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Reid G, Williams M, Cheng YY, Sarun K, Winata P, Kirschner MB, Mugridge N, Weiss J, Molloy M, Brahmbhatt H, MacDiarmid J, van Zandwijk N. Therapeutic potential of synthetic microRNA mimics based on the miR-15/107 consensus sequence. Cancer Gene Ther 2025:10.1038/s41417-025-00885-w. [PMID: 40121357 DOI: 10.1038/s41417-025-00885-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 02/11/2025] [Accepted: 03/06/2025] [Indexed: 03/25/2025]
Abstract
MicroRNA expression is frequently suppressed in cancer, and previously we demonstrated coordinate downregulation of multiple related microRNAs of the miR-15/107 group in malignant pleural mesothelioma (PM). From an alignment of the miR-15 family and the related miR-103/107, we derived a consensus sequence and used this to generate synthetic mimics. The synthetic mimics displayed tumour suppressor activity in PM cells in vitro, which was greater than that of a mimic based on the native miR-16 sequence. These mimics were also growth inhibitory in cells from non-small cell lung (NSCLC), prostate, breast and colorectal cancer, and sensitised all cell lines to the chemotherapeutic drug gemcitabine. The increased activity corresponded to enhanced inhibition of the expression of target genes and was associated with an increase in predicted binding to target sites, and proteomic analysis revealed a strong effect on proteins involved in RNA and DNA processes. Applying the novel consensus mimics to xenograft models of PM and NSCLC in vivo using EGFR-targeted nanocells loaded with mimic led to tumour growth inhibition. These results suggest that mimics based on the consensus sequence of the miR-15/107 group have therapeutic potential in a range of cancer types.
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Affiliation(s)
- Glen Reid
- Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia.
- School of Medicine, University of Sydney, Sydney, NSW, Australia.
- Department of Pathology, University of Otago, Dunedin, New Zealand.
| | - Marissa Williams
- Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia
- School of Medicine, University of Sydney, Sydney, NSW, Australia
| | - Yuen Yee Cheng
- Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia
- School of Medicine, University of Sydney, Sydney, NSW, Australia
- Institute for Biomedical Materials and Devices (IBMD), University of Technology Sydney, Sydney, Australia
| | - Kadir Sarun
- Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia
| | - Patrick Winata
- Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia
| | - Michaela B Kirschner
- Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
| | | | | | - Mark Molloy
- The Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, Australia
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Kim S, Park H, Hong HJ, Lee S, Kim S, Lee YK, Shong M, Kim YC. Liposomal Codelivery of Doxorubicin and Curcumin Sensitizes Antitumor Activity and Reduces Tumor Metastasis. ACS APPLIED BIO MATERIALS 2024; 7:8367-8376. [PMID: 39591430 DOI: 10.1021/acsabm.4c01146] [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] [Indexed: 11/28/2024]
Abstract
Multidrug resistance (MDR) is a major obstacle to traditional cancer treatment using chemotherapeutic agents like doxorubicin (DOX). MDR affects drug dosage regimens and enables the recurrence and metastasis of cancer. Because DOX causes severe side effects at high dosages, it is important to use an MDR modulator to make cancer cells sensitive to DOX. This work focused on a liposome-based codelivery system containing curcumin (CUR) and DOX, focusing on CUR as an MDR modulator. The synergistic effect was maximized when the ratio of DOX and CUR was 1:1, and the synthesis of liposomal drugs was successfully verified. In addition, a successful MDR reversal effect was demonstrated through rhodamine 123 assay, Western blotting, and immunofluorescence. Compared to the conventional DOX treatment, the dual-drug treatment exhibits a significantly improved anticancer effect. In the murine metastasis 4T1 IP tumor model, the dual-drug-encapsulating liposomes successfully suppressed tumor growth and reversed the tumoral effect (omental tumor metastasis, fat, and muscle weight loss) into a normal state.
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Affiliation(s)
- Suyeon Kim
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
| | - Heewon Park
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
| | - Hyun Jung Hong
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
- Life Science Research Institute, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
| | - Susam Lee
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
| | - Sejin Kim
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
| | - Yong-Kyu Lee
- Department of Chemical and Biological Engineering, Korea National University of Transportation, Chungju, Chung-Buk 27469, Republic of Korea
| | - Minho Shong
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
| | - Yeu-Chun Kim
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
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Oršolić N, Jazvinšćak Jembrek M. Potential Strategies for Overcoming Drug Resistance Pathways Using Propolis and Its Polyphenolic/Flavonoid Compounds in Combination with Chemotherapy and Radiotherapy. Nutrients 2024; 16:3741. [PMID: 39519572 PMCID: PMC11547968 DOI: 10.3390/nu16213741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 10/25/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Conventional cancer treatments include surgical resection, chemotherapy, hyperthermia, immunotherapy, hormone therapy, and locally targeted therapies such as radiation therapy. Standard cancer therapies often require the use of multiple agents, which can activate nuclear factor kappa B (NF-κB) in tumor cells, leading to reduced cell death and increased drug resistance. Moreover, the use of multiple agents also contributes to added toxicity, resulting in poor treatment outcomes. Cancer cells gradually develop resistance to almost all chemotherapeutics through various mechanisms, such as drug efflux, alterations in drug metabolism and transport, changes in signal transduction pathways, enhanced DNA repair capacity, evasion of apoptosis, increased mutations, reactivation of drug targets, interaction with the cancer microenvironment, cancer cell-stroma interactions, epithelial-mesenchymal transition (EMT)-mediated chemoresistance, epigenetic modifications, metabolic alterations, and the effect of cancer stem cells (CSCs). Developing new strategies to improve chemotherapy sensitivity while minimizing side effects is essential for achieving better therapeutic outcomes and enhancing patients' quality of life. One promising approach involves combining conventional cancer treatments with propolis and its flavonoids. These natural compounds may enhance tumor response to treatment while reducing toxicity. Propolis and its components can sensitize cancer cells to chemotherapeutic agents, likely by inhibiting NF-κB activation, reprogramming tumor-associated macrophages (TAMs; an M2-like phenotype), and thereby reducing the release of matrix metalloproteinase (MMP)-9, cytokines, chemokines, and the vascular endothelial growth factor (VEGF). By reducing TAMs, propolis and its components may also overcome EMT-mediated chemoresistance, disrupt the crosstalk between macrophages and CSCs, inhibit the maintenance of stemness, and reverse acquired immunosuppression, thus promoting an antitumor response mediated by cytotoxic T-cells. This review highlights the potential of flavonoids to modulate the responsiveness of cancer to conventional treatment modalities. The evidence suggests that novel therapeutic strategies incorporating flavonoids could be developed to improve treatment outcomes. The positive effects of combining propolis with chemotherapeutics include reduced cytotoxicity to peripheral blood leukocytes, liver, and kidney cells. Therefore, polyphenolic/flavonoid components may hold potential for use in combination with chemotherapeutic agents in the clinical treatment of various types of cancers.
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Affiliation(s)
- Nada Oršolić
- Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, HR-10000 Zagreb, Croatia
| | - Maja Jazvinšćak Jembrek
- Division of Molecular Medicine, Laboratory for Protein Dynamics, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia;
- School of Medicine, Catholic University of Croatia, Ilica 244, HR-10000 Zagreb, Croatia
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Gupta KB, Taylor TL, Panda SS, Thangaraju M, Lokeshwar BL. Curcumin-Dichloroacetate Hybrid Molecule as an Antitumor Oral Drug against Multidrug-Resistant Advanced Bladder Cancers. Cancers (Basel) 2024; 16:3108. [PMID: 39272966 PMCID: PMC11394085 DOI: 10.3390/cancers16173108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/04/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024] Open
Abstract
Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10-15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers.
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Affiliation(s)
| | - Truett L Taylor
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
| | - Siva S Panda
- Department of Chemistry and Biochemistry, College of Science and Mathematics, Augusta University, Augusta, GA 30912, USA
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Muthusamy Thangaraju
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Bal L Lokeshwar
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
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Butera F, Sero JE, Dent LG, Bakal C. Actin networks modulate heterogeneous NF-κB dynamics in response to TNFα. eLife 2024; 13:e86042. [PMID: 39110005 PMCID: PMC11524587 DOI: 10.7554/elife.86042] [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: 01/08/2023] [Accepted: 08/05/2024] [Indexed: 11/01/2024] Open
Abstract
The canonical NF-κB transcription factor RELA is a master regulator of immune and stress responses and is upregulated in pancreatic ductal adenocardinoma (PDAC) tumours. In this study, we characterised previously unexplored endogenous RELA-GFP dynamics in PDAC cell lines through live single-cell imaging. Our observations revealed that TNFα stimulation induces rapid, sustained, and non-oscillatory nuclear translocation of RELA. Through Bayesian analysis of single-cell datasets with variation in nuclear RELA, we predicted that RELA heterogeneity in PDAC cell lines is dependent on F-actin dynamics. RNA-seq analysis identified distinct clusters of RELA-regulated gene expression in PDAC cells, including TNFα-induced RELA upregulation of the actin regulators NUAK2 and ARHGAP31. Further, siRNA-mediated depletion of ARHGAP31 and NUAK2 altered TNFα-stimulated nuclear RELA dynamics in PDAC cells, establishing a novel negative feedback loop that regulates RELA activation by TNFα. Additionally, we characterised the NF-κB pathway in PDAC cells, identifying how NF-κB/IκB proteins genetically and physically interact with RELA in the absence or presence of TNFα. Taken together, we provide computational and experimental support for interdependence between the F-actin network and the NF-κB pathway with RELA translocation dynamics in PDAC.
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Affiliation(s)
- Francesca Butera
- Chester Beatty Laboratories, Division of Cancer Biology, Institute of Cancer ResearchLondonUnited Kingdom
| | - Julia E Sero
- Department of Life Sciences, University of BathBathUnited Kingdom
| | - Lucas G Dent
- Chester Beatty Laboratories, Division of Cancer Biology, Institute of Cancer ResearchLondonUnited Kingdom
| | - Chris Bakal
- Chester Beatty Laboratories, Division of Cancer Biology, Institute of Cancer ResearchLondonUnited Kingdom
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Thongpon P, Intuyod K, Chomwong S, Pongking T, Klungsaeng S, Muisuk K, Charoenram N, Sitthirach C, Thanan R, Pinlaor P, Pinlaor S. Curcumin synergistically enhances the efficacy of gemcitabine against gemcitabine-resistant cholangiocarcinoma via the targeting LAT2/glutamine pathway. Sci Rep 2024; 14:16059. [PMID: 38992159 PMCID: PMC11239878 DOI: 10.1038/s41598-024-66945-7] [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: 11/25/2023] [Accepted: 07/05/2024] [Indexed: 07/13/2024] Open
Abstract
Cholangiocarcinoma (CCA) is often diagnosed late, leading to incomplete tumor removal, drug resistance and reduced chemotherapy efficacy. Curcumin has the potential for anti-cancer activity through various therapeutic properties and can improve the efficacy of chemotherapy. We aimed to investigate the synergistic effect of a combination of curcumin and gemcitabine against CCA, targeting the LAT2/glutamine pathway. This combination synergistically suppressed proliferation in gemcitabine-resistant CCA cells (KKU-213BGemR). It also resulted in a remarkable degree of CCA cell apoptosis and cell cycle arrest, characterized by a high proportion of cells in the S and G2/M phases. Knockdown of SLC7A8 decreased the expressions of glutaminase and glutamine synthetase, resulting in inhibited cell proliferation and sensitized CCA cells to gemcitabine treatment. Moreover, in vivo experiments showed that a combination curcumin and gemcitabine significantly reduced tumor size, tumor growth rate and LAT2 expression in a gemcitabine-resistant CCA xenograft mouse model. Suppression of tumor progression in an orthotopic CCA hamster model provided strong support for clinical application. In conclusion, curcumin synergistically enhances gemcitabine efficacy against gemcitabine-resistant CCA by induction of apoptosis, partly via inhibiting LAT2/glutamine pathway. This approach may be an alternative strategy for the treatment of gemcitabine-resistant in CCA patients.
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Affiliation(s)
- Phonpilas Thongpon
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Kitti Intuyod
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Sasitorn Chomwong
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Thatsanapong Pongking
- Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Sirinapha Klungsaeng
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Kanha Muisuk
- Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Naruechar Charoenram
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Chutima Sitthirach
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Raynoo Thanan
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Porntip Pinlaor
- Centre for Research and Development in Medical Diagnostic Laboratory, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.
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Zhai LL, Li WB, Chen LJ, Wang W, Ju TF, Yin DL. Curcumin inhibits the invasion and migration of pancreatic cancer cells by upregulating TFPI-2 to regulate ERK- and JNK-mediated epithelial-mesenchymal transition. Eur J Nutr 2024; 63:639-651. [PMID: 38129361 DOI: 10.1007/s00394-023-03296-5] [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: 04/29/2023] [Accepted: 11/28/2023] [Indexed: 12/23/2023]
Abstract
PURPOSE Pancreatic cancer (PC) is one of the most deadly human malignancies. Curcumin is a natural polyphenolic compound with wide-ranging pharmacological effects. Growing evidence suggests that curcumin has anticancer activity against PC, but the mechanism remains incompletely elucidated. This study aimed to investigate the effects and mechanisms of curcumin on the invasion and migration of PC cells. METHODS Effect of curcumin on tissue factor pathway inhibitor (TFPI)-2 mRNA expression in PC cells was initially identified using qRT-PCR. Cytotoxicity of curcumin was assessed with MTT assays and IC50 was calculated. Involvement of ERK and JNK pathways, as well as protein expression of TFPI-2 and epithelial-mesenchymal transition (EMT)-related markers, were detected using immunoblotting. Invasion and migration of PC cells were examined using Transwell assays. TFPI-2 expression was manipulated by transfection with siRNA and shRNA. Rescue assays were used to validate the effect of curcumin on cell invasion and migration via TFPI-2. RESULTS Curcumin increased the expression of TFPI-2 mRNA and protein in PC cells and attenuated cell invasion and migration. Curcumin also inhibited ERK and JNK pathways and EMT in PC cells. Knockdown of TFPI-2 partially reversed the inhibition of ERK and JNK pathways and EMT by curcumin. Mechanistically, curcumin upregulated TFPI-2, thereby inhibiting the ERK and JNK pathways, leading to the inhibition of EMT in PC cells. CONCLUSION Collectively, curcumin inhibits ERK- and JNK-mediated EMT through upregulating TFPI-2, which in turn suppresses the migration and invasion of PC cells. These findings provide new insights into the antitumor mechanism of curcumin.
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Affiliation(s)
- Lu-Lu Zhai
- Department of General Surgery, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, People's Republic of China
- Department of General Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 Huansha Road, Hangzhou, 310006, People's Republic of China
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, People's Republic of China
| | - Wei-Bo Li
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, People's Republic of China
| | - Long-Jiang Chen
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, People's Republic of China
| | - Wei Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, People's Republic of China
| | - Tong-Fa Ju
- Department of General Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 Huansha Road, Hangzhou, 310006, People's Republic of China.
| | - Da-Long Yin
- Department of General Surgery, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, People's Republic of China.
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Uehara M, Domoto T, Takenaka S, Takeuchi O, Shimasaki T, Miyashita T, Minamoto T. Glycogen synthase kinase 3β: the nexus of chemoresistance, invasive capacity, and cancer stemness in pancreatic cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:4. [PMID: 38318525 PMCID: PMC10838383 DOI: 10.20517/cdr.2023.84] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 12/20/2023] [Accepted: 01/17/2024] [Indexed: 02/07/2024]
Abstract
The treatment of pancreatic cancer remains a significant clinical challenge due to the limited number of patients eligible for curative (R0) surgery, failures in the clinical development of targeted and immune therapies, and the pervasive acquisition of chemotherapeutic resistance. Refractory pancreatic cancer is typified by high invasiveness and resistance to therapy, with both attributes related to tumor cell stemness. These malignant characteristics mutually enhance each other, leading to rapid cancer progression. Over the past two decades, numerous studies have produced evidence of the pivotal role of glycogen synthase kinase (GSK)3β in the progression of over 25 different cancer types, including pancreatic cancer. In this review, we synthesize the current knowledge on the pathological roles of aberrant GSK3β in supporting tumor cell proliferation and invasion, as well as its contribution to gemcitabine resistance in pancreatic cancer. Importantly, we discuss the central role of GSK3β as a molecular hub that mechanistically connects chemoresistance, tumor cell invasion, and stemness in pancreatic cancer. We also discuss the involvement of GSK3β in the formation of desmoplastic tumor stroma and in promoting anti-cancer immune evasion, both of which constitute major obstacles to successful cancer treatment. Overall, GSK3β has characteristics of a promising therapeutic target to overcome chemoresistance in pancreatic cancer.
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Affiliation(s)
- Masahiro Uehara
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan
- Authors contributed equally
| | - Takahiro Domoto
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan
- Authors contributed equally
| | - Satoshi Takenaka
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
- Department of Surgery, Toyama City Hospital, Toyama 939-8511, Japan
| | - Osamu Takeuchi
- Biomedical Laboratory, Department of Research, Kitasato University Kitasato Institute Hospital, Tokyo 108-8642, Japan
| | - Takeo Shimasaki
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan
- Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan
| | - Tomoharu Miyashita
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
- Department of Surgery, Toyama City Hospital, Toyama 939-8511, Japan
| | - Toshinari Minamoto
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan
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Gudarzi R, Shabani F, Mohammad-Alizadeh-Charandabi S, Naghshineh E, Shaseb E, Mirghafourvand M. Effect of curcumin on painful symptoms of endometriosis: A triple-blind randomized controlled trial. Phytother Res 2024; 38:147-155. [PMID: 37818734 DOI: 10.1002/ptr.8030] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 09/18/2023] [Accepted: 09/22/2023] [Indexed: 10/13/2023]
Abstract
Endometriosis is one of the most common gynecological disorders. This study aimed to determine the effect of curcumin on painful symptoms of endometriosis and the quality of life in affected women. This randomized controlled trial was conducted on 68 women with endometriosis referred to Shahid Beheshti Infertility Center in Isfahan, Iran, 2022. The participants were allocated to intervention (n = 34) and control (n = 34) groups by the blocked randomization method. Curcumin capsules with a dose of 500 mg were given to the intervention group twice a day for 8 weeks, and the placebo with the same dose was given to the control group. The questionnaires of Endometriosis Health Profile, painful symptoms of endometriosis, and visual analogue scale were used to collect data. Independent t, ANCOVA, and Mann-Whitney U-tests were used to compare the outcomes between the study groups. After the intervention, based on the ANCOVA with the adjusting of the baseline values and Mann-Whitney U-test, there was no statistically significant difference in the amounts of usual pain (p = 0.496) and pain at its worst (p = 0.320), quality of life (p = 0.556), and visual pain (p = 0.845). The results showed that using curcumin does not affect the painful symptoms and quality of life of women with endometriosis. Future clinical trials are needed to investigate and highlight the role of curcumin in endometriosis.
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Affiliation(s)
- Reyhaneh Gudarzi
- Department of Midwifery, Student Research Committee, Faculty of Nursing and Midwifery, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Shabani
- Midwifery Department, Faculty of Nursing and Midwifery, Tabriz University of medical Sciences, Tabriz, Iran
| | | | - Elham Naghshineh
- Department of Obstetrics and Gynecology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Elnaz Shaseb
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mojgan Mirghafourvand
- Social Determinants of Health Research Center, Faculty of Nursing and Midwifery, Tabriz University of Medical Sciences, Tabriz, Iran
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10
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Fatima F, Chourasiya NK, Mishra M, Kori S, Pathak S, Das R, Kashaw V, Iyer AK, Kashaw SK. Curcumin and its Derivatives Targeting Multiple Signaling Pathways to Elicit Anticancer Activity: A Comprehensive Perspective. Curr Med Chem 2024; 31:3668-3714. [PMID: 37221681 DOI: 10.2174/0929867330666230522144312] [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: 12/04/2022] [Revised: 03/23/2023] [Accepted: 04/07/2023] [Indexed: 05/25/2023]
Abstract
The uncontrolled growth and spread of aberrant cells characterize the group of disorders known as cancer. According to GLOBOCAN 2022 analysis of cancer patients in either developed countries or developing countries the main concern cancers are breast cancer, lung cancer, and liver cancer which may rise eventually. Natural substances with dietary origins have gained interest for their low toxicity, anti-inflammatory, and antioxidant effects. The evaluation of dietary natural products as chemopreventive and therapeutic agents, the identification, characterization, and synthesis of their active components, as well as the enhancement of their delivery and bioavailability, have all received significant attention. Thus, the treatment strategy for concerning cancers must be significantly evaluated and may include the use of phytochemicals in daily lifestyle. In the present perspective, we discussed one of the potent phytochemicals, that has been used over the past few decades known as curcumin as a panacea drug of the "Cure-all" therapy concept. In our review firstly we included exhausted data from in vivo and in vitro studies on breast cancer, lung cancer, and liver cancer which act through various cancer-targeting pathways at the molecular level. Now, the second is the active constituent of turmeric known as curcumin and its derivatives are enlisted with their targeted protein in the molecular docking studies, which help the researchers design and synthesize new curcumin derivatives with respective implicated molecular and cellular activity. However, curcumin and its substituted derivatives still need to be investigated with unknown targeting mechanism studies in depth.
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Affiliation(s)
- Firdous Fatima
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Nikhil Kumar Chourasiya
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Mitali Mishra
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivam Kori
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Sandhya Pathak
- Department of Chemistry, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Varsha Kashaw
- Sagar Institute of Pharmaceutical Sciences, Sagar (M.P.), India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
- Molecular Imaging Program, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Sushil Kumar Kashaw
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
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11
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Singh K, Adhikari B, Low J, Brennan MA, Newman L, Brennan CS, Utama-Ang N. Development, characterization, and consumer acceptance evaluation of thermally stable capsule beads containing mixed extracts of green tea and turmeric. Sci Rep 2023; 13:19299. [PMID: 37935858 PMCID: PMC10630281 DOI: 10.1038/s41598-023-46339-x] [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: 07/18/2023] [Accepted: 10/31/2023] [Indexed: 11/09/2023] Open
Abstract
The aim of this study was to investigate the ability of shell (coating) formulations comprised of alginate and glucono delta lactone (GDL) to encapsulate a mixture of green tea and turmeric extracts. Three concentrations of alginate and GDL were used at 0.5%, 0.75%, and 1%, w/v and their solid ratio was varied using a factorial design. A response surface model was applied to optimize the retention of catechin and curcuminoid contents, to determine encapsulation efficiency, and to minimize undesirable flavor and taste. Increasing the concentration of alginate and GDL significantly increased the retention of catechin and curcuminoid contents, encapsulation efficiency, and consumer acceptance (p < 0.05). The encapsulating solution containing 1% of each alginate and GDL performed the best against each criterion. The thermal treatment carried out at the boiling point of water for 15 min had a significant impact on the retention of catechin and curcuminoid content which, in the thermally-treated beads, was 5.15 and 3.85 times higher than unencapsulated, respectively. The consumer acceptance of the encapsulated beads after thermal treatment was higher than that of the unencapsulated formulations as they exhibited lesser pungent flavor and bitterness. The innovative process of thermally stable microencapsulation can produce anti-cancer activity compounds involved in functional food industrial sectors.
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Affiliation(s)
- Kanjana Singh
- Division of Product Development Technology, Faculty of Agro-Industry, Chiang Mai University, Chiang Mai, 50100, Thailand
- School of Science, RMIT University, Melbourne, VIC, 3083, Australia
| | - Benu Adhikari
- School of Science, RMIT University, Melbourne, VIC, 3083, Australia
| | - Julia Low
- School of Science, RMIT University, Melbourne, VIC, 3083, Australia
| | | | - Lisa Newman
- School of Science, RMIT University, Melbourne, VIC, 3083, Australia
| | | | - Niramon Utama-Ang
- Division of Product Development Technology, Faculty of Agro-Industry, Chiang Mai University, Chiang Mai, 50100, Thailand.
- Cluster of High Value Products From Thai Rice and Plants for Health, Faculty of Agro-Industry, Chiang Mai University, Chiang Mai, 50100, Thailand.
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12
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Chen SY, Kokalari I, Parnell SR, Smith GN, Zeng BH, Way TF, Chuang FS, Rwei AY. Structure Property Relationship of Micellar Waterborne Poly(Urethane-Urea): Tunable Mechanical Properties and Controlled Release Profiles with Amphiphilic Triblock Copolymers. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2023. [PMID: 37433143 PMCID: PMC10373496 DOI: 10.1021/acs.langmuir.3c00921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/13/2023]
Abstract
Waterborne polyurethane (WPU) has attracted significant interest as a promising alternative to solvent-based polyurethane (SPU) due to its positive impact on safety and sustainability. However, significant limitations of WPU, such as its weaker mechanical strength, limit its ability to replace SPU. Triblock amphiphilic diols are promising materials to enhance the performance of WPU due to their well-defined hydrophobic-hydrophilic structures. Yet, our understanding of the relationship between the hydrophobic-hydrophilic arrangements of triblock amphiphilic diols and the physical properties of WPU remains limited. In this study, we show that by controlling the micellar structure of WPU in aqueous solution via the introduction of triblock amphiphilic diols, the postcuring efficiency and the resulting mechanical strength of WPU can be significantly enhanced. Small-angle neutron scattering confirmed the microstructure and spatial distribution of hydrophilic and hydrophobic segments in the engineered WPU micelles. In addition, we show that the control of the WPU micellar structure through triblock amphiphilic diols renders WPU attractive in the applications of controlled release, such as drug delivery. Here, curcumin was used as a model hydrophobic drug, and the drug release behavior from WPU-micellar-based drug delivery systems was characterized. It was found that curcumin-loaded WPU drug delivery systems were highly biocompatible and exhibited antibacterial properties in vitro. Furthermore, the sustained release profile of the drug was found to be dependent on the structure of the triblock amphiphilic diols, suggesting the possibility of controlling the drug release profile via the selection of triblock amphiphilic diols. This work shows that by shedding light on the structure-property relationship of triblock amphiphilic diol-containing WPU micelles, we may enhance the applicability of WPU systems and move closer to realizing their promising potential in real-life applications.
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Affiliation(s)
- Shu-Yi Chen
- Department of Chemical Engineering, Delft University of Technology, 2629 HZ Delft, The Netherlands
- Institute of Organic and Polymeric Materials, National Taipei University of Technology, 10608 Taipei, Taiwan
- Research and Development Center for Smart Textile Technology, National Taipei University of Technology, 10608 Taipei, Taiwan
| | - Ida Kokalari
- Department of Chemical Engineering, Delft University of Technology, 2629 HZ Delft, The Netherlands
| | - Steven R Parnell
- Department of Radiation Science and Technology, Delft University of Technology, 2629 HZ Delft, The Netherlands
| | | | - Bing-Hong Zeng
- Institute of Organic and Polymeric Materials, National Taipei University of Technology, 10608 Taipei, Taiwan
- Research and Development Center for Smart Textile Technology, National Taipei University of Technology, 10608 Taipei, Taiwan
| | - Tun-Fun Way
- Institute of Organic and Polymeric Materials, National Taipei University of Technology, 10608 Taipei, Taiwan
- Research and Development Center for Smart Textile Technology, National Taipei University of Technology, 10608 Taipei, Taiwan
| | - Fu-Sheng Chuang
- Institute of Organic and Polymeric Materials, National Taipei University of Technology, 10608 Taipei, Taiwan
- Research and Development Center for Smart Textile Technology, National Taipei University of Technology, 10608 Taipei, Taiwan
- Department of Fashion and Design, Lee-Ming Institute of Technology, No. 22, Sec. 3, Tai-Lin Rd., Taishan Dist., New Taipei City 243, Taiwan
| | - Alina Y Rwei
- Department of Chemical Engineering, Delft University of Technology, 2629 HZ Delft, The Netherlands
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13
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Sahin TK, Bilir B, Kucuk O. Modulation of inflammation by phytochemicals to enhance efficacy and reduce toxicity of cancer chemotherapy. Crit Rev Food Sci Nutr 2023; 63:2494-2508. [DOI: https:/doi.org/10.1080/10408398.2021.1976721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- Taha Koray Sahin
- Department of Internal Medicine, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Birdal Bilir
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Omer Kucuk
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
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14
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Svolacchia F, Brongo S, Catalano A, Ceccarini A, Svolacchia L, Santarsiere A, Scieuzo C, Salvia R, Finelli F, Milella L, Saturnino C, Sinicropi MS, Fabrizio T, Giuzio F. Natural Products for the Prevention, Treatment and Progression of Breast Cancer. Cancers (Basel) 2023; 15:cancers15112981. [PMID: 37296944 DOI: 10.3390/cancers15112981] [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: 05/01/2023] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
In this review, we summarize the most used natural products as useful adjuvants in BC by clarifying how these products may play a critical role in the prevention, treatment and progression of this disease. BC is the leading cancer, in terms of incidence, that affects women. The epidemiology and pathophysiology of BC were widely reported. Inflammation and cancer are known to influence each other in several tumors. In the case of BC, the inflammatory component precedes the development of the neoplasm through a slowly increasing and prolonged inflammation that also favors its growth. BC therapy involves a multidisciplinary approach comprising surgery, radiotherapy and chemotherapy. There are numerous observations that showed that the effects of some natural substances, which, in integration with the classic protocols, can be used not only for prevention or integration in order to prevent recurrences and induce a state of chemoquiescence but also as chemo- and radiosensitizers during classic therapy.
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Affiliation(s)
- Fabiano Svolacchia
- Department of Medical-Surgical Sciences and Biotechnologies, La Sapienza University, 00118 Rome, Italy
- Department of Medical Sciences, Policlinic Foundation Tor Vergata University, 00133 Rome, Italy
| | - Sergio Brongo
- Department of Plastic Surgery, University of Salerno, 84131 Campania, Italy
| | - Alessia Catalano
- Department of Pharmacy-Drug Sciences, University of Bari "Aldo Moro", 70126 Bari, Italy
| | - Agostino Ceccarini
- U.O.C. Primary Care and Territorial Health, Social and Health Department, State Hospital, 47893 San Marino, San Marino
| | - Lorenzo Svolacchia
- Department of Medical-Surgical Sciences and Biotechnologies, La Sapienza University, 00118 Rome, Italy
| | - Alessandro Santarsiere
- Department of Science, University of Basilicata, 85100 Potenza, Italy
- CNRS, UMR 7042-LIMA, ECPM, Université de Strasbourg, Université de Haute-Alsace, 67000 Strasbourg, France
| | - Carmen Scieuzo
- Department of Science, University of Basilicata, 85100 Potenza, Italy
- Spinoff XFlies s.r.l., University of Basilicata, 85100 Potenza, Italy
| | - Rosanna Salvia
- Department of Science, University of Basilicata, 85100 Potenza, Italy
- Spinoff XFlies s.r.l., University of Basilicata, 85100 Potenza, Italy
| | | | - Luigi Milella
- Department of Science, University of Basilicata, 85100 Potenza, Italy
| | - Carmela Saturnino
- Department of Science, University of Basilicata, 85100 Potenza, Italy
| | - Maria Stefania Sinicropi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Tommaso Fabrizio
- Department of Plastic Surgery, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy
| | - Federica Giuzio
- U.O.C. Primary Care and Territorial Health, Social and Health Department, State Hospital, 47893 San Marino, San Marino
- Department of Science, University of Basilicata, 85100 Potenza, Italy
- Spinoff TNcKILLERS s.r.l., University of Basilicata, 85100 Potenza, Italy
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15
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Pouliquen DL, Trošelj KG, Anto RJ. Curcuminoids as Anticancer Drugs: Pleiotropic Effects, Potential for Metabolic Reprogramming and Prospects for the Future. Pharmaceutics 2023; 15:1612. [PMID: 37376060 DOI: 10.3390/pharmaceutics15061612] [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: 04/28/2023] [Revised: 05/21/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
The number of published studies on curcuminoids in cancer research, including its lead molecule curcumin and synthetic analogs, has been increasing substantially during the past two decades. Insights on the diversity of inhibitory effects they have produced on a multitude of pathways involved in carcinogenesis and tumor progression have been provided. As this wealth of data was obtained in settings of various experimental and clinical data, this review first aimed at presenting a chronology of discoveries and an update on their complex in vivo effects. Secondly, there are many interesting questions linked to their pleiotropic effects. One of them, a growing research topic, relates to their ability to modulate metabolic reprogramming. This review will also cover the use of curcuminoids as chemosensitizing molecules that can be combined with several anticancer drugs to reverse the phenomenon of multidrug resistance. Finally, current investigations in these three complementary research fields raise several important questions that will be put among the prospects for the future research related to the importance of these molecules in cancer research.
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Affiliation(s)
- Daniel L Pouliquen
- Université d'Angers, Inserm, CNRS, Nantes Université, CRCI2NA, F-49000 Angers, France
| | - Koraljka Gall Trošelj
- Laboratory for Epigenomics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Ruby John Anto
- Molecular Bioassay Laboratory, Institute of Advanced Virology, Thiruvananthapuram 695317, India
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16
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Fang YT, Yang WW, Niu YR, Sun YK. Recent advances in targeted therapy for pancreatic adenocarcinoma. World J Gastrointest Oncol 2023; 15:571-595. [PMID: 37123059 PMCID: PMC10134207 DOI: 10.4251/wjgo.v15.i4.571] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/11/2022] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%–90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC – erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.
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Affiliation(s)
- Yu-Ting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ya-Ru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang 065001, Hebei Province, China
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17
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Sulforaphane Potentiates Gemcitabine-Mediated Anti-Cancer Effects against Intrahepatic Cholangiocarcinoma by Inhibiting HDAC Activity. Cells 2023; 12:cells12050687. [PMID: 36899823 PMCID: PMC10000472 DOI: 10.3390/cells12050687] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/19/2023] [Accepted: 02/20/2023] [Indexed: 02/24/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver cancer, has high mortality rates because of its limited treatment options and acquired resistance to chemotherapy. Sulforaphane (SFN), a naturally occurring organosulfur compound found in cruciferous vegetables, exhibits multiple therapeutic properties, such as histone deacetylase (HDAC) inhibition and anti-cancer effects. This study assessed the effects of the combination of SFN and gemcitabine (GEM) on human iCCA cell growth. HuCCT-1 and HuH28 cells, representing moderately differentiated and undifferentiated iCCA, respectively, were treated with SFN and/or GEM. SFN concentration dependently reduced total HDAC activity and promoted total histone H3 acetylation in both iCCA cell lines. SFN synergistically augmented the GEM-mediated attenuation of cell viability and proliferation by inducing G2/M cell cycle arrest and apoptosis in both cell lines, as indicated by the cleavage of caspase-3. SFN also inhibited cancer cell invasion and decreased the expression of pro-angiogenic markers (VEGFA, VEGFR2, HIF-1α, and eNOS) in both iCCA cell lines. Notably, SFN effectively inhibited the GEM-mediated induction of epithelial-mesenchymal transition (EMT). A xenograft assay demonstrated that SFN and GEM substantially attenuated human iCCA cell-derived tumor growth with decreased Ki67+ proliferative cells and increased TUNEL+ apoptotic cells. The anti-cancer effects of every single agent were markedly augmented by concomitant use. Consistent with the results of in vitro cell cycle analysis, G2/M arrest was indicated by increased p21 and p-Chk2 expression and decreased p-Cdc25C expression in the tumors of SFN- and GEM-treated mice. Moreover, treatment with SFN inhibited CD34-positive neovascularization with decreased VEGF expression and GEM-induced EMT in iCCA-derived xenografted tumors. In conclusion, these results suggest that combination therapy with SFN with GEM is a potential novel option for iCCA treatment.
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18
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Abstract
C-Myc overexpression is a common finding in pancreatic cancer and predicts the aggressive behavior of cancer cells. It binds to the promoter of different genes, thereby regulating their transcription. C-Myc is downstream of KRAS and interacts with several oncogenic and proliferative pathways in pancreatic cancer. C-Myc enhances aerobic glycolysis in cancer cells and regulates glutamate biosynthesis from glutamine. It provides enough energy for cancer cells' metabolism and sufficient substrate for the synthesis of organic molecules. C-Myc overexpression is associated with chemoresistance, intra-tumor angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis in pancreatic cancer. Despite its title, c-Myc is not "undruggable" and recent studies unveiled that it can be targeted, directly or indirectly. Small molecules that accelerate c-Myc ubiquitination and degradation have been effective in preclinical studies. Small molecules that hinder c-Myc-MAX heterodimerization or c-Myc/MAX/DNA complex formation can functionally inhibit c-Myc. In addition, c-Myc can be targeted through transcriptional, post-transcriptional, and translational modifications.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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19
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Abe T, Horisawa Y, Kikuchi O, Ozawa-Umeta H, Kishimoto A, Katsuura Y, Imaizumi A, Hashimoto T, Shirakawa K, Takaori-Kondo A, Yusa K, Asakura T, Kakeya H, Kanai M. Pharmacologic characterization of TBP1901, a prodrug form of aglycone curcumin, and CRISPR-Cas9 screen for therapeutic targets of aglycone curcumin. Eur J Pharmacol 2022; 935:175321. [PMID: 36228744 DOI: 10.1016/j.ejphar.2022.175321] [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: 04/25/2022] [Revised: 10/04/2022] [Accepted: 10/05/2022] [Indexed: 11/16/2022]
Abstract
Curcumin (aglycone curcumin) has antitumor properties in a variety of malignancies via the alteration of multiple cancer-related biological pathways; however, its clinical application has been hampered due to its poor bioavailability. To overcome this limitation, we have developed a synthesized curcumin β-D-glucuronide sodium salt (TBP1901), a prodrug form of aglycone curcumin. In this study, we aimed to clarify the pharmacologic characteristics of TBP1901. In β-glucuronidase (GUSB)-proficient mice, both curcumin β-D-glucuronide and its active metabolite, aglycone curcumin, were detected in the blood after TBP1901 injection, whereas only curcumin β-D-glucuronide was detected in GUSB-impaired mice, suggesting that GUSB plays a pivotal role in the conversion of TBP1901 into aglycone curcumin in vivo. TBP1901 itself had minimal antitumor effects in vitro, whereas it demonstrated significant antitumor effects in vivo. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screen disclosed the genes associated with NF-κB signaling pathway and mitochondria were among the highest hit. In vitro, aglycone curcumin inhibited NF-kappa B signaling pathways whereas it caused production of reactive oxygen species (ROS). ROS scavenger, N-acetyl-L-cysteine, partially reversed antitumor effects of aglycone curcumin. In summary, TBP1901 can exert antitumor effects as a prodrug of aglycone curcumin through GUSB-dependent activation.
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Affiliation(s)
| | - Yoshihito Horisawa
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Osamu Kikuchi
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | | | | | | | | | - Kotaro Shirakawa
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Akifumi Takaori-Kondo
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kosuke Yusa
- Stem Cell Genetics, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Tadashi Asakura
- Radioisotope Research Facilities, Jikei University School of Medicine, Tokyo, Japan
| | - Hideaki Kakeya
- Department of System Chemotherapy and Molecular Sciences, Division of Medicinal Frontier Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
| | - Masashi Kanai
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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20
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Dual-drug loaded nanomedicine hydrogel as a therapeutic platform to target both residual glioblastoma and glioma stem cells. Int J Pharm 2022; 628:122341. [DOI: 10.1016/j.ijpharm.2022.122341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 10/19/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022]
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21
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Sharma P, Kumar D, Shri R, Kumar S. Mechanistic Insights and Docking Studies of Phytomolecules as Potential Candidates in the Management of Cancer. Curr Pharm Des 2022; 28:2704-2724. [PMID: 35473540 DOI: 10.2174/1381612828666220426112116] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/09/2022] [Indexed: 12/16/2022]
Abstract
BACKGROUND Cancer is a leading risk of death globally. According to the World Health Organization, it is presently the second most important disease that causes death in both developing and developed countries. Remarkable progress has been made in the war against cancer with the development of numerous novel chemotherapy agents. However, it remains an immense challenge to discover new efficient therapeutic potential candidates to combat cancer. OBJECTIVES The majority of the currently used anticancer drugs are of natural origins, such as curcumin, colchicine, vinca alkaloid, paclitaxel, bergenin, taxols, and combretastatin. Concerning this, this review article presents the structure of the most potent molecules along with IC50 values, structure-activity relationships, mechanistic studies, docking studies, in silico studies of phytomolecules, and important key findings on human cancer cell lines. METHODS A viewpoint of drug design and development of antiproliferative agents from natural phytomolecules has been established by searching peer-reviewed literature from Google Scholar, PubMed, Scopus, Springer, Science Direct, and Web of Science over the past few years. RESULTS Our analysis revealed that this article would assist chemical biologists and medicinal chemists in industry and academia in gaining insights into the anticancer potential of phytomolecules. CONCLUSION In vitro and in silico studies present phytomolecules, such as curcumin, colchicine, vinca alkaloids, colchicine, bergenin, combretastatin, and taxol encompassing anticancer agents, offerings abundant sanguinity and capacity in the arena of drug discovery to inspire the investigators towards the continual investigations on these phytomolecules. It is extremely expected that efforts in this track will strengthen and grant some budding cancer therapeutics candidates in the near future.
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Affiliation(s)
- Pooja Sharma
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, Punjab, India.,Khalsa College of Pharmacy, Amritsar-143001, Punjab, India
| | - Dinesh Kumar
- Department of Pharmaceutical Sciences, Sri Sai College of Pharmacy, Manawala, Amritsar-143115, Punjab, India
| | - Richa Shri
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, Punjab, India
| | - Suresh Kumar
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, Punjab, India
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22
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Talib WH, Awajan D, Hamed RA, Azzam AO, Mahmod AI, AL-Yasari IH. Combination Anticancer Therapies Using Selected Phytochemicals. Molecules 2022; 27:5452. [PMID: 36080219 PMCID: PMC9458090 DOI: 10.3390/molecules27175452] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/17/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer is still one of the most widespread diseases globally, it is considered a vital health challenge worldwide and one of the main barriers to long life expectancy. Due to the potential toxicity and lack of selectivity of conventional chemotherapeutic agents, discovering alternative treatments is a top priority. Plant-derived natural products have high potential in cancer treatment due to their multiple mechanisms of action, diversity in structure, availability in nature, and relatively low toxicity. In this review, the anticancer mechanisms of the most common phytochemicals were analyzed. Furthermore, a detailed discussion of the anticancer effect of combinations consisting of natural product or natural products with chemotherapeutic drugs was provided. This review should provide a strong platform for researchers and clinicians to improve basic and clinical research in the development of alternative anticancer medicines.
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Affiliation(s)
- Wamidh H. Talib
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan
| | - Dima Awajan
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan
| | - Reem Ali Hamed
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan
| | - Aya O. Azzam
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan
| | - Asma Ismail Mahmod
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan
| | - Intisar Hadi AL-Yasari
- Department of Genetic Engineering, College of Biotechnology, Al-Qasim Green University, Babylon 964, Iraq
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Huang Q, Zhang Y, Zheng Y, Yang H, Yang Y, Mo Y, Li L, Zhang H. Molecular Mechanism of Curcumin and Its Analogs as Multifunctional Compounds against Pancreatic Cancer. Nutr Cancer 2022; 74:3096-3108. [PMID: 35583289 DOI: 10.1080/01635581.2022.2071451] [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: 07/06/2021] [Revised: 03/30/2022] [Accepted: 04/25/2022] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer (PC) is one of the most common malignant tumors with a poor prognosis and high mortality. Surgical resection is the most effective treatment for PC; however, only a minority of patients have resectable tumors. Chemotherapy is the primary treatment for PC. Curcumin is a natural chemical substance obtained from plants with a wide range of pharmacological activities. Research evidence suggests that curcumin can influence PC development through multiple molecular mechanisms. The synthesis of novel curcumin analogs and preparation of curcumin nano-formulations are effective strategies to overcome the low bioavailability of curcumin in the treatment of PC. This review aims to summarize the mechanisms of action of curcumin in preclinical and clinical studies on PC and research progress in enhancing its bioavailability.
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Affiliation(s)
- Qun Huang
- Department of Ophthalmology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ya Zhang
- Endocrinology Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanlin Zheng
- Department of Ophthalmology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hongjing Yang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yang Yang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ya Mo
- Department of Ophthalmology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Liuying Li
- Department of Integrated Chinese and Western Medicine, The First People's Hospital of Zigong City, Zigong, China
| | - Hong Zhang
- Emergency Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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24
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Mohammadi A, Khanbabaei H, Zandi F, Ahmadi A, Haftcheshmeh SM, Johnston TP, Sahebkar A. Curcumin: A therapeutic strategy for targeting the Helicobacter pylori-related diseases. Microb Pathog 2022; 166:105552. [DOI: 10.1016/j.micpath.2022.105552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 04/16/2022] [Accepted: 04/19/2022] [Indexed: 12/12/2022]
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Homayoonfal M, Asemi Z, Yousefi B. Potential anticancer properties and mechanisms of thymoquinone in osteosarcoma and bone metastasis. Cell Mol Biol Lett 2022; 27:21. [PMID: 35236304 PMCID: PMC8903697 DOI: 10.1186/s11658-022-00320-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 02/08/2022] [Indexed: 12/14/2022] Open
Abstract
Despite great advances, therapeutic approaches of osteosarcoma, the most prevalent class of preliminary pediatric bone tumors, as well as bone-related malignancies, continue to demonstrate insufficient adequacy. In recent years, a growing trend toward applying natural bioactive compounds, particularly phytochemicals, as novel agents for cancer treatment has been observed. Bioactive phytochemicals exert their anticancer features through two main ways: they induce cytotoxic effects against cancerous cells without having any detrimental impact on normal cell macromolecules such as DNA and enzymes, while at the same time combating the oncogenic signaling axis activated in tumor cells. Thymoquinone (TQ), the most abundant bioactive compound of Nigella sativa, has received considerable attention in cancer treatment owing to its distinctive properties, including apoptosis induction, cell cycle arrest, angiogenesis and metastasis inhibition, and reactive oxygen species (ROS) generation, along with inducing immune system responses and reducing side effects of traditional chemotherapeutic drugs. The present review is focused on the characteristics and mechanisms by which TQ exerts its cytotoxic effects on bone malignancies.
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Affiliation(s)
- Mina Homayoonfal
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Ueda G, Matsuo Y, Murase H, Aoyama Y, Kato T, Omi K, Hayashi Y, Imafuji H, Saito K, Tsuboi K, Morimoto M, Ogawa R, Takahashi H, Mitsui A, Kimura M, Takiguchi S. 10Z‑Hymenialdisine inhibits angiogenesis by suppressing NF‑κB activation in pancreatic cancer cell lines. Oncol Rep 2022; 47:48. [PMID: 35014682 PMCID: PMC8771196 DOI: 10.3892/or.2022.8259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 12/08/2021] [Indexed: 12/24/2022] Open
Abstract
10Z-Hymenialdisine is a natural product derived from the marine sponge Axinella carteri. 10Z-Hymenialdisine has anti-inflammatory effects exerted through NF-κB; however, it is unclear whether 10Z-Hymenialdisine has anti-angiogenic effects in cancer cells. In the present study, both the anti-angiogenic and antimetastatic effects of this compound in pancreatic cancer were investigated. It was initially confirmed that 10Z-Hymenialdisine significantly inhibited the proliferation of pancreatic cancer cells. Next, using both reverse transcription-quantitative PCR and ELISA, it was demonstrated that 10Z-Hymenialdisine significantly suppressed the expression of VEGF and IL-8 mRNAs and proteins in pancreatic cancer. Immunohistochemical analysis revealed that 10Z-Hymenialdisine inhibited NF-κB activity in pancreatic cancer cell lines. It was also identified that 10Z-Hymenialdisine inhibited tube formation in EA.hy926 cells. In vivo, 10Z-Hymenialdisine significantly inhibited the growth of BxPC-3 pancreatic cancer cells that were subcutaneously injected into model mice. In conclusion, the present study demonstrated that 10Z-Hymenialdisine exerted anti-angiogenic effects by suppressing NF-κB activity and angiogenic factors, such as VEGF and IL-8, in pancreatic cancer cell lines. 10Z-Hymenialdisine has potential applications as a novel therapeutic agent for the treatment of pancreatic cancer.
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Affiliation(s)
- Goro Ueda
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Yoichi Matsuo
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Hiromichi Murase
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Yoshinaga Aoyama
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Tomokatsu Kato
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Kan Omi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Yuichi Hayashi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Hiroyuki Imafuji
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Kenta Saito
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Ken Tsuboi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Mamoru Morimoto
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Ryo Ogawa
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Hiroki Takahashi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
| | - Akira Mitsui
- Department of Gastroenterological Surgery, Nagoya City University West Medical Center, Kita‑ku, Nagoya, Aichi 462-8508, Japan
| | - Masahiro Kimura
- Department of Gastrointestinal Surgery, Nagoya City East Medical Center, Chikusa‑ku, Nagoya, Aichi 464-8547, Japan
| | - Shuji Takiguchi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences and Medical School, Mizuho‑cho, Mizuho‑ku, Nagoya, Aichi 467-8601, Japan
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Lv D, Nong W, Guan Y. Edible ligand-metal-organic frameworks: Synthesis, structures, properties and applications. Coord Chem Rev 2022. [DOI: 10.1016/j.ccr.2021.214234] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Kumar A, Hegde M, Parama D, Kunnumakkara AB. Curcumin: The Golden Nutraceutical on the Road to Cancer Prevention and Therapeutics. A Clinical Perspective. Crit Rev Oncog 2022; 27:33-63. [PMID: 37183937 DOI: 10.1615/critrevoncog.2023045587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
Cancer is considered as the major public health scourge of the 21st century. Although remarkable strides were made for developing targeted therapeutics, these therapies suffer from lack of efficacy, high cost, and debilitating side effects. Therefore, the search for safe, highly efficacious, and affordable therapies is paramount for establishing a treatment regimen for this deadly disease. Curcumin, a known natural, bioactive, polyphenol compound from the spice turmeric (Curcuma longa), has been well documented for its wide range of pharmacological and biological activities. A plethora of literature indicates its potency as an anti-inflammatory and anti-cancer agent. Curcumin exhibits anti-neoplastic attributes via regulating a wide array of biological cascades involved in mutagenesis, proliferation, apoptosis, oncogene expression, tumorigenesis, and metastasis. Curcumin has shown a wide range of pleiotropic anti-proliferative effect in multiple cancers and is a known inhibitor of varied oncogenic elements, including nuclear factor kappa B (NF-κB), c-myc, cyclin D1, Bcl-2, VEGF, COX-2, NOS, tumor necrosis factor alpha (TNF-α), interleukins, and MMP-9. Further, curcumin targets different growth factor receptors and cell adhesion molecules involved in tumor growth and progression, making it a most promising nutraceutical for cancer therapy. To date, curcumin-based therapeutics have completed more than 50 clinical trials for cancer. Although creative experimentation is still elucidating the immense potential of curcumin, systematic validation by proper randomized clinical trials warrant its transition from lab to bedside. Therefore, this review summarizes the outcome of diverse clinical trials of curcumin in various cancer types.
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Affiliation(s)
- Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam-781039, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam-781039, India
| | - Dey Parama
- Cancer Biology Laboratory, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati, Assam-781039, India
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam-781039, India
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Wroński P, Wroński S, Kurant M, Malinowski B, Wiciński M. Curcumin May Prevent Basement Membrane Disassembly by Matrix Metalloproteinases and Progression of the Bladder Cancer. Nutrients 2021; 14:32. [PMID: 35010907 PMCID: PMC8746354 DOI: 10.3390/nu14010032] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/18/2021] [Accepted: 12/19/2021] [Indexed: 12/25/2022] Open
Abstract
Authors present a review of crucial mechanisms contributing to the invasion of the basement membrane (BM) of the urothelium by cancer cells and to the progression of bladder cancer (BC). The breeching of the urothelial BM, facilitated by an aberrant activation of matrix metalloproteinases (MMP) is particularly perilous. Inhibition of activation of these proteinases constitutes a logic opportunity to restrain progression. Because of limited efficacy of current therapeutic methods, the search for the development of alternative approaches constitutes "the hot spot" of modern oncology. Recent studies revealed significant anticancer potential of natural phytochemicals. Especially, curcumin has emerged as a one of the most promising phytochemicals and showed its efficacy in several human malignancies. Therefore, this article addresses experimental and clinical data indicating multi-directional inhibitory effect of curcumin on the growth of bladder cancer. We particularly concentrate on the mechanisms, by which curcumin inhibits the MMP's activities, thereby securing BM integrity and alleviating the eventual cancer invasion into the bladder muscles. Authors review the recently accumulating data, that curcumin constitutes a potent factor contributing to the more effective treatment of the bladder cancer.
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Affiliation(s)
- Paweł Wroński
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland; (P.W.); (B.M.)
- Department of Oncological Urology, The Franciszek Lukaszczyk Oncology Center, Romanowskiej 2, 85-796 Bydgoszcz, Poland
| | - Stanisław Wroński
- Department of Urology, Jan Biziel Memorial University Hospital, Ujejskiego 75, 85-168 Bydgoszcz, Poland;
| | - Marcin Kurant
- Department of Urology, District Hospital, 10 Lesna Street, 89-600 Chojnice, Poland;
| | - Bartosz Malinowski
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland; (P.W.); (B.M.)
| | - Michał Wiciński
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland; (P.W.); (B.M.)
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Xuan B, Chen YCS, Wong KC, Chen R, Lo PS, Lakerveld R, Tong HHY, Chow SF. Impact of cocrystal solution-state stability on cocrystal dissociation and polymorphic drug recrystallization during dissolution. Int J Pharm 2021; 610:121239. [PMID: 34742828 DOI: 10.1016/j.ijpharm.2021.121239] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/12/2021] [Accepted: 10/25/2021] [Indexed: 10/19/2022]
Abstract
The present study aimed to investigate how cocrystal solution-state stability may affect the polymorphic drug formation and transition during dissolution. In this work, curcumin-resorcinol (CUR-RES), curcumin-hydroquinone (CUR-HYQ) and curcumin-phloroglucinol (CUR-PHL) cocrystals were employed for dissolution studies in three buffer systems to study the effects of solvent and cocrystal thermodynamic stability. The undissolved solids were collected at designed time points and characterized by powder X-ray diffraction, differential scanning calorimetry and scanning electron microscopy. In pH 1.2 buffer, three cocrystals generated > 94% of metastable CUR form III with trace amount of stable CUR form I, while the phase purity of CUR form III recrystallized from buffers containing ethanol (EtOH) were decreased dramatically. For the same cocrystal, the cocrystal form maintained longer in the pH 1.2 buffer when compared with buffers containing EtOH. The phase purity of recrystallized CUR form III in the metastable cocrystal systems followed a linear relationship against CUR solubility, while the thermodynamically stable cocrystal resulted in a non-linear relationship. Due to different intermolecular interactions analyzed by 1H NMR, the stable cocrystal required a higher supersaturation level to precipitate pure CUR form III, in comparison to two metastable cocrystals. Our study offers important insights into mitigating the risk of recrystallization of drug polymorphs during cocrystal dissolution and demonstrates the potential use of cocrystals for drug polymorph preparation, both of which are crucial to the pharmaceutical cocrystal development and reformulation of existing drugs.
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Affiliation(s)
- Bianfei Xuan
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Yu Chee Sonia Chen
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; Department of Pharmacy, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Kong Ching Wong
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Ruipeng Chen
- Department of Chemical and Biological Engineering, The Hong Kong University of Science & Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Po Sang Lo
- Department of Chemical and Biological Engineering, The Hong Kong University of Science & Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Richard Lakerveld
- Department of Chemical and Biological Engineering, The Hong Kong University of Science & Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Henry Hoi Yee Tong
- School of Health Sciences and Sports, Macao Polytechnic Institute, Macao, China
| | - Shing Fung Chow
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Shatin, Hong Kong, China.
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Segovia-Mendoza M, García-Quiroz J, Díaz L, García-Becerra R. Combinations of Calcitriol with Anticancer Treatments for Breast Cancer: An Update. Int J Mol Sci 2021; 22:12741. [PMID: 34884550 PMCID: PMC8657847 DOI: 10.3390/ijms222312741] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/16/2021] [Accepted: 11/19/2021] [Indexed: 12/12/2022] Open
Abstract
Preclinical, clinical, and epidemiological studies indicate that vitamin D3 (VD) deficiency is a risk factor for the development of breast cancer. Underlying mechanisms include the ability of calcitriol to induce cell differentiation, inhibit oncogenes expression, and modify different signaling pathways involved in the control of cell proliferation. In addition, calcitriol combined with different kinds of antineoplastic drugs has been demonstrated to enhance their beneficial effects in an additive or synergistic fashion. However, a recognized adjuvant regimen based on calcitriol for treating patients with breast cancer has not yet been fully established. Accordingly, in the present work, we review and discuss the preclinical and clinical studies about the combination of calcitriol with different oncological drugs, aiming to emphasize its main therapeutic benefits and opportunities for the treatment of this pathology.
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Affiliation(s)
- Mariana Segovia-Mendoza
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico;
| | - Janice García-Quiroz
- Departamento de Biología de la Reproducción Dr. Carlos Gual Castro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Belisario Domínguez Sección XVI, Tlalpan, Ciudad de México 14080, Mexico;
| | - Lorenza Díaz
- Departamento de Biología de la Reproducción Dr. Carlos Gual Castro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Belisario Domínguez Sección XVI, Tlalpan, Ciudad de México 14080, Mexico;
| | - Rocío García-Becerra
- Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
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Verma E, Kumar A, Devi Daimary U, Parama D, Girisa S, Sethi G, Kunnumakkara AB. Potential of baicalein in the prevention and treatment of cancer: A scientometric analyses based review. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104660] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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Kunnumakkara AB, Rana V, Parama D, Banik K, Girisa S, Henamayee S, Thakur KK, Dutta U, Garodia P, Gupta SC, Aggarwal BB. COVID-19, cytokines, inflammation, and spices: How are they related? Life Sci 2021; 284:119201. [PMID: 33607159 PMCID: PMC7884924 DOI: 10.1016/j.lfs.2021.119201] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/20/2021] [Accepted: 01/30/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Cytokine storm is the exaggerated immune response often observed in viral infections. It is also intimately linked with the progression of COVID-19 disease as well as associated complications and mortality. Therefore, targeting the cytokine storm might help in reducing COVID-19-associated health complications. The number of COVID-19 associated deaths (as of January 15, 2021; https://www.worldometers.info/coronavirus/) in the USA is high (1199/million) as compared to countries like India (110/million). Although the reason behind this is not clear, spices may have some role in explaining this difference. Spices and herbs are used in different traditional medicines, especially in countries such as India to treat various chronic diseases due to their potent antioxidant and anti-inflammatory properties. AIM To evaluate the literature available on the anti-inflammatory properties of spices which might prove beneficial in the prevention and treatment of COVID-19 associated cytokine storm. METHOD A detailed literature search has been conducted on PubMed for collecting information pertaining to the COVID-19; the history, origin, key structural features, and mechanism of infection of SARS-CoV-2; the repurposed drugs in use for the management of COVID-19, and the anti-inflammatory role of spices to combat COVID-19 associated cytokine storm. KEY FINDINGS The literature search resulted in numerous in vitro, in vivo and clinical trials that have reported the potency of spices to exert anti-inflammatory effects by regulating crucial molecular targets for inflammation. SIGNIFICANCE As spices are derived from Mother Nature and are inexpensive, they are relatively safer to consume. Therefore, their anti-inflammatory property can be exploited to combat the cytokine storm in COVID-19 patients. This review thus focuses on the current knowledge on the role of spices for the treatment of COVID-19 through suppression of inflammation-linked cytokine storm.
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Affiliation(s)
- Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India.
| | - Varsha Rana
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Kishore Banik
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Sahu Henamayee
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Krishan Kumar Thakur
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Uma Dutta
- Cell and Molecular Biology Lab, Department of Zoology, Cotton University, Guwahati, Assam 781001, India
| | | | - Subash C Gupta
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
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Levan enhanced the NF-κB suppression activity of an oral nano PLGA-curcumin formulation in breast cancer treatment. Int J Biol Macromol 2021; 189:223-231. [PMID: 34419542 DOI: 10.1016/j.ijbiomac.2021.08.115] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/23/2021] [Accepted: 08/15/2021] [Indexed: 11/21/2022]
Abstract
Chemoresistance (CR) is one of the reasons why chemotherapy agents like Gemcitabine (GMC) remain insufficient in healing breast cancer. Activation of Nuclear Factor-kappa B (NF-κB) during chemotherapy is known as an important factor in the development of CR. The hydrophobic polyphenol curcumin is shown to inhibit NF-κB and hence CR. The aim of this work was to increase the poor bioavailability of curcumin by loading it into the nano-micelles made of Poly (Lactide-co-Glycolide) (PLGA) and levan, where levan as a natural fructose homopolymer makes the nano-micelle more stable and increases its uptake using the fructose moieties. In this study, a PLGA-levan-curcumin formulation (PLC) was designed and characterized. The size was measured as 154.16 ± 1.45 nm with a 67.68% encapsulation efficiency (EE%). The incorporation between the components was approved. Levan made the nano-micelles stable for at least three months, increased their uptake, and led to a 10,000-fold increase in the solubility of curcumin. The enhanced bioavailability of curcumin reduced the NF-κB levels elevated by GMC, both in vitro and in vivo. The PLC showed a complete tumor treatment, while GMC only showed a rate of 52%. These point to the great potential of the PLC to be used simultaneously with chemotherapy.
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Zhang SX, Liu W, Ai B, Sun LL, Chen ZS, Lin LZ. Current Advances and Outlook in Gastric Cancer Chemoresistance: A Review. Recent Pat Anticancer Drug Discov 2021; 17:26-41. [PMID: 34587888 DOI: 10.2174/1574892816666210929165729] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 08/19/2021] [Accepted: 09/20/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Surgical resection of the lesion is the standard primary treatment of gastric cancer. Unfortunately, most patients are already in the advanced stage of the disease when they are diagnosed with gastric cancer. Alternative therapies, such as radiation therapy and chemotherapy, can achieve only very limited benefits. The emergence of cancer drug resistance has always been the major obstacle to the cure of tumors. The main goal of modern cancer pharmacology is to determine the underlying mechanism of anticancer drugs. OBJECTIVE Here, we mainly review the latest research results related to the mechanism of chemotherapy resistance in gastric cancer, the application of natural products in overcoming the chemotherapy resistance of gastric cancer, and the new strategies currently being developed to treat tumors based on immunotherapy and gene therapy. CONCLUSION The emergence of cancer drug resistance is the main obstacle in achieving alleviation and final cure for gastric cancer. Mixed therapies are considered to be a possible way to overcome chemoresistance. Natural products are the main resource for discovering new drugs specific for treating chemoresistance, and further research is needed to clarify the mechanism of natural product activity in patients. .
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Affiliation(s)
- Sheng-Xiong Zhang
- Guangdong Province Work Injury Rehabilitation Hospital, Guangzhou, 510440. China
| | - Wei Liu
- College of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006. China
| | - Bo Ai
- Huazhong University of Science and Technology, Wuhan, 430030. China
| | - Ling-Ling Sun
- The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405. China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, St. John's University, Queens, NY 11439, New York. United States
| | - Li-Zhu Lin
- The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405. China
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Sahin TK, Bilir B, Kucuk O. Modulation of inflammation by phytochemicals to enhance efficacy and reduce toxicity of cancer chemotherapy. Crit Rev Food Sci Nutr 2021; 63:2494-2508. [PMID: 34529530 DOI: 10.1080/10408398.2021.1976721] [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] [Indexed: 02/06/2023]
Abstract
Treatment of cancer with chemotherapeutic drugs is associated with numerous adverse effects as well as the eventual development of resistance to chemotherapy. There is a great need for complementary therapies such as botanicals and nutritional supplements with little or no side effects that prevent resistance to chemotherapy and reduce its adverse effects. Inflammation plays a major role in the development of chemoresistance and the adverse effects of chemotherapy. Phytochemicals have well-established anti-inflammatory effects; thus, they could be used as complementary therapies along with chemotherapy to increase its efficacy and reduce its toxicity. Botanical compounds inhibit the NF-κB signaling pathway, which plays an important role in the generation of inflammation, chemotherapy resistance, and modulation of cell survival and apoptosis. Botanicals have previously been studied extensively for their cancer chemopreventive activities and are generally considered safe for human consumption. The present review focuses on the modulation of inflammation by phytochemicals and their role in increasing the efficacy and reducing the toxicity of cancer chemotherapy.
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Affiliation(s)
- Taha Koray Sahin
- Department of Internal Medicine, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Birdal Bilir
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Omer Kucuk
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
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Kumar A, Harsha C, Parama D, Girisa S, Daimary UD, Mao X, Kunnumakkara AB. Current clinical developments in curcumin-based therapeutics for cancer and chronic diseases. Phytother Res 2021; 35:6768-6801. [PMID: 34498308 DOI: 10.1002/ptr.7264] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 06/16/2021] [Accepted: 08/14/2021] [Indexed: 12/19/2022]
Abstract
The last decade has seen an unprecedented rise in the prevalence of chronic diseases worldwide. Different mono-targeted approaches have been devised to treat these multigenic diseases, still most of them suffer from limited success due to the off-target debilitating side effects and their inability to target multiple pathways. Hence a safe, efficacious, and multi-targeted approach is the need for the hour to circumvent these challenging chronic diseases. Curcumin, a natural compound extracted from the rhizomes of Curcuma longa, has been under intense scrutiny for its wide medicinal and biological properties. Curcumin is known to manifest antibacterial, antiinflammatory, antioxidant, antifungal, antineoplastic, antifungal, and proapoptotic effects. A plethora of literature has already established the immense promise of curcuminoids in the treatment and clinical management of various chronic diseases like cancer, cardiovascular, metabolic, neurological, inflammatory, and infectious diseases. To date, more than 230 clinical trials have opened investigations to understand the pharmacological aspects of curcumin in human systems. Still, further randomized clinical studies in different ethnic populations warrant its transition to a marketed drug. This review summarizes the results from different clinical trials of curcumin-based therapeutics in the prevention and treatment of various chronic diseases.
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Affiliation(s)
- Aviral Kumar
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Choudhary Harsha
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Uzini Devi Daimary
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
| | - Xinliang Mao
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, India
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He F, Zhang S, Li Y, Chen X, Du Z, Shao C, Ding K. The structure elucidation of novel arabinogalactan LRP1-S2 against pancreatic cancer cells growth in vitro and in vivo. Carbohydr Polym 2021; 267:118172. [PMID: 34119144 DOI: 10.1016/j.carbpol.2021.118172] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/23/2021] [Accepted: 05/01/2021] [Indexed: 10/21/2022]
Abstract
The fruit of Lycium ruthenicum Murr is used as traditional medicine and functional food. Previously we reported that one RG-I pectin from this fruit might inhibit pancreatic cancer cells growth. We further hypothesized that there might be other type of polysaccharides in this fruit also have anti-tumor effect. Here, we showed novel structure of a homogeneous polysaccharide named LRP1-S2 from this fruit and its anti-pancreatic cancer effect. Structure analyses suggested that LRP1-S2 was a novel arabinogalactan with the molecular weight (Mw) of 17.0 kDa. Bioactivity test showed that LRP1-S2 might attenuate the proliferation of pancreatic cancer cells in vitro and in vivo without significant cytotoxicity to normal pancreatic HPDE6-C7 cells and LO2 liver cells. Mechanism study indicated that it might induce apoptosis of BxPC-3 by inactivating P38 MAPK/NF-κB and GSK-3β/β-Catenin signaling pathways. These results suggested that LRP1-S2 could be a potential anti-tumor leading compound for functional food and new drug development. CHEMICAL COMPOUNDS: arabinogalactan, pectin, galactan, arabinan, RN-1, HH1-1, LRP1-S2, LRP3-S1.
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Affiliation(s)
- Fei He
- Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, PR China
| | - Shihai Zhang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Nanjing 210023, PR China
| | - Yanan Li
- Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, PR China
| | - Xia Chen
- Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, PR China
| | - Zhenyun Du
- Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, PR China
| | - Chenghao Shao
- Department of General Surgery, Changzheng Hospital, Naval Medical University (Second Military Medical University), No.415 Fengyang Road, Shanghai 200003, PR China.
| | - Kan Ding
- Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, PR China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Nanjing 210023, PR China.
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Parama D, Rana V, Girisa S, Verma E, Daimary UD, Thakur KK, Kumar A, Kunnumakkara AB. The promising potential of piperlongumine as an emerging therapeutics for cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:323-354. [PMID: 36046754 PMCID: PMC9400693 DOI: 10.37349/etat.2021.00049] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 07/04/2021] [Indexed: 12/24/2022] Open
Abstract
In spite of the immense advancement in the diagnostic and treatment modalities, cancer continues to be one of the leading causes of mortality across the globe, responsible for the death of around 10 million patients every year. The foremost challenges faced in the treatment of this disease are chemoresistance, adverse effects of the drugs, and the high cost of treatment. Though scientific studies over the past few decades have foreseen and are focusing on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action, many more of these agents are not still explored. Piperlongumine (PL), or piplartine, is one such alkaloid isolated from Piper longum Linn. which is shown to be safe and has significant potential in the prevention and therapy of cancer. Numerous shreds of evidence have established the ability of this alkaloid and its analogs and nanoformulations in modulating various complex molecular pathways such as phosphatidylinositol-3-kinase/protein kinase B /mammalian target of rapamycin, nuclear factor kappa-B, Janus kinases/signal transducer and activator of transcription 3, etc. and inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases, etc. In addition, PL was also shown to inhibit radioresistance and chemoresistance and sensitize the cancer cells to the standard chemotherapeutic agents. Therefore, this compound has high potential as a drug candidate for the prevention and treatment of different cancers. The current review briefly reiterates the anti-cancer properties of PL against different types of cancer, which permits further investigation by conducting clinical studies.
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Affiliation(s)
- Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Varsha Rana
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Elika Verma
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Uzini Devi Daimary
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Krishan Kumar Thakur
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Aviral Kumar
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
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Kong WY, Ngai SC, Goh BH, Lee LH, Htar TT, Chuah LH. Is Curcumin the Answer to Future Chemotherapy Cocktail? Molecules 2021; 26:4329. [PMID: 34299604 PMCID: PMC8303331 DOI: 10.3390/molecules26144329] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/07/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022] Open
Abstract
The rise in cancer cases in recent years is an alarming situation worldwide. Despite the tremendous research and invention of new cancer therapies, the clinical outcomes are not always reassuring. Cancer cells could develop several evasive mechanisms for their survivability and render therapeutic failure. The continuous use of conventional cancer therapies leads to chemoresistance, and a higher dose of treatment results in even greater toxicities among cancer patients. Therefore, the search for an alternative treatment modality is crucial to break this viscous cycle. This paper explores the suitability of curcumin combination treatment with other cancer therapies to curb cancer growth. We provide a critical insight to the mechanisms of action of curcumin, its role in combination therapy in various cancers, along with the molecular targets involved. Curcumin combination treatments were found to enhance anticancer effects, mediated by the multitargeting of several signalling pathways by curcumin and the co-administered cancer therapies. The preclinical and clinical evidence in curcumin combination therapy is critically analysed, and the future research direction of curcumin combination therapy is discussed.
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Affiliation(s)
- Wei-Yang Kong
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, Semenyih 43500, Selangor, Malaysia; (W.-Y.K.); (S.C.N.)
| | - Siew Ching Ngai
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, Semenyih 43500, Selangor, Malaysia; (W.-Y.K.); (S.C.N.)
| | - Bey-Hing Goh
- Biofunctional Molecule Exploratory Research Group, School of Pharmacy, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia; (B.-H.G.); (T.-T.H.)
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China
| | - Learn-Han Lee
- Novel Bacteria and Drug Discovery (NBDD) Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia;
| | - Thet-Thet Htar
- Biofunctional Molecule Exploratory Research Group, School of Pharmacy, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia; (B.-H.G.); (T.-T.H.)
| | - Lay-Hong Chuah
- Biofunctional Molecule Exploratory Research Group, School of Pharmacy, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia; (B.-H.G.); (T.-T.H.)
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Girisa S, Henamayee S, Parama D, Rana V, Dutta U, Kunnumakkara AB. Targeting Farnesoid X receptor (FXR) for developing novel therapeutics against cancer. MOLECULAR BIOMEDICINE 2021; 2:21. [PMID: 35006466 PMCID: PMC8607382 DOI: 10.1186/s43556-021-00035-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/17/2021] [Indexed: 12/14/2022] Open
Abstract
Cancer is one of the lethal diseases that arise due to the molecular alterations in the cell. One of those alterations associated with cancer corresponds to differential expression of Farnesoid X receptor (FXR), a nuclear receptor regulating bile, cholesterol homeostasis, lipid, and glucose metabolism. FXR is known to regulate several diseases, including cancer and cardiovascular diseases, the two highly reported causes of mortality globally. Recent studies have shown the association of FXR overexpression with cancer development and progression in different types of cancers of breast, lung, pancreas, and oesophagus. It has also been associated with tissue-specific and cell-specific roles in various cancers. It has been shown to modulate several cell-signalling pathways such as EGFR/ERK, NF-κB, p38/MAPK, PI3K/AKT, Wnt/β-catenin, and JAK/STAT along with their targets such as caspases, MMPs, cyclins; tumour suppressor proteins like p53, C/EBPβ, and p-Rb; various cytokines; EMT markers; and many more. Therefore, FXR has high potential as novel biomarkers for the diagnosis, prognosis, and therapy of cancer. Thus, the present review focuses on the diverse role of FXR in different cancers and its agonists and antagonists.
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Affiliation(s)
- Sosmitha Girisa
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Sahu Henamayee
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Dey Parama
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Varsha Rana
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Uma Dutta
- Cell and Molecular Biology Lab, Department of Zoology, Cotton University, Guwahati, Assam, 781001, India.
| | - Ajaikumar B Kunnumakkara
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India.
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Xuan YZ, Jin CR, Yang KJ. TGF-β downregulation overcomes gemcitabine resistance in oral squamous cell carcinoma. Cancer Biomark 2021; 29:179-187. [PMID: 32741805 DOI: 10.3233/cbm-201456] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of this study was to explore the mechanisms by which oral cancer acquires resistance to gemcitabine. METHODS Oral squamous cell carcinoma (OSCC) cells were treated with gemcitabine upon infection or with a lentivirus harboring short hairpin RNA (shRNA) targeted to transforming growth factor-β (TGF-β). Then, Western blot, ELISA, migration assay, MTT assay, and animal experiments were used to explore the mechanism of resistance to gemcitabine treatment. RESULTS After the treatment of non-transfected cells with gemcitabine, NF-κB and AKT activities were increased, which may have induced the OSCC resistance to gemcitabine. Then, we found that TGF-β downregulation effectively reduced NF-κB and AKT phosphorylation levels after the administration of gemcitabine and increased the OSCC sensitivity to gemcitabine, resulting in cell death and the blunting of OSCC resistance to gemcitabine. The EMT was also reduced by TGF-β downregulation combined with gemcitabine treatment. CONCLUSION Cellular levels of TGF-β constitute an important factor in gemcitabine resistance and TGF-β silencing might represent a novel and potent strategy for overcoming OSCC resistance to gemcitabine.
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Affiliation(s)
- Yun-Ze Xuan
- Department of Dentistry, Affiliated Hospital of Yanbian University, Yanji, Jilin, China.,Department of Dentistry, Affiliated Hospital of Yanbian University, Yanji, Jilin, China
| | - Cheng-Ri Jin
- Department of Dentistry, Affiliated Hospital of Yanbian University, Yanji, Jilin, China.,Department of Dentistry, Affiliated Hospital of Yanbian University, Yanji, Jilin, China
| | - Kang-Juan Yang
- Department of Cell Biology and Medical Genetics, Yanbian University College of Basic Medicine, Yanji, Jilin, China
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Chidambara Murthy KN, Jayaprakasha GK, Safe S, Patil BS. Citrus limonoids induce apoptosis and inhibit the proliferation of pancreatic cancer cells. Food Funct 2021; 12:1111-1120. [PMID: 33427831 DOI: 10.1039/d0fo02740e] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
In our recent study, we demonstrated that certain limonoids isolated from citrus seeds induced apoptosis in human pancreatic (Panc-28) cells. In this study, limonin, nomilin and limonexic acid (LNA) were investigated for understanding the possible mode of cytotoxicity in cultured pancreatic cancer (Panc-28) cells. All three limonoids inhibited Panc-28 cell proliferation, with IC50 values less than 50 μM after 72 h of incubation. The induction of apoptosis was confirmed through the cleavage of caspase-3, decreased mitochondrial membrane potential, and expression of apoptosis-related proteins. The Bax/Bcl2 expression ratio was increased up to 11-fold in cells pre-treated with 60 μM limonoids for 48 h. Apart from this, the limonoids also induced the expression of p21, and exhibited anti-inflammatory activity through decreasing the expression of cox-2, NF-κB and IL-6. Based on these results, we were interested in understanding the possible mode of inhibition by LNA, which exhibited the highest activity. The treatment of Panc-28 cells resulted in dose- and time-dependent induction of apoptosis-inducible proteins. In addition, treatment with 60 μM LNA resulted in the activation of Akt-associated signals to induce apoptosis, and the same was confirmed by the effects of the compounds on pAkt, p53, VEGF and caspase proteins. The results of this study demonstrated the cytotoxicity of limonoids to human pancreatic cancer cells through the modulation of genes involved in proliferation and survival.
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Affiliation(s)
- K N Chidambara Murthy
- Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University, College Station, TX 77845-2119, USA.
| | - G K Jayaprakasha
- Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University, College Station, TX 77845-2119, USA.
| | - Stephen Safe
- Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University, College Station, TX 77845-2119, USA. and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA.
| | - Bhimanagouda S Patil
- Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University, College Station, TX 77845-2119, USA.
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C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer. Sci Rep 2021; 11:10078. [PMID: 33980911 PMCID: PMC8115044 DOI: 10.1038/s41598-021-89530-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 04/27/2021] [Indexed: 12/19/2022] Open
Abstract
The activity of histone acetyltransferases (HATs) plays a central role in an epigenetic modification in cooperation with HDACs (histone deacetyl transferases). It is likely that malfunction of this enzymatic machinery controlling epigenetic modification is relevant to carcinogenesis and tumor progression. However, in pancreatic cancer, the clinical relevance of HAT activity and histone acetylation has remained unclear. We identified that H3 acetylation was expressed in all pancreatic cancer patients, indicating that H3 acetylation may be essential in pancreatic cancer cells. We also found that the HAT inhibitor C646 augmented anti-tumor effects in vitro by inhibiting cell proliferation and cell cycle progression concomitantly with suppression of acetylated H3K9 and H3K27 expression. C646 or p300 and CBP (CREB-binding protein)-specific siRNA treatment inhibited the transcription of the G2/M cell cycle regulatory proteins cyclin B1 and CDK1 (cyclin-dependent kinase 1). C646 treatment also inhibited tumor growth in vivo in a xenograft mouse model. C646 could be an effective therapeutic agent for pancreatic cancer. The epigenetic status of pancreatic cancers based on their level of histone H3 acetylation may influence patient survival. Epigenetic stratification according to H3K27 acetylation could be useful for predicting disease prognosis as well as the therapeutic efficacy of C646 in pancreatic cancer.
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Omi K, Matsuo Y, Ueda G, Aoyama Y, Kato T, Hayashi Y, Imafuji H, Saito K, Tsuboi K, Morimoto M, Ogawa R, Takahashi H, Takiguchi S. Escin inhibits angiogenesis by suppressing interleukin‑8 and vascular endothelial growth factor production by blocking nuclear factor‑κB activation in pancreatic cancer cell lines. Oncol Rep 2021; 45:55. [PMID: 33760162 PMCID: PMC7962110 DOI: 10.3892/or.2021.8006] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 12/21/2020] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer (PaCa) is one of the most aggressive types of cancer. Thus, the development of new and more effective therapies is urgently required. Escin, a pentacyclic triterpenoid from the horse chestnut, has been reported to exhibit antitumor potential by reducing cell proliferation and blocking the nuclear factor‑κB (NF‑κB) signaling pathway in several types of cancer. Our previous study reported that NF‑κB enhanced the secretion of interleukin (IL)‑8 and vascular endothelial growth factor (VEGF), thereby inducing angiogenesis in PaCa cell lines. In the present study, it was examined whether escin inhibited angiogenesis by blocking NF‑κB activation in PaCa. It was initially confirmed that escin, at concentrations >10 µM, significantly inhibited the proliferation of several PaCa cell lines. Next, using immunocytochemical staining, it was found that escin inhibited the nuclear translocation of NF‑κB. Furthermore, ELISA confirmed that NF‑κB activity in the escin‑treated PaCa cells was significantly inhibited and reverse transcription‑quantitative PCR showed that the mRNA expression levels of tumor necrosis factor‑α‑induced IL‑8 and VEGF were significantly suppressed following escin treatment in the PaCa cell lines. ELISA also showed that escin decreased the secretion of IL‑8 and VEGF from the PaCa cells. Furthermore, tube formation in immortalized human endothelial cells was inhibited following incubation with the supernatants from escin‑treated PaCa cells. These results indicated that escin inhibited angiogenesis by reducing the secretion of IL‑8 and VEGF by blocking NF‑κB activity in PaCa. In conclusion, escin could be used as a novel molecular therapy for PaCa.
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Affiliation(s)
- Kan Omi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Yoichi Matsuo
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Goro Ueda
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Yoshinaga Aoyama
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Tomokatsu Kato
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Yuichi Hayashi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Hiroyuki Imafuji
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Kenta Saito
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Ken Tsuboi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Mamoru Morimoto
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Ryo Ogawa
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Hiroki Takahashi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Shuji Takiguchi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
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Sphyris N, King C, Hoar J, Werden SJ, Vijay GV, Miura N, Gaharwar A, Sarkar TR. Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth. Oncotarget 2021; 12:823-844. [PMID: 33889304 PMCID: PMC8057273 DOI: 10.18632/oncotarget.27940] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/25/2021] [Indexed: 12/23/2022] Open
Abstract
Hypoxia stimulates neoangiogenesis, promoting tumor outgrowth, and triggers the epithelial-mesenchymal transition (EMT), which bestows cells with mesenchymal traits and multi-lineage differentiation potential. Here, we investigated whether EMT can confer endothelial attributes upon carcinoma cells, augmenting tumor growth and vascularization. Following orthotopic implantation of MCF-7 human epithelial breast cancer cells into mice, tumors of different sizes were immunostained for markers of hypoxia and EMT. Larger tumors were well-vascularized with CD31-positive cells of human origin. Hypoxic regions, demarcated by HIF-1α staining, exhibited focal areas of E-cadherin loss and elevated levels of vimentin and the EMT-mediator FOXC2. Implantation of MCF-7 cells, co-mixed with human mammary epithelial (HMLE) cells overexpressing the EMT-inducer Snail, markedly potentiated tumor growth and vascularization, compared with MCF-7 cells injected alone or co-mixed with HMLE-vector cells. Intra-tumoral vessels contained CD31-positive cells derived from either donor cell type. FOXC2 knockdown abrogated the potentiating effects of HMLE-Snail cells on MCF-7 tumor growth and vascularization, and compromised endothelial transdifferentiation of mesenchymal cells cultured in endothelial growth medium. Hence, cells that have undergone EMT can promote tumor growth and neovascularization either indirectly, by promoting endothelial transdifferentiation of carcinoma cells, or directly, by acquiring an endothelial phenotype, with FOXC2 playing key roles in these processes.
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Affiliation(s)
- Nathalie Sphyris
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Present address: Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.,These authors contributed equally to this work
| | - Cody King
- Department of Biochemistry, Texas A&M University, College Station, TX, USA
| | - Jonathan Hoar
- Department of Biology, Texas A&M University, College Station, TX, USA
| | - Steven J Werden
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Geraldine V Vijay
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Naoyuki Miura
- Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Akhilesh Gaharwar
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, USA
| | - Tapasree Roy Sarkar
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Biology, Texas A&M University, College Station, TX, USA.,These authors contributed equally to this work
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Girisa S, Kumar A, Rana V, Parama D, Daimary UD, Warnakulasuriya S, Kumar AP, Kunnumakkara AB. From Simple Mouth Cavities to Complex Oral Mucosal Disorders-Curcuminoids as a Promising Therapeutic Approach. ACS Pharmacol Transl Sci 2021; 4:647-665. [PMID: 33860191 PMCID: PMC8033761 DOI: 10.1021/acsptsci.1c00017] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Indexed: 02/08/2023]
Abstract
Oral diseases are among the most common encountered health issues worldwide, which are usually associated with anomalies of the oral cavity, jaws, and salivary glands. Despite the availability of numerous treatment modalities for oral disorders, a limited clinical response has been observed because of the inefficacy of the drugs and countless adverse side effects. Therefore, the development of safe, efficacious, and wide-spectrum therapeutics is imperative in the battle against oral diseases. Curcumin, extracted from the golden spice turmeric, is a well-known natural polyphenol that has been extensively studied for its broad pleiotropic attributes and its ability to modulate multiple biological processes. It is well-documented to target pro-inflammatory mediators like NF-κB, ROS, COX-2, IL-1, IL-2, TGF-β, growth factors, apoptotic proteins, receptors, and various kinases. These properties make curcumin a promising nutraceutical in the treatment of many oral diseases like oral submucous fibrosis, oral mucositis, oral leukoplakia, oral erythroplakia, oral candidiasis, aphthous stomatitis, oral lichen planus, dental caries, periodontitis, and gingivitis. Numerous in vitro and in vivo studies have shown that curcumin alleviates the symptoms of most of the oral complications, including the inhibition of the progression of oral cancer. In this regard, many clinical trials have been completed, and many are ongoing to investigate the "curcumin effect" in oral maladies. Therefore, the current review delineates the mechanistic framework of curcumin's propensity in curbing oral diseases and present outcomes of the clinical trials of curcumin-based therapeutics that can provide a breakthrough in the clinical management of these diseases.
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Affiliation(s)
- Sosmitha Girisa
- Cancer
Biology Laboratory and DBT-AIST International Center for Translational
and Environmental Research (DAICENTER), Department of Biosciences
and Bioengineering, Indian Institute of
Technology (IIT) Guwahati, Guwahati, Assam 781039, India
| | - Aviral Kumar
- Cancer
Biology Laboratory and DBT-AIST International Center for Translational
and Environmental Research (DAICENTER), Department of Biosciences
and Bioengineering, Indian Institute of
Technology (IIT) Guwahati, Guwahati, Assam 781039, India
| | - Varsha Rana
- Cancer
Biology Laboratory and DBT-AIST International Center for Translational
and Environmental Research (DAICENTER), Department of Biosciences
and Bioengineering, Indian Institute of
Technology (IIT) Guwahati, Guwahati, Assam 781039, India
| | - Dey Parama
- Cancer
Biology Laboratory and DBT-AIST International Center for Translational
and Environmental Research (DAICENTER), Department of Biosciences
and Bioengineering, Indian Institute of
Technology (IIT) Guwahati, Guwahati, Assam 781039, India
| | - Uzini Devi Daimary
- Cancer
Biology Laboratory and DBT-AIST International Center for Translational
and Environmental Research (DAICENTER), Department of Biosciences
and Bioengineering, Indian Institute of
Technology (IIT) Guwahati, Guwahati, Assam 781039, India
| | - Saman Warnakulasuriya
- Department
of Oral Medicine, King’s College
London and WHO Collaborating Centre for Oral Cancer and Precancer, London WC2R 2LS, United Kingdom
| | - Alan Prem Kumar
- Medical
Science Cluster, Cancer Translational Research Programme, Yong Loo
Lin School of Medicine, National University
of Singapore, Singapore 117600, Singapore
- Cancer
Science Institute of Singapore, National
University of Singapore, Singapore 117600, Singapore
- National
University Cancer Institute, National University
Health Systems, Singapore 117600, Singapore
| | - Ajaikumar B. Kunnumakkara
- Cancer
Biology Laboratory and DBT-AIST International Center for Translational
and Environmental Research (DAICENTER), Department of Biosciences
and Bioengineering, Indian Institute of
Technology (IIT) Guwahati, Guwahati, Assam 781039, India
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Potential Role of Curcumin and Its Nanoformulations to Treat Various Types of Cancers. Biomolecules 2021; 11:biom11030392. [PMID: 33800000 PMCID: PMC8001478 DOI: 10.3390/biom11030392] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/27/2021] [Accepted: 03/03/2021] [Indexed: 12/17/2022] Open
Abstract
Cancer is a major burden of disease globally. Each year, tens of millions of people are diagnosed with cancer worldwide, and more than half of the patients eventually die from it. Significant advances have been noticed in cancer treatment, but the mortality and incidence rates of cancers are still high. Thus, there is a growing research interest in developing more effective and less toxic cancer treatment approaches. Curcumin (CUR), the major active component of turmeric (Curcuma longa L.), has gained great research interest as an antioxidant, anticancer, and anti-inflammatory agent. This natural compound shows its anticancer effect through several pathways including interfering with multiple cellular mechanisms and inhibiting/inducing the generation of multiple cytokines, enzymes, or growth factors including IκB kinase β (IκKβ), tumor necrosis factor-alpha (TNF-α), signal transducer, and activator of transcription 3 (STAT3), cyclooxygenase II (COX-2), protein kinase D1 (PKD1), nuclear factor-kappa B (NF-κB), epidermal growth factor, and mitogen-activated protein kinase (MAPK). Interestingly, the anticancer activity of CUR has been limited primarily due to its poor water solubility, which can lead to low chemical stability, low oral bioavailability, and low cellular uptake. Delivering drugs at a controlled rate, slow delivery, and targeted delivery are other very attractive methods and have been pursued vigorously. Multiple CUR nanoformulations have also been developed so far to ameliorate solubility and bioavailability of CUR and to provide protection to CUR against hydrolysis inactivation. In this review, we have summarized the anticancer activity of CUR against several cancers, for example, gastrointestinal, head and neck, brain, pancreatic, colorectal, breast, and prostate cancers. In addition, we have also focused on the findings obtained from multiple experimental and clinical studies regarding the anticancer effect of CUR in animal models, human subjects, and cancer cell lines.
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Yang L, Sun X, Huang J, Zhu S, Li Y. Study on the Application of a Novel Nano-Curcumin Drug for Alzheimer’s Disease. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease hallmarked by impaired cognitive function and memory decline; it is accompanied by a variety of mental symptoms and behavioral disorders. This disease has a serious impact on society, families, and the afflicted patients.
Curcumin (Cur) nanoparticles were preparation by modifying curcumin with polyethylene glycol-polylactic acid (PEG-PLA) amphiphilic block copolymer. The resulting nanodrug can successfully penetrate the blood brain barrier (BBB) and concentrate in the main pathological areas of AD. As measured
with a Zeta particle size analyzer, the particle size of PEG-PLA/Cur was 100 ± 0.53 nm, and it was electrically neutral. In vitro experiments revealed that PEG-PLA/Cur successfully penetrated the membrane of PC12 cells and inhibited proliferation. PEG-PLA/Cur also exhibited an
inhibitory effect on the production of amyloid β protein (Aβ fiber) and depolymerization activity on Aβ fiber aggregates. PEG-PLA/Cur represents a novel nanodrug with the potential to treat AD.
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Affiliation(s)
- Liu Yang
- Department of Neurology, First Affiliated Hospital of Jinan University, Guangzhou 510623, Guangdong, PR China
| | - Xin Sun
- Outpatient Department of University of Jinan Affiliated First Hospital, Guangzhou 510623, Guangdong, PR China
| | - Jun Huang
- Department of Anesthesiology, Fourth People’s Hospital of Chenzhou City, Hunan Province, Chenzhou 423000, Hunan, PR China
| | - Shimiao Zhu
- Department of Rehabilitation, Affiliated Hospital of Hunan Xiangnan College, Chenzhou 423000, Hunan, PR China
| | - Yan Li
- Department of Hyperbaric Oxygen, Affiliated Hospital of Hunan Xiangnan College, Chenzhou 423000, Hunan, PR China
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Curcumin-loaded Polyethyleneimine and chitosan polymer-based Mucoadhesive liquid crystalline systems as a potential platform in the treatment of cervical Cancer. J Mol Liq 2021. [DOI: 10.1016/j.molliq.2020.115080] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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