part of treatment regimens for metastasized colorectal cancer. However, inhibition of the EGFR has been shown to protect human glioma cells from cell death under hypoxic conditions. In colon carcinoma cells, the consequences of EGFR blockade in hypoxia (e.g., induced by bevacizumab) have not been evaluated yet. LIM1215 and SW948 colon carcinoma and LNT-229 glioblastoma cells were treated with cetuximab, PD153035, and erlotinib and analyzed for cell density and viability. The sequential administration of either cetuximab followed by bevacizumab (CET->BEV) or bevacizumab followed by cetuximab (BEV->CET) was investigated in a LIM1215 (KRAS wildtype) and SW948 (KRAS mutant) xenograft mouse model. In vitro, cetuximab protected from hypoxia. In the LIM1215 model, a survival benefit with cetuximab and bevacizumab monotherapy was observed, but only the sequence CET->BEV showed an additional benefit. This effect was confirmed in the SW948 model. Our observations support the hypothesis that bevacizumab modulates the tumor microenvironment (e.g., by inducing hypoxia) where cetuximab could trigger protective effects when administered later on. The sequence CET->BEV therefore seems to be superior as possible mutual adverse effects are bypassed.
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Badic B, Durand S, El Khoury F, De La Grange P, Gentien D, Simon B, Le Jossic-Corcos C, Corcos L. Prognostic impact of cancer stem cell markers ABCB1, NEO1 and HIST1H2AE in colorectal cancer. Am J Transl Res 2020; 12:5797-5807. [PMID: 33042459 PMCID: PMC7540150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 03/23/2020] [Indexed: 06/11/2023]
Abstract
Colon cancer develops according to a defined temporal sequence of genetic and epigenetic molecular events that may primarily affect cancer stem cells. In an attempt to identify new markers of such cells that would help predict patient outcome, we performed a comparative transcriptome analysis of colon cancer stem cells and normal colon stem cells. We identified 162 mRNAs, either over- or under-expressed. According to Cox multivariate regression with our set of 83 colorectal cancers, low expression of ABCB1, NEO1, tumor size and the presence of distant metastases were predictive factors for overall survival. Combined expression of ABCC1 and NEO1 was a significant predictor for overall survival in our cohort, which was confirmed by external validation in 221 colorectal cancers from the Cancer Genome Atlas (TCGA) portal. Tumor size, lymph node involvement and HIST1H2AE expression were also independently correlated with disease-free survival. Taken together, our results suggest that molecular markers of colorectal cancers ABCB1, NEO1 and HIST1H2AE are prognostic factors in colorectal cancer patients. It can be proposed that surveying expression of these marker genes should help better characterizing CRC prognosis, and help selecting the best therapeutic options.
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Affiliation(s)
- Bogdan Badic
- INSERM UMR 1101, Université de Brest22 Avenue Camille Desmoulins, 29238 Brest, France
| | - Stéphanie Durand
- INSERM UMR 1078, Université de Brest22 Avenue Camille Desmoulins, 29238 Brest, France
- Present address: EA7500, Université de Limoges, Faculté des Sciences et Techniques123 Avenue Albert Thomas, 87060 Limoges, France
| | - Flaria El Khoury
- INSERM UMR 1078, Université de Brest22 Avenue Camille Desmoulins, 29238 Brest, France
- Present address: CNRS UMR 9197, Neuro-PSI1 Avenue de la Terrasse, 91198 Gif-Sur-Yvette, France
| | | | - David Gentien
- Institut Curie, Département de Recherche Translationnelle, Plateforme Génomique1 Avenue Claude Vellefaux, 75010 Paris, France
| | - Brigitte Simon
- INSERM UMR 1078, Université de Brest22 Avenue Camille Desmoulins, 29238 Brest, France
| | | | - Laurent Corcos
- INSERM UMR 1078, Université de Brest22 Avenue Camille Desmoulins, 29238 Brest, France
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Gu L, Liu Y, Jiang C, Sun L, Zhou H. Identification and clinical validation of metastasis-associated biomarkers based on large-scale samples in colon-adenocarcinoma. Pharmacol Res 2020; 160:105087. [PMID: 32683036 DOI: 10.1016/j.phrs.2020.105087] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/14/2020] [Accepted: 07/14/2020] [Indexed: 02/07/2023]
Abstract
AIM Distant metastasis is the main cause of death in patients with colon-adenocarcinoma(COAD). Due to the lack of effective molecular markers and treatment, the prognosis of patients with metastatic colon cancer is still rather poor. METHODS Metastatic related signature (MRS) of stage I and stage IV in colon cancer were identified from different cohorts. Univariate cox regression is used to analyze the relationship between MRS and the overall survival. L1000FWD and DGIdb databases are used to identify molecular drugs. Expression and functional experimental validation of the hub MRS were carried out. RESULTS 16 MRS were identified, of which 14 MRS was significantly correlated with overall survival. Further functional enrichment analysis showed that MRS was significantly involved with important biological functions such as cell migration, and apoptosis. As important metastatic related genes, GSR, FAS and CYP1B1 have significant interaction with drug molecules. Further studies have confirmed that the expression of FAS and GSR is low, and inhibition of its expression can promote the metastasis of COAD. CYP1B1 expression is highly expressed, and inhibition of its expression can attenuate the malignant biological behavior of colon cancer. CONCLUSION Our research could increase the understanding of the mechanism of colon cancer metastasis and provide theoretical basis for the treatment of metastatic colon cancer.
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Affiliation(s)
- Lei Gu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China
| | - Ye Liu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China
| | - Chunhui Jiang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China
| | - Longci Sun
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China
| | - Hong Zhou
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
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Su GL, Wang YY, Wang JC, Liu H. A meta-analysis comparing regorafenib with TAS-102 for treating refractory metastatic colorectal cancer. J Int Med Res 2020; 48:300060520926408. [PMID: 32660291 PMCID: PMC7361493 DOI: 10.1177/0300060520926408] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Objective We performed this meta-analysis to compare the efficacy and toxicity of regorafenib and TAS-102. Methods Electronic databases were searched to identify studies comparing the efficacy and safety of regorafenib and TAS-102 in patients with chemotherapy-refractory metastatic colorectal cancer using pooled analyses. Results Three clinical trials were included in this analysis. Regarding the reasons for treatment discontinuation, regorafenib was significantly associated with disease progression (odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.21–0.50) and adverse events (OR = 4.38, 95% CI = 2.69–7.13). However, overall (OR = 0.97, 95% CI = 0.81–1.17) and progression-free survival (OR = 1.01, 95% CI = 0.86–1.18) did not significantly differ between the groups. The most common treatment-related adverse events in the regorafenib group were neutropenia (OR = 0.06, 95% CI = 0.03–0.11), hand–foot syndrome (OR = 50.34, 95% CI = 10.44–242.84), and liver dysfunction (OR = 34.51, 95% CI = 8.30–143.43). Conversely, the incidence of thrombocytopenia did not differ between the two groups. Conclusions Regorafenib and TAS-102 have similar efficacy but different adverse event profiles. Differences in the toxicity profiles of the two drugs will help guide treatment selection.
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Affiliation(s)
- Guan-Li Su
- Department of Psychiatry and Psychotherapy, The First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yuan-Yuan Wang
- Department of Gastrointestinal Tumor Surgery, The First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jin-Cheng Wang
- Department of Psychiatry and Psychotherapy, The First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Hao Liu
- Department of Nuclear Medicine, The First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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Al-Obeed O, El-Obeid AS, Matou-Nasri S, Vaali-Mohammed MA, AlHaidan Y, Elwatidy M, Al Dosary H, Alehaideb Z, Alkhayal K, Haseeb A, McKerrow J, Ahmad R, Abdulla MH. Herbal melanin inhibits colorectal cancer cell proliferation by altering redox balance, inducing apoptosis, and modulating MAPK signaling. Cancer Cell Int 2020; 20:126. [PMID: 32322173 PMCID: PMC7161222 DOI: 10.1186/s12935-020-01206-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 04/05/2020] [Indexed: 12/18/2022] Open
Abstract
Background Colorectal carcinoma is one of the most deadly cancers that requests effective and safe chemotherapy. Evaluation of natural product-based anticancer drugs as adjuvant treatment with fewer side effects is largely unexplored research fields. Herbal melanin (HM) is an extract of the seed coats of Nigella sativa that modulates an inflammatory response through toll-like receptor 4 (TLR4). This TLR4 receptor is also involved in the modulation of apoptosis. We therefore explored the anticancer potential of HM and specifically its effect on the molecular mechanisms underlying adenocarcinoma and metastatic colorectal cancer (mCRC) cell death in vitro. Methods Cell viability was evaluated using the MTT assay. Cellular reactive oxygen species (ROS), glutathione levels, and apoptotic status were assessed using fluorometric and colorimetric detection methods. HM-induced apoptotic and other signaling pathways were investigated using Western blot technology and mitochondrial transition pore assay kit. TLR4 receptor downregulation and blockade were performed using siRNA technology and neutralizing antibody, respectively. Results Our results showed that HM inhibited the proliferation of the colorectal adenocarcinoma HT29 and mCRC SW620 cell lines. Furthermore, HM enhanced ROS production and decreased glutathione levels. HM-induced apoptosis was associated with mitochondrial outer membrane permeability and cytochrome c release, inhibition of the Bcl2 family proteins, and activation of caspase-3/-7. In addition, HM modulated MAPK pathways by activating the JNK pathway and by inhibiting ERK phosphorylation. TLR4 receptor downregulation enhanced HM-induced apoptosis while TLR4 receptor blockade partially alleviated HM-inhibited ERK phosphorylation. Conclusion Altogether, these findings indicate that HM exerts pro-apoptotic effects and inhibits MAPK pathway through TLR4 in mCRC and colorectal adenocarcinoma cells, suggesting HM as a promising natural-based drug for the treatment of colorectal cancer.
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Affiliation(s)
- Omar Al-Obeed
- 1Colorectal Research Chair, Department of Surgery, King Khalid University Hospital and College of Medicine, King Saud University, PO Box 7805 (37), Riyadh, 11472 Saudi Arabia
| | - Adila Salih El-Obeid
- 2Department of Biobank, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, PO Box 22490, Riyadh, 11426 Saudi Arabia.,3Faculty of Pharmacology, Ahfad University for Women, Khartoum, Sudan
| | - Sabine Matou-Nasri
- 4Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, PO Box 22490, Riyadh, 11426 Saudi Arabia
| | - Mansoor-Ali Vaali-Mohammed
- 1Colorectal Research Chair, Department of Surgery, King Khalid University Hospital and College of Medicine, King Saud University, PO Box 7805 (37), Riyadh, 11472 Saudi Arabia
| | - Yazeid AlHaidan
- 4Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, PO Box 22490, Riyadh, 11426 Saudi Arabia
| | - Mohammed Elwatidy
- 1Colorectal Research Chair, Department of Surgery, King Khalid University Hospital and College of Medicine, King Saud University, PO Box 7805 (37), Riyadh, 11472 Saudi Arabia
| | - Hamad Al Dosary
- 1Colorectal Research Chair, Department of Surgery, King Khalid University Hospital and College of Medicine, King Saud University, PO Box 7805 (37), Riyadh, 11472 Saudi Arabia
| | - Zeyad Alehaideb
- 4Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, PO Box 22490, Riyadh, 11426 Saudi Arabia
| | - Khayal Alkhayal
- 1Colorectal Research Chair, Department of Surgery, King Khalid University Hospital and College of Medicine, King Saud University, PO Box 7805 (37), Riyadh, 11472 Saudi Arabia
| | - Adil Haseeb
- 5Department of Physics, Faculty of Science, University of Khartoum, Khartoum, Sudan
| | - James McKerrow
- 6Skaggs School of Pharmacy and Pharmaceutical Chemistry, University of California, La Jolla, San Diego, CA USA
| | - Rehan Ahmad
- 1Colorectal Research Chair, Department of Surgery, King Khalid University Hospital and College of Medicine, King Saud University, PO Box 7805 (37), Riyadh, 11472 Saudi Arabia
| | - Maha-Hamadien Abdulla
- 1Colorectal Research Chair, Department of Surgery, King Khalid University Hospital and College of Medicine, King Saud University, PO Box 7805 (37), Riyadh, 11472 Saudi Arabia
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Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther 2020; 5:22. [PMID: 32296018 PMCID: PMC7082344 DOI: 10.1038/s41392-020-0116-z] [Citation(s) in RCA: 1002] [Impact Index Per Article: 200.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/24/2019] [Accepted: 12/31/2019] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in the world and was responsible for nearly 881,000 cancer-related deaths in 2018. Surgery and chemotherapy have long been the first choices for cancer patients. However, the prognosis of CRC has never been satisfying, especially for patients with metastatic lesions. Targeted therapy is a new optional approach that has successfully prolonged overall survival for CRC patients. Following successes with the anti-EGFR (epidermal growth factor receptor) agent cetuximab and the anti-angiogenesis agent bevacizumab, new agents blocking different critical pathways as well as immune checkpoints are emerging at an unprecedented rate. Guidelines worldwide are currently updating the recommended targeted drugs on the basis of the increasing number of high-quality clinical trials. This review provides an overview of existing CRC-targeted agents and their underlying mechanisms, as well as a discussion of their limitations and future trends.
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Affiliation(s)
- Yuan-Hong Xie
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China
| | - Ying-Xuan Chen
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China.
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China.
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Sensi F, D’Angelo E, Piccoli M, Pavan P, Mastrotto F, Caliceti P, Biccari A, Corallo D, Urbani L, Fassan M, Spolverato G, Riello P, Pucciarelli S, Agostini M. Recellularized Colorectal Cancer Patient-derived Scaffolds as in vitro Pre-clinical 3D Model for Drug Screening. Cancers (Basel) 2020; 12:681. [PMID: 32183226 PMCID: PMC7140024 DOI: 10.3390/cancers12030681] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/04/2020] [Accepted: 03/12/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) shows highly ineffective therapeutic management. An urgent unmet need is the random assignment to adjuvant chemotherapy of high-risk stage II and stage III CRC patients without any predictive factor of efficacy. In the field of drug discovery, a critical step is the preclinical evaluation of drug cytotoxicity, efficacy, and efficiency. We proposed a patient-derived 3D preclinical model for drug evaluation that could mimic in vitro the patient's disease. Surgically resected CRC tissue and adjacent healthy colon mucosa were decellularized by a detergent-enzymatic treatment. Scaffolds were recellularized with HT29 and HCT116 cells. Qualitative and quantitative characterization of matched recellularized samples were evaluated through histology, immunofluorescences, scanning electron microscopy, and DNA amount quantification. A chemosensitivity test was performed using an increasing concentration of 5-fluorouracil (5FU). In vivo studies were carried out using zebrafish (Danio rerio) animal model. Permeability test and drug absorption were also determined. The decellularization protocol allowed the preservation of the original structure and ultrastructure. Five days after recellularization with HT29 and HCT116 cell lines, the 3D CRC model exhibited reduced sensitivity to 5FU treatments compared with conventional 2D cultures. Calculated the half maximal inhibitory concentration (IC50) for HT29 treated with 5FU resulted in 11.5 µM in 3D and 1.3 µM in 2D, and for HCT116, 9.87 µM in 3D and 1.7 µM in 2D. In xenograft experiments, HT29 extravasation was detected after 4 days post-injection, and we obtained a 5FU IC50 fully comparable to that observed in the 3D CRC model. Using confocal microscopy, we demonstrated that the drug diffused through the repopulated 3D CRC scaffolds and co-localized with the cell nuclei. The bioengineered CRC 3D model could be a reliable preclinical patient-specific platform to bridge the gap between in vitro and in vivo drug testing assays and provide effective cancer treatment.
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Affiliation(s)
- Francesca Sensi
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35129 Padua, Italy; (F.S.); (M.P.); (D.C.)
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, 30172 Mestre (Venice), Italy;
| | - Edoardo D’Angelo
- First Surgical Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (E.D.); (G.S.); (S.P.)
- LIFELAB Program, Consorzio per la Ricerca Sanitaria-CORIS, Veneto Region, 129 Padua, Italy;
| | - Martina Piccoli
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35129 Padua, Italy; (F.S.); (M.P.); (D.C.)
| | - Piero Pavan
- Department of Industrial Engineering, University of Padua, 35131 Padua, Italy;
| | - Francesca Mastrotto
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy; (F.M.); (P.C.)
| | - Paolo Caliceti
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy; (F.M.); (P.C.)
| | - Andrea Biccari
- LIFELAB Program, Consorzio per la Ricerca Sanitaria-CORIS, Veneto Region, 129 Padua, Italy;
| | - Diana Corallo
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35129 Padua, Italy; (F.S.); (M.P.); (D.C.)
| | - Luca Urbani
- Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK;
- Faculty of Life Sciences & Medicine, King’s College London, London WC2R 2LS, UK
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine, University of Padua, 35100 Padua, Italy;
| | - Gaya Spolverato
- First Surgical Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (E.D.); (G.S.); (S.P.)
| | - Pietro Riello
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, 30172 Mestre (Venice), Italy;
| | - Salvatore Pucciarelli
- First Surgical Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (E.D.); (G.S.); (S.P.)
| | - Marco Agostini
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35129 Padua, Italy; (F.S.); (M.P.); (D.C.)
- First Surgical Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (E.D.); (G.S.); (S.P.)
- LIFELAB Program, Consorzio per la Ricerca Sanitaria-CORIS, Veneto Region, 129 Padua, Italy;
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50
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Chen P, Ni W, Xie T, Sui X. Meta-Analysis of 5-Fluorouracil-Based Chemotherapy Combined With Traditional Chinese Medicines for Colorectal Cancer Treatment. Integr Cancer Ther 2019; 18:1534735419828824. [PMID: 30791729 PMCID: PMC7242800 DOI: 10.1177/1534735419828824] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
This meta-analysis evaluates the clinical evidence for the addition of traditional Chinese medicines (TCMs) to 5-fluorouracil (5-FU)-based regimens for colorectal cancer (CRC) in terms of tumor response rate (TRR). Five electronic databases were searched for randomized controlled trials of 5-FU-based chemotherapy combined with TCMs compared to the same 5-FU-based regimen. Forty-five randomized controlled trials were involved in this study, and all the data were analyzed by Stata software (version 14.0). Our results suggested that the TRR of the group with TCMs combined with 5-FU-based regimens was higher than that in the group with 5-FU regimens alone (risk ratio [RR] 1.36 [1.25-1.49], I2 = 0%). Furthermore, both nonoral administration (RR 1.51 [1.29-1.76], I2 = 0%) and oral administration (RR 1.31 [1.18-1.45], I2 = 0%) of TCMs showed benefits to the CRC treatment. Further sensitivity analysis of specific plant-based TCMs found that fuling, sheshecao, banzhilian, eshu, baizhu, huangqi, yiyiren, and dangshen had significantly higher contributions to the results of the risk ratio. Therefore, TCMs may have the potential to improve the efficacy of 5-FU-based chemotherapy for CRC.
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Affiliation(s)
- Peng Chen
- 1 Shanghai University of Traditional Chinese Medicine, Shanghai, China.,2 Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Wei Ni
- 2 Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Tian Xie
- 1 Shanghai University of Traditional Chinese Medicine, Shanghai, China.,2 Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xinbing Sui
- 2 Hangzhou Normal University, Hangzhou, Zhejiang, China
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