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Liang LW, Luo RH, Huang ZL, Tang LN. Clinical observation of nivolumab combined with cabozantinib in the treatment of advanced hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:103631. [DOI: 10.4251/wjgo.v17.i4.103631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/25/2024] [Accepted: 02/07/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a particularly serious kind of liver cancer. Liver cancer ranks third in terms of mortality rate worldwide, putting it among the leading causes of deaths from cancer. HCC is the primary kind of liver cancer and makes up the vast majority of cases, accounting for approximately 90% of occurrences. Numerous research have verified this information. the progress of fatty liver, alcohol induced cirrhosis, smoking habits, obesity caused by overweight, and metabolic diseases such as diabetes. The treatment strategies for HCC can be divided into two categories: One is curative treatment, including liver transplantation, surgical resection, and ablation therapy or selective arterial radiation embolization, aimed at completely eliminating the lesion; Another type is non curative treatment options, including transarterial chemoembolization and systemic therapy, which focus on controlling disease progression and prolonging patient survival. The majority of HCC patients are found to be in an advanced stage and need systemic therapy. Sorafenib and lenvatinib are frequently used as first-line medications in traditional HCC treatment to slow the disease's progression. For second-line treatment, regorafenib, cabozantinib, or remdesizumab are used to inhibit tumors through different mechanisms and prolong survival. In recent years, with the in-depth exploration of the pathogenesis and progression mechanism of HCC, as well as the rapid progress within the domain of tumor immunotherapy, the treatment prospects for advanced HCC patients have shown a positive transformation. This transformation is reflected in the fact that more and more patients are gradually gaining significant and considerable therapeutic advantages from advanced immunotherapy regimens, bringing unprecedented improvements to their treatment outcomes. In order to enable activated T cells to attack tumor cells, immune checkpoint inhibitors interfere with the inhibitory.
AIM To evaluate the effects of nivolumab in combination with cabozantinib on patient tumor markers and immune function, as well as the therapeutic efficacy of this combination in treating advanced HCC, a study was conducted.
METHODS In all, 100 patients with advanced HCC who were brought to our hospital between July 2022 and July 2023 and who did not match the requirements for surgical resection had their clinical data thoroughly analyzed retrospectively in this study. Among them, half of the patients (50 cases) only received oral cabozantinib as a single treatment regimen (set as the control group), while the other half of the patients (50 cases) received intravenous infusion of nivolumab in addition to oral cabozantinib (set as the observation group). The objective of the probe is to examine the variations in disease control rate (DCR) and objective response rate (ORR) between two groups; At the same time, changes in the levels of T lymphocyte subsets (CD3+, CD4+, CD8+) and tumor markers, including AFP, GP-73, and AFP-L3, were evaluated; In addition, changes in liver and kidney function indicators and adverse reactions during treatment were also monitored. For patients with advanced HCC, this research also calculated and analyzed the progression free survival of two patient groups throughout the course of a 12-month follow-up to assess the effectiveness and safety of this therapeutic approach.
RESULTS Upon comparing baseline information for both groups of subjects before treatment, it was found that no statistically significant alterations had occurred (P > 0.05). After the therapeutic intervention, the observation group and control group's ORR and DCR differed statistically significantly (P < 0.05). The observation group's scores significantly improved. Subsequent examination revealed that the observation group's T lymphocyte subset levels had significantly changed, mostly exhibiting an increase in CD3+, CD4+, and CD4+/CD8+ levels while CD8+ levels had comparatively dropped. There was a significant difference (P < 0.05) between these changes and those in the control group. The observation group also showed positive improvements in tumor markers; AFP, GP-73, and AFP-L3 levels were considerably lower in the group under observation than in the control group, with statistically significant differences (P < 0.05). When liver function was assessed, total bilirubin and alanine aminotransferase were found to be considerably lower in the observation group than in the control group (P < 0.05). The incidence of adverse responses was not statistically significant (P > 0.05), indicating that the incidence of adverse responses did not differ significantly between the two groups.
CONCLUSION When treating advanced HCC, nivolumab and cabozantinib together have the ability to increase T lymphocyte numbers, reduce tumor marker levels, effectively prolong survival time, and have better efficacy than simple control treatment, with good safety.
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Affiliation(s)
- Lu-Wen Liang
- Infection and Liver Disease Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400000, China
| | - Rong-Hong Luo
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Zhi-Li Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Li-Na Tang
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
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Li Q, Lou Z, Wang C, Li Y. In vitro anticancer effects in hepatocellular carcinoma (HCC) and protein interaction study of xanthoangelol. Int J Biol Macromol 2025; 302:138530. [PMID: 39653233 DOI: 10.1016/j.ijbiomac.2024.138530] [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: 08/11/2024] [Revised: 11/13/2024] [Accepted: 12/06/2024] [Indexed: 02/09/2025]
Abstract
Xanthoangelol (C25H28O4), a natural flavonoid derived from chalcones, has shown potential pharmacological activities. However, its primary interaction mechanism with proteins and cells is not well understood. In the present study, we focus on the anticancer effects of xanthoangelol against hepatocellular carcinoma (HCC) as well as its binding affinity with a plasma drug carrier protein, α2-macroglobulin. The anticancer effects of xanthoangelol on human HCC cell line HepG2 cells were assayed using MTT, LDH, qPCR, and caspase activity assays. Efficient binding of the xanthoangelol with α2-macroglobulin was established by experimental and molecular docking studies. It was found that xanthoangelol significantly mitigates cell viability through upregulating intrinsic (Bax/Bcl-2, caspase-9) and extrinsic (caspase-8) apoptotic pathways. Moreover, it was detected that xanthoangelol induces ER stress through the upregulation of CHOP in HepG2 cells. Fluorescence spectra show that xanthoangelol strongly interacts with α2-macroglobulin mediated by a static quenching mechanism and Trp1237 and Tyr1323 residues were exposed to the solvent with the addition of xanthoangelol. Meanwhile, both experimental and theoretical studies display that hydrophilic forces play a key role in the formation of xanthoangelol-α2-macroglobulin complex, leading to a slight conformational change in α2-macroglobulin. In conclusion, our findings suggest that xanthoangelol, which has a high binding affinity for a plasma carrier protein, may inhibit the viability of HCC by inducing apoptosis and ER stress.
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Affiliation(s)
- Qiaobei Li
- Department of Ultrasonic Diagnosis, The First Hospital of China Medical University, Shenyang 110001, China
| | - Zhe Lou
- Department of Cardiovascular Ultrasonic Diagnosis, The First Hospital of China Medical University, Shenyang 110001, China
| | - Chunyan Wang
- Department of Ultrasonic Diagnosis, The First Hospital of China Medical University, Shenyang 110001, China
| | - Yinyan Li
- Department of Ultrasonic Diagnosis, The First Hospital of China Medical University, Shenyang 110001, China.
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Feng L, Wang X, Gao Z, Tong Y, Yuan X, Wu T, Xia D, Hu Y. Enhancing Chemotherapy Efficacy via an Autologous Erythrocyte-Anchoring Strategy with a Closed-System Drug-Transfer Device. ACS Biomater Sci Eng 2025; 11:429-441. [PMID: 39696880 DOI: 10.1021/acsbiomaterials.4c02128] [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: 12/20/2024]
Abstract
Chemotherapeutic drugs often fail to localize efficiently to tumors when administered intravenously, causing off-target effects. This study proposes an autologous erythrocyte (ER)-anchoring strategy to improve chemotherapy efficacy and reduce side effects. Utilizing a modified hemodialysis instrument, a closed-system drug-transfer device was developed for autologous ER procurement and immunogenicity mitigation. Doxorubicin (DOX) and indocyanine green (ICG) were encapsulated in autologous ERs and then modified with DSPE-PEG-FA. The final product, DOX-ICG@ER-D, was reintroduced into circulation to enhance chemotherapy. These obtained DOX-ICG@ER-D showed good stability, minimal cardiotoxicity, and extended circulation time. Compared to free DOX, DOX-ICG@ER-D had a higher accumulation of DOX in hepatocellular carcinoma and the release of DOX could be controlled by laser irradiation. Tumor-bearing rats treated by these DOX-ICG@ER-D demonstrated improved antitumor efficacy and reduced cardiotoxicity. Thus, this autologous ER-anchoring strategy offers a promising alternative to intravenous chemotherapy in the clinic.
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Affiliation(s)
- Lingzi Feng
- College of Engineering and Applied Sciences, MOE Key Laboratory of High Performance Polymer Materials & Technology, Nanjing University, Nanjing 210033, China
- Institute for Applied Research in Public Health, School of Public Health, Nantong University, Nantong, Jiangsu 226019, P. R. China
| | - Xiangqian Wang
- Department of Radiotherapy, Nantong Tumor Hospital & Affiliated Tumor Hospital of Nantong University, Nantong 226361, P. R. China
| | - Ziyi Gao
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu 210029, China
| | - Yuqing Tong
- College of Engineering and Applied Sciences, MOE Key Laboratory of High Performance Polymer Materials & Technology, Nanjing University, Nanjing 210033, China
| | - Xiaopeng Yuan
- Department of Radiotherapy, Nantong Tumor Hospital & Affiliated Tumor Hospital of Nantong University, Nantong 226361, P. R. China
| | - Ting Wu
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu 210029, China
| | - Donglin Xia
- Institute for Applied Research in Public Health, School of Public Health, Nantong University, Nantong, Jiangsu 226019, P. R. China
| | - Yong Hu
- College of Engineering and Applied Sciences, MOE Key Laboratory of High Performance Polymer Materials & Technology, Nanjing University, Nanjing 210033, China
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Wang Y, Wang Q, Tao S, Li H, Zhang X, Xia Y, Wang Y, Yang C, Sui C. Identification of SPP1 + macrophages in promoting cancer stemness via vitronectin and CCL15 signals crosstalk in liver cancer. Cancer Lett 2024; 604:217199. [PMID: 39216547 DOI: 10.1016/j.canlet.2024.217199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/14/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024]
Abstract
Macrophages play a multifaceted role in cancer biology, with both pro-tumorigenic and anti-tumorigenic functions. Understanding the mechanisms underlying macrophage involvement in cancer progression is essential for the development of therapeutic strategies. Our study analyzed single-cell RNA sequencing data from 12 patients with liver cancer and identified a subpopulation of macrophages characterized by elevated expression of SPP1, which correlates with poor prognosis in liver cancer patients. These SPP1+ macrophages induce upregulation of tumor stemness through a vitronectin (VTN)-dependent paracrine mechanism. Mechanistically, VTN derived from SPP1+ macrophages promote integrin αvβ5/adenosine 5'-monophosphate-activated protein kinase (AMPK)/Yes-associated protein 1 (YAP1)/SYR-box transcription factor 4 (SOX4) signaling, mediating liver tumor stemness and progression. Conversely, CCL15 produced by liver cancer cells drives polarization of M0 macrophages toward an SPP1+ macrophage phenotype, establishing a positive feedback loop of macrophage-tumor stemness. Furthermore, the presence of SPP1+ macrophages confers chemoresistance in liver cancer, and inhibition of the macrophage-tumor feedback loop through targeting integrin αvβ5/YAP1 signaling sensitizes liver cancer cells to chemotherapy. Our study highlights the crucial role of SPP1+ macrophages in liver cancer progression, providing novel insights for clinical liver cancer therapy.
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Affiliation(s)
- Yizhou Wang
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, PR China; Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, 200438, PR China.
| | - Qing Wang
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, PR China.
| | - Shuangfen Tao
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, PR China.
| | - Haoyu Li
- Department of Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, PR China.
| | - Xiaofeng Zhang
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, PR China; Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, 200438, PR China.
| | - Yong Xia
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, PR China; Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, 200438, PR China.
| | - Yue Wang
- Department of Stem Cell and Regeneration Medicine, Translational Medicine Research Center, Naval Medical University, Shanghai, 200433, PR China; Department of Histology and Embryology, Basic Medicine Collage, Naval Medical University, Shanghai, 200433, PR China; Shanghai Key Laboratory of Cell Engineering, Shanghai, 200062, PR China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200092, PR China.
| | - Cheng Yang
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, PR China; Shanghai GoBroad Cancer Hospital, China Pharmaceutical University, Shanghai, 200131, PR China.
| | - Chengjun Sui
- Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, PR China.
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Yang B, Wen F, Cui Y. Integrative transcriptome analysis identifies a crotonylation gene signature for predicting prognosis and drug sensitivity in hepatocellular carcinoma. J Cell Mol Med 2024; 28:e70083. [PMID: 39428564 PMCID: PMC11491312 DOI: 10.1111/jcmm.70083] [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: 05/25/2024] [Revised: 08/29/2024] [Accepted: 09/03/2024] [Indexed: 10/22/2024] Open
Abstract
Hepatocellular carcinoma (HCC) stands as the most prevalent and treatment-resistant malignant tumour, characterized by a dismal prognosis. Croton acylation (CA) has recently gained attention as a critical factor in cancer pathogenesis. This study sought to rapidly identify prognostic features of HCC linked to CA. Differential analysis was conducted between tumour tissues and adjacent non-tumour tissues in the TCGA-LIHC and GSE76427 datasets to uncover differentially expressed genes (DEG1 and DEG2). The intersection of DEG1 and DEG2 highlighted DEGs with consistent expression patterns. Single-sample gene set enrichment analysis scores were calculated for 18 lysine crotonylation-related genes (LCRGs) identified in prior research, showing significant differences between tumour and normal groups. Subsequently, weighted gene co-expression network analysis was employed to identify key module genes correlated with the LCRG score. Candidate genes were identified by overlapping consistently expressed DEGs with key module genes. Prognostic features were identified, and risk scores were determined via regression analysis. Patients were categorized into risk groups based on the optimal cutoff value. Gene set enrichment analysis (GSEA) and immunoassays were also performed. The prognostic features were further validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A total of 88 candidate genes were identified from 1179 consistently expressed DEGs and 4200 key module genes. Seven prognostic features were subsequently identified: TMCO3, RAP2A, ITGAV, ZFYVE26, CHST9, HMGN4, and KLHL21. GSEA revealed that DEGs between risk groups were primarily associated with chylomicron metabolism, among other pathways. Additionally, activated CD4+ T cells demonstrated the strongest positive correlation with risk scores, and most immune checkpoints showed significant differences between risk groups, with ASXL1 exhibiting the strongest correlation with risk scores. The Tumour Immune Dysfunction and Exclusion score was notably higher in the high-risk group. Moreover, in both the TCGA-LIHC and ICGC-LIRI-JP datasets, the expression of other prognostic features was elevated in tumour tissues, with the exception of CHST9. RT-qPCR confirmed the increased expression of TMCO3, RAP2A, ITGAV, ZFYVE26, and HMGN4. This study establishes a risk model for HCC based on seven crotonylation-associated prognostic features, offering a theoretical framework for the diagnosis and treatment of HCC.
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Affiliation(s)
- Bailu Yang
- Department of Hepatic SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic Surgery, Ministry of EducationThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Fukai Wen
- Department of Hepatic SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic Surgery, Ministry of EducationThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Yifeng Cui
- Department of Hepatic SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
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6
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Fatima T, Mubasher MM, Rehman HM, Niyazi S, Alanzi AR, Kalsoom M, Khalid S, Bashir H. Computational modeling study of IL-15-NGR peptide fusion protein: a targeted therapeutics for hepatocellular carcinoma. AMB Express 2024; 14:91. [PMID: 39133343 PMCID: PMC11319546 DOI: 10.1186/s13568-024-01747-8] [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: 05/30/2024] [Accepted: 07/25/2024] [Indexed: 08/13/2024] Open
Abstract
The primary challenge to improving existing cancer treatment is to develop drugs that specifically target tumor cell. NGR peptide is tumor homing peptide that selectively target cancer cells while interleukin 15 is a pleiotropic cytokine with anticancer properties. This study computationally engineered a IL15-NGR fusion peptide by linking the homing peptide NGR with the targeting peptide IL-15. After evaluating and validating the chimeric peptide, we docked it to the IL-15Rα/IL-15Rβ/γc heterodimer receptor, examining the interactions and binding energy and lastly, molecular dynamics simulations were performed. The secondary and tertiary structures, along with physicochemical properties of the designed IL-15-NGR chimeric protein, were predicted using GOR IV, trRosetta and ProtParam online servers respectively. The quality and 3D structure validation were confirmed via ProSA-web and SAVES 6.0 analysis which predicted an ERRAT score of 96.72%, with 97.6% of residues in the Ramachandran plot, validating its structure. Finally, Docking, MD simulations and interaction analysis were performed using ClusPro 2.0 and GROMACS and PDBsum, which exhibited significant hydrogen bonding and salt bridges, confirming the formation of a stable docked complex. These results were further corroborated by simulation analysis, which demonstrated a stable and dynamic behavior of the docked complex in a biological environment. The predicted high expression value of fusion protein was 0.844 in E.coli using SOLUPROT tool. These findings suggest efficient expression of the IL15-NGR fusion protein if its gene is inserted into E. coli and indicates its potential as a safe and effective anticancer treatment, paving the way for targeted therapeutic interventions.
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Affiliation(s)
- Tehreem Fatima
- Centre for Applied Molecular Biology (CAMB), University of the Punjab, 87-West canal, Bank Road, Lahore, 53700, Pakistan
| | | | - Hafiz Muhammad Rehman
- Centre for Applied Molecular Biology (CAMB), University of the Punjab, 87-West canal, Bank Road, Lahore, 53700, Pakistan.
- University Institute of Medical Lab Technology, Faculty of Allied health sciences, The University of Lahore, Lahore, 54590, Pakistan.
| | - Sakina Niyazi
- School of Biotechnology, IFTM University, Moradabad, 244102, India
| | - Abdullah R Alanzi
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Maria Kalsoom
- Centre for Applied Molecular Biology (CAMB), University of the Punjab, 87-West canal, Bank Road, Lahore, 53700, Pakistan
| | - Sania Khalid
- Centre for Applied Molecular Biology (CAMB), University of the Punjab, 87-West canal, Bank Road, Lahore, 53700, Pakistan
| | - Hamid Bashir
- Centre for Applied Molecular Biology (CAMB), University of the Punjab, 87-West canal, Bank Road, Lahore, 53700, Pakistan.
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Xu X, Liu Y, Liu Y, Yu Y, Yang M, Lu L, Chan L, Liu B. Functional hydrogels for hepatocellular carcinoma: therapy, imaging, and in vitro model. J Nanobiotechnology 2024; 22:381. [PMID: 38951911 PMCID: PMC11218144 DOI: 10.1186/s12951-024-02547-9] [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: 10/09/2023] [Accepted: 05/13/2024] [Indexed: 07/03/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most common malignancies worldwide and is characterized by high rates of morbidity and mortality, posing a serious threat to human health. Interventional embolization therapy is the main treatment against middle- and late-stage liver cancer, but its efficacy is limited by the performance of embolism, hence the new embolic materials have provided hope to the inoperable patients. Especially, hydrogel materials with high embolization strength, appropriate viscosity, reliable security and multifunctionality are widely used as embolic materials, and can improve the efficacy of interventional therapy. In this review, we have described the status of research on hydrogels and challenges in the field of HCC therapy. First, various preparation methods of hydrogels through different cross-linking methods are introduced, then the functions of hydrogels related to HCC are summarized, including different HCC therapies, various imaging techniques, in vitro 3D models, and the shortcomings and prospects of the proposed applications are discussed in relation to HCC. We hope that this review is informative for readers interested in multifunctional hydrogels and will help researchers develop more novel embolic materials for interventional therapy of HCC.
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Affiliation(s)
- Xiaoying Xu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, 519000, Guangdong, China
| | - Yu Liu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, 519000, Guangdong, China
| | - Yanyan Liu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, 519000, Guangdong, China
| | - Yahan Yu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, 519000, Guangdong, China
| | - Mingqi Yang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, 519000, Guangdong, China
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, 519000, Guangdong, China.
| | - Leung Chan
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, 519000, Guangdong, China.
| | - Bing Liu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, 519000, Guangdong, China.
- Guangzhou First People's Hospital, the Second Affiliated Hospital, School of Medicine, South China University of Technology, 510006, Guangzhou, China.
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Li S, Liang F, Huang D, Wu H, Tan X, Ma J, Wei C, Wang S, Huang Z, Yang G, He X, Yang J. Diterpenoids from the Aerial Parts of Isodon serra with Selective Cytotoxic Activity. Molecules 2024; 29:2733. [PMID: 38930799 PMCID: PMC11207078 DOI: 10.3390/molecules29122733] [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: 05/11/2024] [Revised: 05/27/2024] [Accepted: 05/31/2024] [Indexed: 06/28/2024] Open
Abstract
Four new diterpenoids, isodosins A-D (1-4), together with nine known compounds (5-13) were isolated and identified from the aerial parts of Isodon serra (Maxim.) Hara. The structures of the new diterpenoids were elucidated based on the analysis of HR-ESI-MS data, 1D/2D-NMR-spectroscopic data, and electronic circular dichroism (ECD) calculations. Cytotoxicities of compounds 2, 3, 5, 6, and 9 against the HepG2 and H1975 cell lines were evaluated with the MTT assay. As a result, compounds 2, 3, and 6 revealed higher levels of cytotoxicity against HepG2 cells than against H1975 cells. Moreover, compund 6 demonstrated the most efficacy in inhibiting the proliferation of HepG2 cells, with an IC50 value of 41.13 ± 3.49 μM. This effect was achieved by inducing apoptosis in a dose-dependent manner. Furthermore, the relationships between the structures and activities of these compounds are briefly discussed.
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Affiliation(s)
- Siqin Li
- School of Traditional Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.L.); (F.L.); (D.H.); (H.W.); (X.T.); (J.M.); (C.W.); (S.W.); (Z.H.)
| | - Fang Liang
- School of Traditional Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.L.); (F.L.); (D.H.); (H.W.); (X.T.); (J.M.); (C.W.); (S.W.); (Z.H.)
| | - Dongdong Huang
- School of Traditional Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.L.); (F.L.); (D.H.); (H.W.); (X.T.); (J.M.); (C.W.); (S.W.); (Z.H.)
| | - Huanling Wu
- School of Traditional Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.L.); (F.L.); (D.H.); (H.W.); (X.T.); (J.M.); (C.W.); (S.W.); (Z.H.)
| | - Xiaohua Tan
- School of Traditional Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.L.); (F.L.); (D.H.); (H.W.); (X.T.); (J.M.); (C.W.); (S.W.); (Z.H.)
| | - Jiang Ma
- School of Traditional Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.L.); (F.L.); (D.H.); (H.W.); (X.T.); (J.M.); (C.W.); (S.W.); (Z.H.)
| | - Caihong Wei
- School of Traditional Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.L.); (F.L.); (D.H.); (H.W.); (X.T.); (J.M.); (C.W.); (S.W.); (Z.H.)
| | - Shixiong Wang
- School of Traditional Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.L.); (F.L.); (D.H.); (H.W.); (X.T.); (J.M.); (C.W.); (S.W.); (Z.H.)
| | - Ziying Huang
- School of Traditional Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.L.); (F.L.); (D.H.); (H.W.); (X.T.); (J.M.); (C.W.); (S.W.); (Z.H.)
| | - Guang Yang
- China Academy of Chinese·Medical Sciences, Beijing 100700, China;
| | - Xin He
- School of Traditional Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.L.); (F.L.); (D.H.); (H.W.); (X.T.); (J.M.); (C.W.); (S.W.); (Z.H.)
| | - Ji Yang
- School of Traditional Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.L.); (F.L.); (D.H.); (H.W.); (X.T.); (J.M.); (C.W.); (S.W.); (Z.H.)
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Min K, Karuppannan SK, Tae G. The impact of matrix stiffness on hepatic cell function, liver fibrosis, and hepatocellular carcinoma-Based on quantitative data. BIOPHYSICS REVIEWS 2024; 5:021306. [PMID: 38846007 PMCID: PMC11151446 DOI: 10.1063/5.0197875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 05/14/2024] [Indexed: 06/09/2024]
Abstract
Over the past few decades, extensive research has explored the development of supportive scaffold materials for in vitro hepatic cell culture, to effectively mimic in vivo microenvironments. It is crucial for hepatic disease modeling, drug screening, and therapeutic evaluations, considering the ethical concerns and practical challenges associated with in vivo experiments. This review offers a comprehensive perspective on hepatic cell culture using bioscaffolds by encompassing all stages of hepatic diseases-from a healthy liver to fibrosis and hepatocellular carcinoma (HCC)-with a specific focus on matrix stiffness. This review begins by providing physiological and functional overviews of the liver. Subsequently, it explores hepatic cellular behaviors dependent on matrix stiffness from previous reports. For hepatic cell activities, softer matrices showed significant advantages over stiffer ones in terms of cell proliferation, migration, and hepatic functions. Conversely, stiffer matrices induced myofibroblastic activation of hepatic stellate cells, contributing to the further progression of fibrosis. Elevated matrix stiffness also correlates with HCC by increasing proliferation, epithelial-mesenchymal transition, metastasis, and drug resistance of HCC cells. In addition, we provide quantitative information on available data to offer valuable perspectives for refining the preparation and development of matrices for hepatic tissue engineering. We also suggest directions for further research on this topic.
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Affiliation(s)
- Kiyoon Min
- School of Materials Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea
| | - Sathish Kumar Karuppannan
- School of Materials Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea
| | - Giyoong Tae
- School of Materials Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea
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10
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Li T, Yi J, Wu H, Wang K, Zhou B. SLC7A11 in hepatocellular carcinoma: potential mechanisms, regulation, and clinical significance. Am J Cancer Res 2024; 14:2326-2342. [PMID: 38859833 PMCID: PMC11162675 DOI: 10.62347/kgcl7357] [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: 03/06/2024] [Accepted: 05/13/2024] [Indexed: 06/12/2024] Open
Abstract
Exploring novel early detection biomarkers and developing more efficacious treatments remain pressing tasks in the current research landscape for hepatocellular carcinoma (HCC). Morphologically and molecularly separate from apoptosis, cell death, and autophagy, ferroptosis is a recently discovered, unique, controlled form of cell death. SLC7A11 (also known as xCT) represents a subunit of the cystine-glutamate antiporter (also known as system Xc(-)). A growing body of research suggests that induction of ferroptosis through SLC7A11 can effectively eliminate hepatocellular carcinoma (HCC) cells, particularly those exhibiting resistance to alternative forms of cell death. Thus, targeting ferroptosis via SLC7A11 may become a new direction for the design of therapeutic strategies for HCC. Although many research articles have investigated the possible roles of SLC7A11 in HCC, a study that summarizes the main findings, including the regulators and mechanisms of action of SLC7A11 in HCC is not available. Therefore, we present a comprehensive overview of the functions of ferroptosis, particularly SLC7A11, in the identification, development, and management of HCC in this review. In addition, we discuss how this knowledge can be translated into treatment by providing a systemic therapy in advanced HCC using sorafenib, the first-line drug targeting multiple kinases and SLC7A11. We further dissect the possible barriers as well as the corresponding solutions and provide insights on how to navigate effective treatment using this knowledge.
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Affiliation(s)
- Tianze Li
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Nanchang UniversityNanchang 330006, Jiangxi, P. R. China
- Queen Mary School, Nanchang UniversityNanchang 330006, Jiangxi, P. R. China
| | - Jianwei Yi
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Nanchang UniversityNanchang 330006, Jiangxi, P. R. China
| | - Huajun Wu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Nanchang UniversityNanchang 330006, Jiangxi, P. R. China
| | - Kai Wang
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Nanchang UniversityNanchang 330006, Jiangxi, P. R. China
- Jiangxi Province Engineering Research Center of Hepatobiliary DiseaseNanchang 330006, Jiangxi, P. R. China
| | - Binghai Zhou
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Nanchang UniversityNanchang 330006, Jiangxi, P. R. China
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11
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Cao J, Hong K, Lv C, Jiang W, Chen Q, Wang R, Wang Y. Reduction-sensitive polymeric carrier for the targeted delivery of a quinazoline derivative for enhanced generation of reactive oxygen species against cancer. Biomater Sci 2024; 12:2626-2638. [PMID: 38526801 DOI: 10.1039/d3bm02136j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors and the development of effective therapeutics against HCC is urgently needed. A novel quinazoline derivative 04NB-03 (Qd04) has been proved to be highly effective against HCC without obvious toxic side-effects. However, the poor water solubility and low bioavailability in vivo severely limit its clinical application. In addition, Qd04 kills tumor cells by inducing an accumulation of endogenous reactive oxygen species (ROS), which is highly impeded by the overexpression of glutathione (GSH) in tumor cells. Herein, we designed a disulfide cross-linked polyamino acid micelle to deliver Qd04 for HCC therapy. The disulfide linkage not only endowed a tumor-targeted delivery of Qd04 by responding to tumor cell GSH but also depleted GSH to achieve increased levels of ROS generation, which improved the therapeutic efficiency of Qd04. Both in vitro and in vivo results demonstrated that the synthesized nanodrug exerted good anti-hepatoma effects, which provided a potential application for HCC therapy in clinics.
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Affiliation(s)
- Jianrong Cao
- College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China.
| | - Keze Hong
- College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China.
| | - Chengqi Lv
- College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China.
| | - Weiting Jiang
- College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China.
| | - Qi Chen
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Rongze Wang
- College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China.
| | - Yong Wang
- College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China.
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12
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Yin X, Rong J, Shao M, Zhang S, Yin L, He Z, Wang X. Aptamer-functionalized nanomaterials (AFNs) for therapeutic management of hepatocellular carcinoma. J Nanobiotechnology 2024; 22:243. [PMID: 38735927 PMCID: PMC11089756 DOI: 10.1186/s12951-024-02486-5] [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: 01/06/2024] [Accepted: 04/17/2024] [Indexed: 05/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) represents one of the deadliest cancers globally, making the search for more effective diagnostic and therapeutic approaches particularly crucial. Aptamer-functionalized nanomaterials (AFNs), an innovative nanotechnology, have paved new pathways for the targeted diagnosis and treatment of HCC. Initially, we outline the epidemiological background of HCC and the current therapeutic challenges. Subsequently, we explore in detail how AFNs enhance diagnostic and therapeutic efficiency and reduce side effects through the specific targeting of HCC cells and the optimization of drug delivery. Furthermore, we address the challenges faced by AFNs in clinical applications and future research directions, with a particular focus on enhancing their biocompatibility and assessing long-term effects. In summary, AFNs represent an avant-garde therapeutic approach, opening new avenues and possibilities for the diagnosis and treatment of HCC.
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Affiliation(s)
- Xiujuan Yin
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Jing Rong
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Min Shao
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Saisai Zhang
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Likang Yin
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Zhenqiang He
- Clinical Medical College, Hebei University, Baoding, 071002, Hebei, China
| | - Xiao Wang
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
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13
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Yang JDI, Liu YC, Wang HC, Hsu FT, Liao TL, Huang MC, Chen JH. Quetiapine Significantly Improves the Effectiveness of Radiotherapy in Combating Hepatocellular Carcinoma Progression in a Hep3B Xenograft Mouse Model. In Vivo 2024; 38:1079-1093. [PMID: 38688627 PMCID: PMC11059866 DOI: 10.21873/invivo.13542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/15/2024] [Accepted: 01/26/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND/AIM In hepatocellular carcinoma (HCC) treatment, radiotherapy (RT) stands as a pivotal approach, yet the emergence of radioresistance poses a formidable challenge. This study aimed to explore the potential synergy between quetiapine and RT for HCC treatment. MATERIALS AND METHODS A Hep3B xenograft mouse model was used, the investigation tracked tumor progression, safety parameters, and molecular mechanisms. RESULTS The findings revealed a synergistic anti-HCC effect when quetiapine was coupled with RT that prolonged tumor growth time and a significantly higher growth inhibition rate compared to the control group. Safety assessments indicated minimal pathological changes, suggesting potential of quetiapine in mitigating RT-induced alterations in liver and kidney functions. Mechanistically, the combination suppressed metastasis and angiogenesis-related proteins, while triggering the activation of apoptosis-related proteins via targeting Epidermal growth factor receptor (EGFR)-mediated signaling. CONCLUSION The potential of the quetiapine and RT combination is emphasized, offering enhanced anti-HCC efficacy, a safety profile, and positioning quetiapine as a radiosensitizer for HCC treatment.
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Affiliation(s)
- Jr-DI Yang
- Division of Urology, Department of Surgery, National Yang-Ming Chiao Tung University Hospital, Yilan, Taiwan, R.O.C
| | - Yu-Chang Liu
- Department of Radiation Oncology, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan, R.O.C
- Department of Radiation Oncology, Show Chwan Memorial Hospital, Changhua, Taiwan, R.O.C
- Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung, Taiwan, R.O.C
| | - Hsiao-Chia Wang
- Department of Emergency Medicine, Cathay General Hospital, Taipei, Taiwan, R.O.C
- School of Medicine, Fu Jen Catholic University, Taipei, Taiwan, R.O.C
| | - Fei-Ting Hsu
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C
| | - Tsai Lan Liao
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan, R.O.C
| | - Meng-Chu Huang
- Department of Medical Imaging, Show Chwan Memorial Hospital, Changhua, Taiwan, R.O.C.
| | - Jiann-Hwa Chen
- Department of Emergency Medicine, Cathay General Hospital, Taipei, Taiwan, R.O.C.;
- School of Medicine, Fu Jen Catholic University, Taipei, Taiwan, R.O.C
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14
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Singh K, Kumar P, Singh AK, Singh N, Singh S, Tiwari KN, Agrawal S, Das R, Singh A, Ram B, Tripathi AK, Mishra SK. In silico and network pharmacology analysis of fucosterol: a potent anticancer bioactive compound against HCC. Med Oncol 2024; 41:130. [PMID: 38676780 DOI: 10.1007/s12032-024-02374-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 03/28/2024] [Indexed: 04/29/2024]
Abstract
The Fucaceae family of marine brown algae includes Ascophyllum nodosum. Fucosterol (FSL) is a unique bioactive component that was identified through GC-MS analysis of the hydroalcoholic extract of A. nodosum. Fucosterol's mechanism of action towards hepatocellular cancer was clarified using network pharmacology and docking study techniques. The probable target gene of FSL has been predicted using the TargetNet and SwissTargetPred databases. GeneCards and the DisGNet database were used to check the targeted genes of FSL. By using the web programme Venny 2.1, the overlaps of FSL and HCC disease demonstrated that 18 genes (1.3%) were obtained as targeted genes Via the STRING database, a protein-protein interaction (PPI) network with 18 common target genes was constructed. With the aid of CytoNCA, hub genes were screened using the Cytoscape software, and the targets' hub genes were exported into the ShinyGo online tool for study of KEGG and gene ontology enrichment. Using the software AutoDock, a hub gene molecular docking study was performed. Ten genes, including AR, CYP19A1, ESR1, ESR2, TNF, PPARA, PPARG, HMGCR, SRC, and IGF1R, were obtained. The 10 targeted hubs docked with FSL successfully. The active components FSL of ASD, the FSL, are engaged in fatty liver disease, cancer pathways, and other signalling pathways, which could prove beneficial for the management of HCC.
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Affiliation(s)
- Kajal Singh
- Department of Biosciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Pradeep Kumar
- Department of Botany, MMV, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India
| | - Amit Kumar Singh
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, UP, 221005, India
| | - Nancy Singh
- Department of Biosciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Sakshi Singh
- Department of Biotechnology, Parul Institute of Applied Science, Parul University, Vadodara, Gujarat, 391760, India
| | - Kavindra Nath Tiwari
- Department of Botany, MMV, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India
| | - Shreni Agrawal
- Department of Bioscience and Biotechnology, Banasthali Vidhyapith, Tonk, Rajsthan, India
| | - Richa Das
- Department of Bioscience and Biotechnology, Banasthali Vidhyapith, Tonk, Rajsthan, India
| | - Anuradha Singh
- Department of Biosciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Bhuwal Ram
- Department of Dravyaguna, IMS, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India
| | - Amit Kumar Tripathi
- School of Basic and Applied Science, Galgotias University, Gautam Buddha Nagar, Greater Noida, Uttar Pradesh, 203201, India
| | - Sunil Kumar Mishra
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, UP, 221005, India.
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15
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Wen X, Huang Z, Yang X, He X, Li L, Chen H, Wang K, Guo Q, Liu J. Development of an aptamer capable of multidrug resistance reversal for tumor combination chemotherapy. Proc Natl Acad Sci U S A 2024; 121:e2321116121. [PMID: 38557176 PMCID: PMC11009676 DOI: 10.1073/pnas.2321116121] [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: 12/13/2023] [Accepted: 02/26/2024] [Indexed: 04/04/2024] Open
Abstract
Multidrug resistance (MDR) is a major factor in the failure of many forms of tumor chemotherapy. Development of a specific ligand for MDR-reversal would enhance the intracellular accumulation of therapeutic agents and effectively improve the tumor treatments. Here, an aptamer was screened against a doxorubicin (DOX)-resistant human hepatocellular carcinoma cell line (HepG2/DOX) via cell-based systematic evolution of ligands by exponential enrichment. A 50 nt truncated sequence termed d3 was obtained with high affinity and specificity for HepG2/DOX cells. Multidrug resistance protein 1 (MDR1) is determined to be a possible recognition target of the selected aptamer. Aptamer d3 binding was revealed to block the MDR of the tumor cells and increase the accumulation of intracellular anticancer drugs, including DOX, vincristine, and paclitaxel, which led to a boost to the cell killing of the anticancer drugs and lowering their survival of the tumor cells. The aptamer d3-mediated MDR-reversal for effective chemotherapy was further verified in an in vivo animal model, and combination of aptamer d3 with DOX significantly improved the suppression of tumor growth by treating a xenograft HepG2/DOX tumor in vivo. This work demonstrates the feasibility of a therapeutic DNA aptamer as a tumor MDR-reversal agent, and combination of the selected aptamer with chemotherapeutic drugs shows great potential for liver cancer treatments.
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Affiliation(s)
- Xiaohong Wen
- State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha410082, China
- College of Chemistry and Chemical Engineering, Hunan University, Changsha410082, China
- Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha410082, China
| | - Zhixiang Huang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha410082, China
- Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha410082, China
- College of Biology, Hunan University, Changsha410082, China
| | - Xiaohai Yang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha410082, China
- College of Chemistry and Chemical Engineering, Hunan University, Changsha410082, China
- Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha410082, China
| | - Xiaoxiao He
- State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha410082, China
- Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha410082, China
- College of Biology, Hunan University, Changsha410082, China
| | - Lie Li
- State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha410082, China
- Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha410082, China
- College of Biology, Hunan University, Changsha410082, China
| | - Haiyan Chen
- State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha410082, China
- Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha410082, China
- College of Biology, Hunan University, Changsha410082, China
| | - Kemin Wang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha410082, China
- College of Chemistry and Chemical Engineering, Hunan University, Changsha410082, China
- Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha410082, China
| | - Qiuping Guo
- State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha410082, China
- Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha410082, China
- College of Biology, Hunan University, Changsha410082, China
| | - Jianbo Liu
- State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha410082, China
- College of Chemistry and Chemical Engineering, Hunan University, Changsha410082, China
- Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha410082, China
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16
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Zhan G, Wei T, Xie H, Xie X, Hu J, Tang H, Cheng Y, Liu H, Li S, Yang G. Autophagy inhibition mediated by trillin promotes apoptosis in hepatocellular carcinoma cells via activation of mTOR/STAT3 signaling. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1575-1587. [PMID: 37676495 DOI: 10.1007/s00210-023-02700-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 08/29/2023] [Indexed: 09/08/2023]
Abstract
Apoptosis and autophagy have been shown to act cooperatively and antagonistically in self-elimination process. On the one side, apoptosis and autophagy can act as partners to induce cell death in a coordinated or cooperative manner; on the flip side, autophagy acts as an antagonist to block apoptotic cell death by promoting cell survival. Our previous research indicated that trillin could induce apoptosis of PLC/PRF/5 cells, but the effects of trillin on autophagy as well as its functional relationship to apoptosis have not been elucidated. Here, the running study aims to investigate the function and molecular mechanism of trillin on autophagy with hepatocellular carcinoma (HCC) cells. The objective of this study is to investigate the molecular mechanism of trillin on autophagy in HCC cells. Protein levels of autophagy markers beclin1, LC3B, and p62 were detected by western blotting. 6-Hydroxyflavone and stattic were used to test the role of trillin regulation of autophagy via serine threonine kinase (AKT)/extracellular-regulated protein kinases (ERK) 1/2/mammalian target of rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Flow cytometry was used to detect caspase 3 activity and apoptosis in PLC/PRF/5 cells treated with trillin for 24 h with or without rapamycin, stattic, and 6-hydroxyflavone. The protein level of autophagy marker beclin1 was decreased, whilst the protein level of p62 was significantly increased by trillin treatment, indicating trillin treatment led to inhibition of autophagy in HCC cells. Trillin treatment could reduce the protein levels of p-AKT and p-ERK1/2, but enhance the protein levels of mTOR and p-mTOR, suggesting that trillin could inhibit AKT/ERK rather than mTOR. The AKT/ERK activator 6-hydroxyflavone could reverse the loss of AKT and ERK1/2 phosphorylation induced by trillin, implying that trillin impairs autophagy through activated mTOR rather than AKT/ERK. STAT3 and p-STAT3 were significantly upregulated by the trillin treatment with an increase in dose from 0 to 50 μM, suggesting that autophagy inhibition is mediated by trillin via activation of STAT3 signaling. The STAT3 inhibitor stattic significantly reversed the increased STAT3 phosphorylation at tyrosine 705 induced by trillin. The mTOR signaling inhibitor rapamycin reversed the trillin-induced mTOR phosphorylation enhancement but exerted no effects on total mTOR levels, suggesting trillin treatment led to inhibition of autophagy in HCC cells through activating mTOR/STAT3 pathway. Furthermore, caspase 3 activities and the total rate of apoptosis were increased by trillin treatment, which was reversed by rapamycin, stattic, and 6-hydroxyflavone, proving that trillin promotes apoptosis via activation of mTOR/STAT3 signaling. Trillin induced autophagy inhibition and promoted apoptosis in PLC/PRF/5 cells via the activation of mTOR/STAT3 signaling. Trillin has the potential to be a viable therapeutic option for HCC treatment.
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Affiliation(s)
- Guangjie Zhan
- Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases, (Hubei Minzu University), Medical School of Hubei MinZu University, Enshi, Hubei, 445000, People's Republic of China
| | - Tiantian Wei
- Suizhou Hospital, Hubei University of Medicine, 441300, Suizhou, Hubei, People's Republic of China
| | - Huichen Xie
- Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases, (Hubei Minzu University), Medical School of Hubei MinZu University, Enshi, Hubei, 445000, People's Republic of China
| | - Xiaoming Xie
- Suizhou Hospital, Hubei University of Medicine, 441300, Suizhou, Hubei, People's Republic of China
| | - Jun Hu
- Department of Medical Genetics, School of Basic Medical Science, Demonstration Center for Experimental Basic Medicine Education, Wuhan University, 430071, Wuhan, Hubei, People's Republic of China
| | - Hao Tang
- Department of Medical Genetics, School of Basic Medical Science, Demonstration Center for Experimental Basic Medicine Education, Wuhan University, 430071, Wuhan, Hubei, People's Republic of China
| | - Yating Cheng
- Department of Medical Genetics, School of Basic Medical Science, Demonstration Center for Experimental Basic Medicine Education, Wuhan University, 430071, Wuhan, Hubei, People's Republic of China
| | - Huaifeng Liu
- School of Life Science, Bengbu Medical College, Bengbu, Anhui, 233030, People's Republic of China
| | - Shujing Li
- School of Life Science, Bengbu Medical College, Bengbu, Anhui, 233030, People's Republic of China.
| | - Guohua Yang
- Department of Medical Genetics, School of Basic Medical Science, Demonstration Center for Experimental Basic Medicine Education, Wuhan University, 430071, Wuhan, Hubei, People's Republic of China.
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17
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Falcone N, Ermis M, Gangrade A, Choroomi A, Young P, Mathes TG, Monirizad M, Zehtabi F, Mecwan M, Rodriguez M, Zhu Y, Byun Y, Khademhosseini A, de Barros NR, Kim H. Drug‐Eluting Shear‐Thinning Hydrogel for the Delivery of Chemo‐ and Immunotherapeutic Agents for the Treatment of Hepatocellular Carcinoma. ADVANCED FUNCTIONAL MATERIALS 2024; 34. [DOI: 10.1002/adfm.202309069] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Indexed: 01/06/2025]
Abstract
AbstractHepatocellular carcinoma (HCC) is a malignant and deadly form of liver cancer with limited treatment options. Transcatheter arterial chemoembolization, a procedure that delivers embolic and chemotherapeutic agents through blood vessels, is a promising cancer treatment strategy. However, it still faces limitations, such as inefficient agent delivery and the inability to address tumor‐induced immunosuppression. Here, a drug‐eluting shear‐thinning hydrogel (DESTH) loaded with chemotherapeutic and immunotherapeutic agents in nanocomposite hydrogels composed of gelatin and nanoclays is presented as a therapeutic strategy for a catheter‐based endovascular anticancer approach. DESTH is manually deliverable using a conventional needle and catheter. In addition, drug release studies show a sustained and pH‐dependent co‐delivery of the chemotherapy doxorubicin (acidic pH) and the immune‐checkpoint inhibitor aPD‐1 (neutral pH). In a mouse liver tumor model, the DESTH‐based chemo/immunotherapy combination has the highest survival rate and smallest residual tumor size. Finally, immunofluorescence analysis confirms that DESTH application enhances cell death and increases intratumoral infiltration of cytotoxic T‐cells. In conclusion, the results show that DESTH, which enables efficient ischemic tumor cell death and effective co‐delivery of chemo‐ and immunotherapeutic agents, may have the potential to be an effective therapeutic modality in the treatment of HCC.
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Affiliation(s)
- Natashya Falcone
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
| | - Menekse Ermis
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
| | - Ankit Gangrade
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
| | - Auveen Choroomi
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
| | - Patric Young
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
| | - Tess G. Mathes
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
| | - Mahsa Monirizad
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
| | - Fatemeh Zehtabi
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
| | - Marvin Mecwan
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
| | - Marco Rodriguez
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
| | - Yangzhi Zhu
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
| | - Youngjoo Byun
- Department of Pathophysiology and Preclinical Science College of Pharmacy Korea University 30019 Sejong Republic of Korea
| | - Ali Khademhosseini
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
| | | | - Han‐Jun Kim
- Terasaki Institute for Biomedical Innovation (TIBI) Los Angeles CA 90024 USA
- Department of Pathophysiology and Preclinical Science College of Pharmacy Korea University 30019 Sejong Republic of Korea
- Vellore Institute of Technology (VIT) Vellore 632014 India
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Shi H, Zou Y, Zhong W, Li Z, Wang X, Yin Y, Li D, Liu Y, Li M. Complex roles of Hippo-YAP/TAZ signaling in hepatocellular carcinoma. J Cancer Res Clin Oncol 2023; 149:15311-15322. [PMID: 37608027 DOI: 10.1007/s00432-023-05272-2] [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: 06/29/2023] [Accepted: 08/09/2023] [Indexed: 08/24/2023]
Abstract
BACKGROUND The Hippo signaling pathway is an evolutionarily conserved signaling module that controls organ size in different species, and the disorder of the Hippo pathway can induce liver cancer in organisms, especially hepatocellular carcinoma (HCC). The exact mechanism that causes cancer is still unknown. Recent studies have shown that it is a classical kinase cascade that phosphorylates the Mst1/2-sav1 complex and activates the phosphorylation of the Lats1/2-mob1A/B complex for inactivating Yap and Taz. These kinases and scaffolds are regarded as primary regulators of the Hippo pathway, and help in activating a variety of carcinogenic processes. Among them, Yap/Taz is seen to be the main effector molecule, which is downstream of the Hippo pathway, and its abnormal activation is related to a variety of human cancers including liver cancer. Currently, since Yap/Taz plays a variety of roles in cancer promotion and tumor regeneration, the Hippo pathway has emerged as an attractive target in recent drug development research. METHODS We collect and review relevant literature in web of Science and Pubmed. CONCLUSION This review highlights the important roles of Yap/Taz in activating Hippo pathway in liver cancer. The recent findings on the crosstalks between the Hippo and other cancer associated pathways and moleculars are also discussed. In this review, we summarized and discussed recent breakthroughs in our understanding of how key components of the Hippo-YAP/TAZ pathway influence the hepatocellular carcinoma, including their effects on tumor occurrence and development, their roles in regulating metastasis, and their function in chemotherapy resistance. Further, the molecular mechanism and roles in regulating cross talk between Hippo-YAP/TAZ pathway and other cancer-associated pathways or oncogenes/cancer suppressor genes were summarized and discussed. More, many other inducers and inhibitors of this signaling cascade and available experimental therapies against the YAP/TAZ/TEAD axis were discussed. Targeting this pathway for cancer therapy may have great significance in the treatment of hepatocellular carcinoma. Graphical summary of the complex role of Hippo-YAP/TAZ signaling in hepatocellular carcinoma.
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Affiliation(s)
- Hewen Shi
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Ying Zou
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Weiwei Zhong
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Zhaoying Li
- Traditional Chinese Medicine Research Center, Shandong Public Health Clinical Center, Jinan, 250102, People's Republic of China
| | - Xiaoxue Wang
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Yancun Yin
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Defang Li
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Ying Liu
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China.
| | - Minjing Li
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China.
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Kaplan Ö. Synergistic induction of apoptosis in liver cancer cells: exploring the combined potential of doxorubicin and XL-888. Med Oncol 2023; 40:318. [PMID: 37794195 DOI: 10.1007/s12032-023-02181-9] [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: 08/14/2023] [Accepted: 09/02/2023] [Indexed: 10/06/2023]
Abstract
Combination therapy has been frequently preferred in treating various types of cancer in recent years. Targeted cancer therapy has also become one of the remarkable treatment modalities. Therefore, the aim of the study to investigate its cytotoxic and apoptotic effects on liver cancer cell lines by combining the classical chemotherapeutic drug doxorubicin (DOX) and a targeted agent, the new generation HSP90 inhibitor XL-888. The molecular docking method was used to predict the binding conformation of XL-888 on the human Hsp90. The single and combined cytotoxic effects of DOX and XL-888 on liver cancer cell lines HepG2 and HUH-7 were determined by MTT assay. The effect of the combined use of two drugs was evaluated using Chou and Talalay method. The levels of apoptotic genes and heat shock proteins gene and protein expression levels were investigated by quantitative real-time polymerase chain reaction and western blotting, respectively. Molecular docking results showed that XL-888 selectively binds to the ATP binding pocket of HSP90 with an estimated free binding energy of - 7.8 kcal/mol. DOX and XL-888 and their combination showed dose-dependent cytotoxic effect. The combination of drugs showed a synergistic effect on both cell lines. The results revealed that the combination of DOX and XL-888 potently induced apoptosis in liver cancer cell lines rather than using drugs alone. The combined treatment of DOX and XL-888 demonstrated synergistic cytotoxic and apoptotic effects on liver cancer cell lines, presenting a promising approach for combination therapy in liver cancer.
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Affiliation(s)
- Özlem Kaplan
- Department of Genetics and Bioengineering, Rafet Kayış Faculty of Engineering, Alanya Alaaddin Keykubat University, Antalya, Turkey.
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20
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Tang B, Xie L, Tang X, Tian J, Xiao S. Blood exosome marker miRNA-30d-5p: Role and regulation mechanism in cell stemness and gemcitabine resistance of hepatocellular carcinoma. Mol Cell Probes 2023; 71:101924. [PMID: 37536457 DOI: 10.1016/j.mcp.2023.101924] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 07/31/2023] [Accepted: 07/31/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND Cancer stem cells (CSCs) are different from regular cancer cells because of their self-renewal feature and differentiation potential, which establishes the backbone of the vital role of CSCs in the progress and drug resistance of hepatocellular carcinoma (HCC). The objective of this study was to evaluate the effects of blood exosome-derived miRNA-30d-5p on the stemness and gemcitabine resistance of HCC cells and the underlying mechanisms. METHODS The expression data of HCC-related miRNAs and mRNAs were downloaded from TCGA database and analyzed for differences. Employing the databases of starBase, TargetScan, miRDB, and mirDIP, we conducted target gene prediction upstream of mRNA. The expression of miRNA-30d-5p and SOCS3 mRNA was assayed by qRT-PCR, and the binding between them was validated by dual luciferase assay. CCK-8 was employed to evaluate cell viability and the IC50 value of gemcitabine. Cells were subjected to a sphere-forming assay to assess their ability to form spheres. Western blot was applied to evaluate the levels of cell surface marker proteins (Nanog, CD133, and Oct4) and exosome markers (CD9, CD81, and FLOT1). RESULTS Bioinformatics analysis found that SOCS3 expression was down-regulated in HCC. qRT-PCR showed that SOCS3 expression was notably lower in HCC cell lines than in normal liver cell WRL68. At the cellular functional level, SOCS3 overexpression inhibited the viability, sphere-forming ability, stemness, and gemcitabine resistance of HCC cells. Bioinformatics analysis demonstrated that miRNA-30d-5p was the upstream regulator of SOCS3 and highly expressed in HCC tissues and cells. Dual luciferase assay demonstrated that miRNA-30d-5p could bind SOCS3. Rescue experiments showed that upregulating SOCS3 could reverse the effects of miRNA-30d-5p overexpression on the viability, sphere-forming ability, and gemcitabine sensitivity of HCC cells. CONCLUSIONS Blood exosome-derived miRNA-30d-5p promoted the stemness and gemcitabine resistance of HCC cells by repressing SOCS3 expression. Hence, the miRNA-30d-5p/SOCS3 axis might be a therapeutic target for chemotherapy resistance and a feasible marker for the prognosis of HCC patients.
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Affiliation(s)
- Biao Tang
- Department of Hepatobiliary Pancreatic Spleen Surgery, The Central Hospital of Yongzhou, Yongzhou, Hunan, 425000, China.
| | - Longhui Xie
- Department of Hepatobiliary Pancreatic Spleen Surgery, The Central Hospital of Yongzhou, Yongzhou, Hunan, 425000, China
| | - Xin Tang
- Department of Hepatobiliary Pancreatic Spleen Surgery, The Central Hospital of Yongzhou, Yongzhou, Hunan, 425000, China
| | - Junjie Tian
- Department of Hepatobiliary Pancreatic Spleen Surgery, The Central Hospital of Yongzhou, Yongzhou, Hunan, 425000, China
| | - Shaofei Xiao
- Department of Hepatobiliary Pancreatic Spleen Surgery, The Central Hospital of Yongzhou, Yongzhou, Hunan, 425000, China
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21
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Fanale D, Corsini LR, Pedone E, Randazzo U, Fiorino A, Di Piazza M, Brando C, Magrin L, Contino S, Piraino P, Bazan Russo TD, Cipolla C, Russo A, Bazan V. Potential agnostic role of BRCA alterations in patients with several solid tumors: One for all, all for one? Crit Rev Oncol Hematol 2023; 190:104086. [PMID: 37536445 DOI: 10.1016/j.critrevonc.2023.104086] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 07/27/2023] [Accepted: 07/30/2023] [Indexed: 08/05/2023] Open
Abstract
Germline BRCA1/2 alterations in the Homologous Recombination (HR) pathway are considered as main susceptibility biomarkers to Hereditary Breast and Ovarian Cancers (HBOC). The modern molecular biology technologies allowed to characterize germline and somatic BRCA1/2 alterations in several malignancies, broadening the landscape of BRCA1/2-alterated tumors. In the last years, BRCA genetic testing, beyond the preventive value, also assumed a predictive and prognostic significance for patient management. The approval of molecules with agnostic indication is leading to a new clinical model, defined "mutational". Among these drugs, the Poly (ADP)-Ribose Polymerase inhibitors (PARPi) for BRCA1/2-deficient tumors were widely studied leading to increasing therapeutic implications. In this Review we provided an overview of the main clinical studies describing the association between BRCA-mutated tumors and PARPi response, focusing on the controversial evidence about the potential agnostic indication based on BRCA1/2 alterations in several solid tumors.
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Affiliation(s)
- Daniele Fanale
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Lidia Rita Corsini
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Erika Pedone
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Ugo Randazzo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Alessia Fiorino
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Marianna Di Piazza
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Chiara Brando
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Luigi Magrin
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Silvia Contino
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Paola Piraino
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Tancredi Didier Bazan Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Calogero Cipolla
- Division of General and Oncological Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Antonio Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Viviana Bazan
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy
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22
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PAN L, QI C, SHEN X, HUANG Y, YANG X, SUN X. Traditional Chinese Medicine syndrome analysis on oxaliplatin-induced peripheral neuropathy and clinical efficacy of Bushen Yiqi formula: a prospective randomized controlled study. J TRADIT CHIN MED 2023; 43:1234-1242. [PMID: 37946486 PMCID: PMC10623258 DOI: 10.19852/j.cnki.jtcm.20230630.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 12/23/2022] [Indexed: 11/12/2023]
Abstract
OBJECTIVES To analyze the distribution characteristics of Traditional Chinese Medicine (TCM) syndromes in patients with oxaliplatin-induced peripheral neuropathy (OIPN) and observe the clinical efficacy of Bushen Yiqi formula (, BSYQF) in treating patients with OIPN. METHODS A total of 89 patients with OIPN were enrolled in this study. The TCM syndrome characteristics were investigated by frequency analysis methodology after collecting and analyzing the TCM syndrome elements of the patients with the OIPN TCM syndrome element scale. Further, 62 cases of cold-dampness obstruction syndrome and kidney-Qi deficiency and cold syndrome were selected and randomly divided into the control group (n = 31) and the treatment group (n = 31). The patients in the treatment group were treated with modified BSYQF, while those in the control group were treated with mecobalamin tablets for 3 weeks. The Levi sensory neurotoxicity score and the neuro-electrophysiological changes were observed before and after the treatment in both groups. RESULTS The distribution of TCM syndrome types in 89 patients with OIPN were in order of kidney-Qi deficiency and cold syndrome (44 cases), cold-dampness obstruction syndrome (18 cases), Yin deficiency of liver and kidney syndrome (11 cases), blood stasis obstruction syndrome (7 cases), and dampness-heat obstruction syndrome (5 cases). Improvement in Levi sensory neurotoxicity score: After 3-week treatment, the total effective rate in the treatment group was higher than that in the control group (P < 0.05). The subgroup analysis showed that the total effective rate in the treatment group of patients with kidney-Qi deficiency and cold syndrome was higher than that in the control group before and after treatment (P < 0.05). Improvement in nerve conduction velocity: The sensory nerve conduction velocity of bilateral ulnar nerves improved in the control group after treatment compared with that before treatment (P < 0.05). The sensory and motor nerve conduction velocities of the bilateral ulnar and bilateral peroneal nerves improved in the treatment group compared with those before treatment and after treatment in the control group (P < 0.05). CONCLUSIONS The modified BSYQF had a definite therapeutic effect on the OIPN in patients with kidney-Qi deficiency and cold syndrome and those with cold-dampness obstruction syndrome. It could effectively reduce the grade of peripheral nerve toxicity and improve nerve conduction velocity, and its curative effect was better than that of mecobalamin tablets.
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Affiliation(s)
- Longci PAN
- 1 Department of Tradition Chinese Medicine, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China
| | - Chunhui QI
- 2 Department of Oncology, Shanghai Qingpu District Hospital of Traditional Chinese Medicine (the Clinical Base of The Institutes of Integrative Medicine, Fudan University), Shanghai 201799, China
| | - Xubo SHEN
- 3 Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Yixian HUANG
- 1 Department of Tradition Chinese Medicine, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China
| | - Xinrong YANG
- 2 Department of Oncology, Shanghai Qingpu District Hospital of Traditional Chinese Medicine (the Clinical Base of The Institutes of Integrative Medicine, Fudan University), Shanghai 201799, China
| | - Xianjun SUN
- 4 Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
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Urade R, Chang WT, Ko CC, Li RN, Yang HM, Chen HY, Huang LY, Chang MY, Wu CY, Chiu CC. A fluorene derivative inhibits human hepatocellular carcinoma cells by ROS-mediated apoptosis, anoikis and autophagy. Life Sci 2023; 329:121835. [PMID: 37295712 DOI: 10.1016/j.lfs.2023.121835] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/02/2023] [Accepted: 06/04/2023] [Indexed: 06/12/2023]
Abstract
Fluorene was previously reported to have anticancer activity against human cancer cells. In this study, we examined the in vitro function of 9-methanesulfonylmethylene-2, 3-dimethoxy-9 H -fluorene (MSDF), a novel fluorene derivative, its anticancer potential in human hepatocellular carcinoma (HCC) cells and its underlying molecular mechanism. The disruption of cellular homeostasis caused by MSDF was found to promote reactive oxygen species (ROS) generation, leading to the activation of cellular apoptosis. As a survival strategy, cells undergo autophagy during oxidative stress. MSDF-induced apoptosis occurred through both receptor-mediated extrinsic and mitochondrial-mediated intrinsic routes. The development of acidic vesicular organelles and the accumulation of LC3-II protein suggest an increase in the autophagic process. Apoptosis was detected by double staining. The MAPK/ERK and PI3K/Akt signaling pathways were indeed suppressed during treatment. Along with elevated ROS generation and apoptosis, MSDF also caused anoikis and cell death by causing cells to lose contact with their extracellular matrix. ROS production was induced by MSDF and sustained by an NAC scavenger. MSDF-induced apoptosis led to increased autophagy, as shown by the suppression of apoptosis by Z-VAD-FMK. However, inhibition of autophagy by inhibitor 3-MA increased MSDF-induced apoptosis. More evidence shows that MSDF downregulated the expression of immune checkpoint proteins, suggesting that MSDF could be used in the future as an adjuvant to improve the effectiveness of HCC immunotherapy. Altogether, our results highlight the potential of MSDF as a multitarget drug for the treatment of HCC.
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Affiliation(s)
- Ritesh Urade
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Wen-Tsan Chang
- Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Ching-Chung Ko
- Department of Medical Imaging, Chi Mei Medical Center, Tainan 71004, Taiwan; Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan717, Taiwan
| | - Ruei-Nian Li
- Department of Biomedical Science and Environment Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Hui-Min Yang
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Hsuan-Yu Chen
- Department of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Lin-Ya Huang
- Department of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Meng-Yang Chang
- Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Chang-Yi Wu
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Chien-Chih Chiu
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; National Laboratory Animal Center, National Applied Research Laboratories, Taipei 115, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
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24
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Nasr M, Kira AY, Saber S, Essa EA, El-Gizawy SA. Lactosylated Chitosan Nanoparticles Potentiate the Anticancer Effects of Telmisartan In Vitro and in a N-Nitrosodiethylamine-Induced Mice Model of Hepatocellular Carcinoma. Mol Pharm 2023; 20:4758-4769. [PMID: 37585079 DOI: 10.1021/acs.molpharmaceut.3c00542] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/17/2023]
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality worldwide. Telmisartan (TLM), a BSC class II drug, has been reported to have antiproliferative activity in HCC. However, its therapeutic activity is limited by poor bioavailability and unpredictable distribution. This work aimed to enhance TLM's liver uptake for HCC management through passive and active targeting pathways utilizing chitosan nanoparticles decorated with lactose (LCH NPs) as a delivery system. In vitro cell cytotoxicity and cellular uptake studies indicated that TLM-LCH NPs significantly (p < 0.05) enhanced the antiproliferative activity and cellular uptake percentage of TLM. In vivo bioavailability and liver biodistribution studies indicated that TLM-LCH NPs significantly (p < 0.05) enhanced TLM concentrations in plasma and the liver. The relative liver uptake of TLM from TLM-LCH NPs was 2-fold higher than that of unmodified NPs and 5-fold higher than that of plain TLM suspension. In vivo studies of a N-nitrosodiethylamine-induced HCC model revealed that administration of TLM through LCH NPs improved liver histology and resulted in lower serum alpha-fetoprotein (AFP), matrix metalloproteinase 2 (MMP-2), vascular endothelial growth factor (VEGF) levels, and liver weight index compared to plain TLM and TLM-loaded unmodified NPs. These results reflected the high potentiality of LCH NPs as a liver-targeted delivery system for TLM in the treatment of HCC.
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Affiliation(s)
- Mohamed Nasr
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Helwan University, Cairo 11790, Egypt
- Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
| | - Ahmed Y Kira
- Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
| | - Ebtessam A Essa
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Tanta 31111, Egypt
| | - Sanaa A El-Gizawy
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Tanta 31111, Egypt
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Chen D, Wang J, Li Y, Xu C, Fanzheng M, Zhang P, Liu L. LncRNA NEAT1 suppresses cellular senescence in hepatocellular carcinoma via KIF11-dependent repression of CDKN2A. Clin Transl Med 2023; 13:e1418. [PMID: 37752791 PMCID: PMC10522973 DOI: 10.1002/ctm2.1418] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 09/02/2023] [Accepted: 09/07/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Therapeutic options for advanced HCC are limited, which is due to a lack of full understanding of pathogenesis. Cellular senescence is a state of cell cycle arrest, which plays important roles in the pathogenesis of HCC. Mechanisms underlying hepatocellular senescence are not fully understood. LncRNA NEAT1 acts as an oncogene and contributes to the development of HCC. Whether NEAT1 modulates hepatocellular senescence in HCC is unknown. METHODS The role of NEAT1 and KIF11 in cellular senescence and tumor growth in HCC was assessed both in vitro and in vivo. RNA pulldown, mass spectrometry, Chromatin immunoprecipitation (ChIP), luciferase reporter assays, RNA FISH and immunofluorescence (IF) staining were used to explore the detailed molecular mechanism of NEAT1 and KIF11 in cellular senescence of HCC. RESULTS We found that NEAT1 was upregulated in tumor tissues and hepatoma cells, which negatively correlated with a senescence biomarker CDKN2A encoding p16INK4a and p14ARF proteins. NEAT1 was reduced in senescent hepatoma cells induced by doxorubicin (DOXO) or serum starvation. Furthermore, NEAT1 deficiency caused senescence in cultured hepatoma cells, and protected against the progression of HCC in a mouse model. During senescence, NEAT1 translocated into cytosol and interacted with a motor protein KIF11, resulting in KIF11 protein degradation and subsequent increased expression of CDKN2A in cultured hepatoma cells. Furthermore, KIF11 knockdown caused senescence in cultured hepatoma cells. Genetic deletion of Kif11 in hepatocytes inhibited the development of HCC in a mouse model. CONCLUSIONS Conclusively, NEAT1 overexpression reduces senescence and promotes tumor progression in HCC tissues and hepatoma cells, whereas NEAT1 deficiency causes senescence and inhibits tumor progression in HCC. This is associated with KIF11-dependent repression of CDKN2A. These findings lay the foundation to develop potential therapies for HCC by inhibiting NEAT1 and KIF11 or inducing senescence.
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Affiliation(s)
- Danlei Chen
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefeiAnhuiChina
- Anhui Provincial Clinical Research Center for Hepatobiliary DiseasesHefeiAnhuiChina
| | - Jinghao Wang
- Zhejiang Cancer HospitalHangzhou Institute of MedicineChinese Academy of SciencesHangzhouZhejiangChina
| | - Yang Li
- Zhejiang Cancer HospitalHangzhou Institute of MedicineChinese Academy of SciencesHangzhouZhejiangChina
| | - Chenglin Xu
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Meng Fanzheng
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefeiAnhuiChina
- Anhui Provincial Clinical Research Center for Hepatobiliary DiseasesHefeiAnhuiChina
| | - Pengfei Zhang
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
- Zhejiang Cancer HospitalHangzhou Institute of MedicineChinese Academy of SciencesHangzhouZhejiangChina
| | - Lianxin Liu
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefeiAnhuiChina
- Anhui Provincial Clinical Research Center for Hepatobiliary DiseasesHefeiAnhuiChina
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Özkan A, Stolley DL, Cressman ENK, McMillin M, Yankeelov TE, Rylander MN. Vascularized Hepatocellular Carcinoma on a Chip to Control Chemoresistance through Cirrhosis, Inflammation and Metabolic Activity. SMALL STRUCTURES 2023; 4:2200403. [PMID: 38073766 PMCID: PMC10707486 DOI: 10.1002/sstr.202200403] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2024]
Abstract
Understanding the effects of inflammation and cirrhosis on the regulation of drug metabolism during the progression of hepatocellular carcinoma (HCC) is critical for developing patient-specific treatment strategies. In this work, we created novel three-dimensional vascularized HCC-on-a-chips (HCCoC), composed of HCC, endothelial, stellate, and Kupffer cells tuned to mimic normal or cirrhotic liver stiffness. HCC inflammation was controlled by tuning Kupffer macrophage numbers, and the impact of cytochrome P450-3A4 (CYP3A4) was investigated by culturing HepG2 HCC cells transfected with CYP3A4 to upregulate expression from baseline. This model allowed for the simulation of chemotherapeutic delivery methods such as intravenous injection and transcatheter arterial chemoembolization (TACE). We showed that upregulation of metabolic activity, incorporation of cirrhosis and inflammation, increase vascular permeability due to upregulated inflammatory cytokines leading to significant variability in chemotherapeutic treatment efficacy. Specifically, we show that further modulation of CYP3A4 activity of HCC cells by TACE delivery of doxorubicin provides an additional improvement to treatment response and reduces chemotherapy-associated endothelial porosity increase. The HCCoCs were shown to have utility in uncovering the impact of the tumor microenvironment (TME) during cancer progression on vascular properties, tumor response to therapeutics, and drug delivery strategies.
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Affiliation(s)
- Alican Özkan
- Department of Mechanical Engineering, The University of Texas, Austin, TX, 78712, United States
- Current address: Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, 02115, United States
| | - Danielle L Stolley
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030. United States
| | - Erik N K Cressman
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030. United States
| | - Matthew McMillin
- Department of Internal Medicine, The University of Texas at Austin, Dell Medical School
- Central Texas Veterans Health Care System, Austin, TX, 78712, United States
| | - Thomas E Yankeelov
- Department of Biomedical Engineering, The University of Texas, Austin, TX, 78712, United States
- Oden Institute for Computational Engineering and Sciences, The University of Texas, Austin, TX, 78712, United States
- Departments of Diagnostic Medicine, The University of Texas, Austin, TX, 78712, United States
- Department of Oncology, The University of Texas, Austin, TX, 78712, United States
- Livestrong Cancer Institutes, Dell Medical School, The University of Texas, Austin, TX, 78712, United States
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Marissa Nichole Rylander
- Department of Mechanical Engineering, The University of Texas, Austin, TX, 78712, United States
- Department of Biomedical Engineering, The University of Texas, Austin, TX, 78712, United States
- Oden Institute for Computational Engineering and Sciences, The University of Texas, Austin, TX, 78712, United States
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Ge WJ, Huang H, Wang T, Zeng WH, Guo M, Ren CR, Fan TY, Liu F, Zeng X. Long non-coding RNAs in hepatocellular carcinoma. Pathol Res Pract 2023; 248:154604. [PMID: 37302276 DOI: 10.1016/j.prp.2023.154604] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/06/2023] [Accepted: 06/06/2023] [Indexed: 06/13/2023]
Abstract
Long noncoding RNAs (lncRNAs) refer to a class of RNAs greater than 200 nucleotides in length, most of which are considered unable to encode proteins, thus deemed to be junk genes formerly. But with emerging studies about lncRNAs coming out in recent years, it is much more clearly depicted that they can regulate gene expression at different levels, with various mechanisms, thus participating in diverse biological or pathological processes, including complicated tumor-associated pathways. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, the third leading cause of cancer-related mortality worldwide, which has been found to tightly associate with aberrant expression of a variety of lncRNAs regulating tumor proliferation, invasion, drug resistance, and so on, making it a potential novel tumor marker and therapeutic target. In this review, we highlight a few lncRNAs that are closely related to the occurrence and progression of HCC and try to cover their multifarious roles from different layers.
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Affiliation(s)
- Wen-Jun Ge
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Huan Huang
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Jiangxi, China
| | - Tao Wang
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Wei-Hong Zeng
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Min Guo
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Chen-Ran Ren
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Ting-Yu Fan
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Fang Liu
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
| | - Xi Zeng
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
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Tustumi F, Coelho FF, de Paiva Magalhães D, Júnior SS, Jeismann VB, Fonseca GM, Kruger JAP, D'Albuquerque LAC, Herman P. Treatment of hepatocellular carcinoma with macroscopic vascular invasion: A systematic review and network meta-analysis. Transplant Rev (Orlando) 2023; 37:100763. [PMID: 37393656 DOI: 10.1016/j.trre.2023.100763] [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: 04/10/2023] [Revised: 05/11/2023] [Accepted: 05/14/2023] [Indexed: 07/04/2023]
Abstract
BACKGROUND This study aimed to evaluate the outcomes of different treatments for patients with hepatocellular carcinoma (HCC) and macroscopic vascular invasion. METHODS A systematic review and meta-analysis of comparative studies was performed to evaluate various treatment modalities for HCC with macroscopic vascular invasion, including liver resection (LR), liver transplantation (LT), transarterial chemoembolization (TACE), transarterial radioembolization (TARE), radiotherapy (RT), radiofrequency ablation (RFA), and antineoplastic systemic therapy (AnST). RESULTS After applying the selection criteria, 31 studies were included. The surgical resection (SR) group (including LR and LT) had a similar mortality rate to the non-surgical resection (NS) group (RD = -0.01; 95% CI -0.05 to 0.03). The SR group had a higher rate of complications (RD = 0.06; 95% CI 0.00 to 0.12) but a higher 3-year overall survival (OS) rate than the NS group (RD = 0.12; 95% CI 0.05 to 0.20). The network analysis revealed that the overall survival was lower in the AnST group. LT and LR had similar survival benefits. The meta-regression suggested that SR has a greater impact on the survival of patients with impaired liver function. DISCUSSION Most likely, LT has a significant impact on long-term survival and consequently would be a better option for HCC with macroscopic vascular invasion in patients with impaired liver function. LT and LR offer a higher chance of long-term survival than NS alternatives, although LR and LR are associated with a higher risk of procedure-related complications.
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Affiliation(s)
- Francisco Tustumi
- Divisão de Cirurgia do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
| | - Fabricio Ferreira Coelho
- Divisão de Cirurgia do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Daniel de Paiva Magalhães
- Divisão de Cirurgia do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Sérgio Silveira Júnior
- Divisão de Cirurgia do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Vagner Birk Jeismann
- Divisão de Cirurgia do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Gilton Marques Fonseca
- Divisão de Cirurgia do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Jaime Arthur Pirola Kruger
- Instituto do Câncer do Estado de São Paulo (ICESP), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Luiz Augusto Carneiro D'Albuquerque
- Divisão de Cirurgia do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Paulo Herman
- Divisão de Cirurgia do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
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Gull N, Arshad F, Naikoo GA, Hassan IU, Pedram MZ, Ahmad A, Aljabali AAA, Mishra V, Satija S, Charbe N, Negi P, Goyal R, Serrano-Aroca Á, Al Zoubi MS, El-Tanani M, Tambuwala MM. Recent Advances in Anticancer Activity of Novel Plant Extracts and Compounds from Curcuma longa in Hepatocellular Carcinoma. J Gastrointest Cancer 2023; 54:368-390. [PMID: 35285010 PMCID: PMC8918363 DOI: 10.1007/s12029-022-00809-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2022] [Indexed: 02/06/2023]
Abstract
PURPOSE Among all forms of cancers, hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. There are several treatment options for HCC ranging from loco-regional therapy to surgical treatment. Yet, there is high morbidity and mortality. Recent research focus has shifted towards more effective and less toxic cancer treatment options. Curcumin, the active ingredient in the Curcuma longa plant, has gained widespread attention in recent years because of its multifunctional properties as an antioxidant, anti-inflammatory, antimicrobial, and anticancer agent. METHODS A systematic search of PubMed, Embase and Google Scholar was performed for studies reporting incidence of HCC, risk factors associated with cirrhosis and experimental use of curcumin as an anti-cancer agent. RESULTS This review exclusively encompasses the anti-cancer properties of curcumin in HCC globally and it's postulated molecular targets of curcumin when used against liver cancers. CONCLUSIONS This review is concluded by presenting the current challenges and future perspectives of novel plant extracts derived from C. longa and the treatment options against cancers.
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Affiliation(s)
- Nighat Gull
- School of Sciences, Maulana Azad National Urdu University, 32, Hyderabad, TS, India
| | - Fareeha Arshad
- Department of Biochemistry, Aligarh Muslim University, U.P., India
| | - Gowhar A Naikoo
- Department of Mathematics and Sciences, College of Arts and Applied Sciences, Dhofar University, Salalah, Sultanate of Oman.
| | - Israr Ul Hassan
- College of Engineering, Dhofar University, Salalah, Sultanate of Oman
| | - Mona Zamani Pedram
- Faculty of Mechanical Engineering-Energy Division, K. N. Toosi University of Technology, P.O. Box: 19395-1999, No. 15-19, Pardis St., Mollasadra Ave., Vanak Sq., Tehran, 1999 143344, Iran
| | - Arif Ahmad
- School of Sciences, Maulana Azad National Urdu University, 32, Hyderabad, TS, India
| | - Alaa A A Aljabali
- Department of Pharmaceutics & Pharmaceutical Technology, Yarmouk University, Irbid, 21163, Jordan
| | - Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Saurabh Satija
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Nitin Charbe
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX, 78363, USA
| | - Poonam Negi
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology & Management Sciences, Solan, 173229, India
| | - Rohit Goyal
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology & Management Sciences, Solan, 173229, India
| | - Ángel Serrano-Aroca
- Biomaterials & Bioengineering Lab, Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia, San Vicente Mártir, 46001, Valencia, Spain
| | - Mazhar S Al Zoubi
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan
| | - Mohamed El-Tanani
- Pharmacological and Diagnostic Research Centre, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan
| | - Murtaza M Tambuwala
- School of Pharmacy & Pharmaceutical Sciences, Ulster University, Northern Ireland, Coleraine, BT52 1SA, County Londonderry, UK.
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Nguyen DT, Nguyen DH, Nguyen VTH. Sorafenib as first-line treatment for patients with primary hepatocellular carcinoma: an outcome evaluation. J Int Med Res 2023; 51:3000605231179928. [PMID: 37314298 DOI: 10.1177/03000605231179928] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023] Open
Abstract
OBJECTIVE To evaluate the clinical outcomes following first-line treatment with sorafenib in patients with primary hepatocellular carcinoma (HCC). METHODS This retrospective cohort study enrolled patients with primary HCC that had been treated with sorafenib. Their data were collected from the hospital medical records database at three time-points: after three cycles, after six cycles and at the end of the sorafenib treatment regimen. The starting dose was 800 mg/day sorafenib but this could be reduced to 600 mg/day or 400 mg/day if patients developed adverse events (AEs). RESULTS A total of 98 patients participated in the study. Of these, nine (9.2%) had a partial response, 47 patients (48.0%) had stable disease and 42 patients (42.9%) had progressive disease. The overall disease control rate was 57.1% (56 of 98 patients). Median progression-free survival for the overall cohort was 4.7 months. The most common AEs were hand-foot skin reaction (49 of 98 patients; 50.0%), fatigue (41 of 98 patients; 41.8%), appetite loss (39 of 98 patients; 39.8%) and hepatotoxicity/transaminitis (24 of 98 patients; 24.5%). The majority of the AEs were toxicity grades 1 and 2. CONCLUSION Sorafenib as a first-line treatment for primary HCC patients provided survival benefits and the AEs were well tolerated by patients.
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Affiliation(s)
- Dung Thi Nguyen
- Department of On-demand GI Medical Oncology, Hanoi Oncology Hospital, Hanoi, Vietnam
| | - Duong Hoang Nguyen
- Department of On-demand GI Medical Oncology, Hanoi Oncology Hospital, Hanoi, Vietnam
| | - Van Thi Hong Nguyen
- Department of On-demand GI Medical Oncology, Hanoi Oncology Hospital, Hanoi, Vietnam
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31
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Sun X, Zhou C, Xia S, Chen X. Small molecule-nanobody conjugate induced proximity controls intracellular processes and modulates endogenous unligandable targets. Nat Commun 2023; 14:1635. [PMID: 36964170 PMCID: PMC10039045 DOI: 10.1038/s41467-023-37237-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 03/08/2023] [Indexed: 03/26/2023] Open
Abstract
Chemically induced proximity (CIP) is a powerful tool to study cellular functions. However with current CIP inducers it is difficult to directly modulate unligandable and endogenous targets, and therapeutic translational potential is also restricted. Herein, we combine CIP and chemical nanobody engineering and create cell-permeable small molecule-nanobody conjugate inducers of proximity (SNACIPs). The SNACIP inducer cRGT carrying a cyclic cell-penetrating peptide rapidly enters live cells and dimerizes eDHFR and GFP-variants. cRGT enables minute-scale, reversible, no-wash and dose-dependent control of cellular processes including signaling cascade, cargo transport and ferroptosis. Small-molecule motifs can also be installed via post-translational modifications. Therefore, latent-type SNACIPs including cRTC are designed that are functionally assembled inside living cells. cRTC contains a nanobody against an intrinsically disordered protein TPX2, a microtubule nucleation factor overexpressed in various cancers. Cancer cell proliferation is inhibited and tumor growth is suppressed in vivo. Hence, SNACIPs are valuable proximity inducers for regulating cellular functions.
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Affiliation(s)
- Xiaofeng Sun
- Laboratory of Chemical Biology & Frontier Biotechnologies, The HIT Center for Life Sciences (HCLS), Harbin Institute of Technology (HIT), Harbin, 150001, PR China
- School of Life Science and Technology, HIT, Harbin, 150001, PR China
| | - Chengjian Zhou
- Laboratory of Chemical Biology & Frontier Biotechnologies, The HIT Center for Life Sciences (HCLS), Harbin Institute of Technology (HIT), Harbin, 150001, PR China
- School of Life Science and Technology, HIT, Harbin, 150001, PR China
| | - Simin Xia
- Laboratory of Chemical Biology & Frontier Biotechnologies, The HIT Center for Life Sciences (HCLS), Harbin Institute of Technology (HIT), Harbin, 150001, PR China
| | - Xi Chen
- Laboratory of Chemical Biology & Frontier Biotechnologies, The HIT Center for Life Sciences (HCLS), Harbin Institute of Technology (HIT), Harbin, 150001, PR China.
- School of Life Science and Technology, HIT, Harbin, 150001, PR China.
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Farasati Far B, Rabie D, Hemati P, Fooladpanjeh P, Faal Hamedanchi N, Broomand Lomer N, Karimi Rouzbahani A, Naimi-Jamal MR. Unresectable Hepatocellular Carcinoma: A Review of New Advances with Focus on Targeted Therapy and Immunotherapy. LIVERS 2023; 3:121-160. [DOI: 10.3390/livers3010011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
With an expected incidence of more than 1 million cases by 2025, liver cancer remains a problem for world health. With over 90% of cases, hepatocellular carcinoma (HCC) is the most prevalent kind of liver cancer. In this review, we presented the range of experimental therapeutics for patients with advanced HCC, the successes and failures of new treatments, areas for future development, the evaluation of dose-limiting toxicity in different drugs, and the safety profile in patients with liver dysfunction related to the underlying chronic liver disease. In addition to the unmet demand for biomarkers to guide treatment decisions and the burgeoning fields of immunotherapy and systemic therapy in hepatocellular carcinoma, the development of old and new drugs, including their failures and current advancements, has been reviewed. This review aims to evaluate the updated optimal clinical treatment of unresectable hepatocellular carcinomas in clinical practice, mainly through targeted therapy. Although surgical treatment can significantly enhance the survival probability of early and intermediate-stage patients, it is unsuitable for most HCC patients due to a lack of donors. Due to their severe toxicity, the few first-line anti-HCC drugs, such as sorafenib, are often reserved for advanced HCC patients for whom other therapies have failed. The second-line drugs are usually alternatives for patients with intolerance or resistance. Consequently, the ongoing growth of possible preclinical drugs and studies on miRNAs, lncRNAs, and numerous other signaling pathway targets for developing novel drugs may introduce additional treatment prospects for HCC.
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Affiliation(s)
- Bahareh Farasati Far
- Department of Chemistry, Iran University of Science and Technology, Tehran 1684613114, Iran
| | - Dorsa Rabie
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Parisa Hemati
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Parastoo Fooladpanjeh
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Neda Faal Hamedanchi
- Faculty of Medicine, Islamic Azad University, Tehran Medical Sciences Branch, Tehran 193951495, Iran
| | - Nima Broomand Lomer
- Faculty of Medicine, Guilan University of Medical Sciences, Rasht 4314637758, Iran
| | - Arian Karimi Rouzbahani
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad 6718773654, Iran
- USERN Office, Lorestan University of Medical Sciences, Khorramabad 6718773654, Iran
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Hegde M, Naliyadhara N, Unnikrishnan J, Alqahtani MS, Abbas M, Girisa S, Sethi G, Kunnumakkara AB. Nanoparticles in the diagnosis and treatment of cancer metastases: Current and future perspectives. Cancer Lett 2023; 556:216066. [PMID: 36649823 DOI: 10.1016/j.canlet.2023.216066] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/31/2022] [Accepted: 01/12/2023] [Indexed: 01/15/2023]
Abstract
Metastasis accounts for greater than 90% of cancer-related deaths. Despite recent advancements in conventional chemotherapy, immunotherapy, targeted therapy, and their rational combinations, metastatic cancers remain essentially untreatable. The distinct obstacles to treat metastases include their small size, high multiplicity, redundancy, therapeutic resistance, and dissemination to multiple organs. Recent advancements in nanotechnology provide the numerous applications in the diagnosis and prophylaxis of metastatic diseases, including the small particle size to penetrate cell membrane and blood vessels and their capacity to transport complex molecular 'cargo' particles to various metastatic regions such as bones, brain, liver, lungs, and lymph nodes. Indeed, nanoparticles (NPs) have demonstrated a significant ability to target specific cells within these organs. In this regard, the purpose of this review is to summarize the present state of nanotechnology in terms of its application in the diagnosis and treatment of metastatic cancer. We intensively reviewed applications of NPs in fluorescent imaging, PET scanning, MRI, and photoacoustic imaging to detect metastasis in various cancer models. The use of targeted NPs for cancer ablation in conjunction with chemotherapy, photothermal treatment, immuno therapy, and combination therapy is thoroughly discussed. The current review also highlights the research opportunities and challenges of leveraging engineering technologies with cancer cell biology and pharmacology to fabricate nanoscience-based tools for treating metastases.
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Affiliation(s)
- Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Nikunj Naliyadhara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Jyothsna Unnikrishnan
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia; BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester, LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia; Computers and Communications Department, College of Engineering, Delta University for Science and Technology, Gamasa, 35712, Egypt
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
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Al-Shafie TA, Mahrous EA, Shukry M, Alshahrani MY, Ibrahim SF, Fericean L, Abdelkader A, Ali MA. A Proposed Association between Improving Energy Metabolism of HepG2 Cells by Plant Extracts and Increasing Their Sensitivity to Doxorubicin. TOXICS 2023; 11:182. [PMID: 36851057 PMCID: PMC9967676 DOI: 10.3390/toxics11020182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 02/01/2023] [Accepted: 02/12/2023] [Indexed: 06/18/2023]
Abstract
Increasing cancer cell sensitivity to chemotherapy by amending aberrant metabolism using plant extracts represents a promising strategy to lower chemotherapy doses while retaining the same therapeutic outcome. Here, we incubated HepG2 cells with four plant extracts that were selected based on an earlier assessment of their cytotoxicity, viz asparagus, green tea, rue, and avocado, separately, before treatment with doxorubicin. MTT assays elucidated a significant decrease in doxorubicin-IC50 following HepG2 incubation with each extract, albeit to a variable extent. The investigated extract's ultra-performance liquid chromatography and gas chromatography coupled with mass spectrometry (UPLC/MS and GC/MS) revealed several constituents with anticancer activity. Biochemical investigation displayed several favorable effects, including the inhibition of hypoxia-inducible factor1α (HIF1α), c-Myc, pyruvate kinase-M2 (PKM2), lactate dehydrogenase-A (LDH-A), glucose-6-phosphate dehydrogenase (G6PD), and glutaminase by asparagus and rue extracts. To less extent, HIF1α, c-Myc, PKM2, and LDH-A were partially inhibited by green tea extract, and HIF1α and glutaminase activity was inhibited by avocado oil. Undesirably, green tea extract increased glutaminase; avocado oil rose c-Myc, and both increased G6PD. In conclusion, our study confirms the potential cytotoxic effects of these plant extracts. It highlights a strong association between the ability of asparagus, green tea, rue, and avocado to sensitize HepG2 cells to doxorubicin and their power to amend cell metabolism, suggesting their use as add-on agents that might aid in clinically lowering the doxorubicin dose.
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Affiliation(s)
- Tamer A. Al-Shafie
- Faculty of Dentistry, Biochemistry Department, Pharos University in Alexandria, Alexandria 21532, Egypt
| | - Engy A. Mahrous
- Faculty of Pharmacy, Pharmacognosy Department, Cairo University, Cairo 11435, Egypt
| | - Mustafa Shukry
- Faculty of Veterinary Medicine, Department of Physiology, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Mohammad Y. Alshahrani
- Research Center for Advanced Materials Science (RCAMS), King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, P.O. Box 61413, Abha 9088, Saudi Arabia
| | - Samah F. Ibrahim
- Department of Clinical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Liana Fericean
- Faculty of Agriculture, Department of Biology and Plant Protection, University of Life Sciences “King Michael I” from Timișoara, Calea Aradului 119, CUI 3487181, 300645 Timisoara, Romania
| | - Afaf Abdelkader
- Faculty of Medicine, Department of Forensic Medicine and Clinical Toxicology, Benha University, Benha 13518, Egypt
| | - Mennatallah A. Ali
- Faculty of Pharmacy, Pharmacology and Therapeutics Department, Pharos University in Alexandria, Alexandria 21532, Egypt
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Identification of Prognostic and Predictive Biomarkers and Druggable Targets among 205 Antioxidant Genes in 21 Different Tumor Types via Data-Mining. Pharmaceutics 2023; 15:pharmaceutics15020427. [PMID: 36839749 PMCID: PMC9959161 DOI: 10.3390/pharmaceutics15020427] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/08/2023] [Accepted: 01/20/2023] [Indexed: 01/31/2023] Open
Abstract
(1) Background: Oxidative stress is crucial in carcinogenesis and the response of tumors to treatment. Antioxidant genes are important determinants of resistance to chemotherapy and radiotherapy. We hypothesized that genes involved in the oxidative stress response may be valuable as prognostic biomarkers for the survival of cancer patients and as druggable targets. (2) Methods: We mined the KM Plotter and TCGA Timer2.0 Cistrome databases and investigated 205 antioxidant genes in 21 different tumor types within the context of this investigation. (3) Results: Of 4347 calculations with Kaplan-Meier statistics, 84 revealed statistically significant correlations between high gene expression and worse overall survival (p < 0.05; false discovery rate ≤ 5%). The tumor types for which antioxidant gene expression was most frequently correlated with worse overall survival were renal clear cell carcinoma, renal papillary cell carcinoma, and hepatocellular carcinoma. Seventeen genes were clearly overexpressed in tumors compared to their corresponding normal tissues (p < 0.001), possibly qualifying them as druggable targets (i.e., ALOX5, ALOX5AP, EPHX4, G6PD, GLRX3, GSS, PDIA4, PDIA6, PRDX1, SELENOH, SELENON, STIP1, TXNDC9, TXNDC12, TXNL1, TXNL4A, and TXNRD1). (4) Conclusions: We concluded that a sub-set of antioxidant genes might serve as prognostic biomarkers for overall survival and as druggable targets. Renal and liver tumors may be the most suitable entities for this approach.
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Sakamoto T, Kuboki S, Furukawa K, Takayashiki T, Takano S, Yoshizumi A, Ohtsuka M. TRIM27-USP7 complex promotes tumour progression via STAT3 activation in human hepatocellular carcinoma. Liver Int 2023; 43:194-207. [PMID: 35753056 DOI: 10.1111/liv.15346] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 05/31/2022] [Accepted: 06/23/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS TRIM27 is stabilized by binding to USP7 and mediates tumour progression in several cancers; however, the roles of TRIM27-USP7 complex on STAT3 activation in HCC are unknown. METHODS Regulations and functions of TRIM27 for activating STAT3 in HCC were assessed using 207 HCC samples or HCC cells. RESULTS TRIM27 expression was increased in some cases of HCC. High TRIM27 expression was an independent predictor for poor prognosis in HCC after surgery. It was correlated with the expression of EpCAM, vimentin, MMP-9, and activation of STAT3 in HCC. TRIM27 expression was correlated with USP7 expression, and HCC with high TRIM27 expression together with high USP7 expression showed enhanced STAT3 activation, resulting in poorer prognosis. p-JAK1 expression was correlated with STAT3 activation in HCC with high TRIM27 expression. In vitro, USP7 knockdown decreased TRIM27 expression, suggesting that USP7 was essential for TRIM27 stabilization. Knocking down of TRIM27 or USP7 suppressed STAT3 activation and overexpression of TRIM27 accelerated STAT3 activation; therefore, the formation of TRIM27-USP7 complex was needed for STAT3 activation, which led to aggressive tumour proliferation and invasion by enhancing EMT and CSC-like property. Binding of JAK1 to TRIM27-USP7 complex was confirmed in vitro. Deletion of TRIM27-USP7 complex by USP7 inhibitor significantly inhibited tumour cell invasion by suppressing STAT3 activation. CONCLUSIONS TRIM27 is stabilized by binding to USP7 and is related to aggressive tumour progression in HCC via STAT3 activation, resulting in poor prognosis after operation. Therefore, TRIM27-USP7 complex is a useful prognostic predictor and a promising therapeutic target for HCC.
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Affiliation(s)
- Toshiya Sakamoto
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Arihito Yoshizumi
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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Qi J, Li J, Bie B, Shi M, Zhu M, Tian J, Zhu K, Sun J, Mu Y, Li Z, Guo Y. miR-3,178 contributes to the therapeutic action of baicalein against hepatocellular carcinoma cells via modulating HDAC10. Phytother Res 2023; 37:295-309. [PMID: 36070933 DOI: 10.1002/ptr.7613] [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: 02/17/2022] [Revised: 08/10/2022] [Accepted: 08/20/2022] [Indexed: 01/19/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of hepatic malignancies with high mortality and poor prognosis. Baicalein, one of the major and bioactive flavonoids isolated from Scutellaria baicalensis Georgi, which is reported to have anti-proliferation effect in varying cancers, including HCC, whose underlying molecular mechanism is still largely unknown. In this study, we found that baicalein significantly inhibited proliferation and colony formation, blocked cell cycle, and promoted apoptosis in HCC cells MHCC-97H and SMMC-7721 in vitro and reduced tumor volume and weight in vivo. Increased microRNA (miR)-3,178 levels and decreased histone deacetylase 10 (HDAC10) expression were found in cells treated with baicalein and in patients' HCC tissues. HDAC10 was identified as a target gene of miR-3,178 by luciferase activity and western blot. Both baicalein treatment and overexpression of miR-3,178 could downregulate HDAC10 protein expression and inactivated AKT, MDM2/p53/Bcl2/Bax and FoxO3α/p27/CDK2/Cyclin E1 signal pathways. Not only that, knockdown of miR-3,178 could partly abolish the effects of baicalein and the restoration of HDAC10 could abated miR-3,178-mediated role in HCC cells. Collectively, baicalein inhibits cell viability, blocks cell cycle, and induces apoptosis in HCC cells by regulating the miR-3,178/HDAC10 pathway. This finding indicated that baicalein might be promising for treatment of HCC.
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Affiliation(s)
- Junan Qi
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,The First Ward of Hepatobiliary Pancreatic and Spleen Surgery, Baoji Municipal Central Hospital, Baoji, China
| | - Jun Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Xi'an, China
| | - Beibei Bie
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Pharmacy, Medical School, Xi'an Peihua University, Xi'an, China
| | - Mengjiao Shi
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Xi'an, China
| | - Mengchen Zhu
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Xi'an, China
| | - Jing Tian
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Xi'an, China
| | - Kai Zhu
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Xi'an, China
| | - Jin Sun
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Xi'an, China
| | - Yanhua Mu
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Xi'an, China
| | - Zongfang Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Xi'an, China.,Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, Xi'an Jiaotong University, Xi'an, China
| | - Ying Guo
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Xi'an, China
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Modulating effect of Cu(II) complexes with enamine and tetrazole derivatives on CYP2C and CYP3A and their cytotoxic and antiproliferative properties in HepG2 spheroids. ACTA BIOMEDICA SCIENTIFICA 2022. [DOI: 10.29413/abs.2022-7.5-2.4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
CYP2C and CYP3A cytochromes are induced by a variety of compounds and affect the pharmacokinetics and pharmacodynamics of a large number of drugs. Currently, the possibility of using copper coordination compounds in antitumor therapy is being actively studied. Evaluation of potential interactions between new molecules and P450 cytochromes is necessary at an early stage of drug design.The aim. To study the modulating effect of Cu(II) complexes with enamine and tetrazole derivatives on CYP2C9, CYP2C19 and CYP3A4 and their cytotoxic and antiproliferative properties on normal human lung fibroblasts MRC-5 and a 3D model of hepatocellular carcinoma HepG2.Materials and methods. Cytotoxic and antiproliferative activities of copper(II) complexes – [CuL2] (1), [Cu2(bipy)2(PT)4] (2), [Cu2(phen)2(PT)4] (3), {[Cu(phen)(MT)2]∙H2O}n (4) (L – anion of 2-anilinomethylidene-5,5-dimethylcyclohexane-1,3-dione; PT – 5-phenyltetrazolate anion; MT – 5-methyltetrazolate anion; bipy – 2,2’-bipyridine; phen – 1,10-phenanthroline) – were examined in 2D and 3D models using fluorescence-based phenotypic screening. The modulating effect on CYP2C9, CYP2C19 and CYP3A4 was studied using fluorescence-based targeted screening. The results of CYP3A4 expression were confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR).Results. Complex (1) increases the CYP3A4 expression and does not affect CYP2C9 and CYP2C19 expression. Complex (2) has no modulating effect on CYP2C and CYP3A. Complexes with 1,10-phenatrolin (3) and (4) induce CYP3A4, inhibit CYP2C9 and do not affect CYP2C19 expression. All compounds have a dose-dependent cytotoxic effect on HepG2 and MRC-5: the compound with 5-methyltetrazolate anion (4) has the same effect on cell lines, compounds with 5-phenyltetrazolate anion (2) and (3) have selective effect. Complexes with 1,10-phenatrolin are effective on both 2D and 3D models.Conclusion. The [Cu2(phen)2(FT)4] complex (3) can be used as a basis for creating an antitumor compound, but further modification of the structure is required to increase the selectivity to tumor cells.
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Corti A, Dominici S, Piaggi S, Pompella A. Enhancement of ferroptosis by boric acid and its potential use as chemosensitizer in anticancer chemotherapy. Biofactors 2022; 49:405-414. [PMID: 36468437 DOI: 10.1002/biof.1919] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 11/15/2022] [Indexed: 12/12/2022]
Abstract
Ferroptosis is a form of regulated cell death (RCD) characterized by intracellular iron ion accumulation and reactive oxygen species (ROS)-induced lipid peroxidation. Ferroptosis in cancer and ferroptosis-related anticancer drugs have recently gained interest in the field of cancer treatment. Boron is an essential trace element playing an important role in several biological processes. Recent studies have described contrasting effects of boric acid (BA) in cancer cells, ranging from protective/mitogenic to damaging/antiproliferative. Interestingly, boron has been shown to interfere with critical factors involved in ferroptosis-intracellular glutathione and lipid peroxidation in the first place. Thus, the present study was aimed to verify the ability of boron to modulate the ferroptotic process in HepG2 cells, a model of hepatocellular carcinoma. Our results indicate that-when used at high, pharmacological concentrations-BA can increase intracellular ROS, glutathione, and TBARS levels, and enhance ferroptosis induced by RSL3 and erastin. Also, high BA concentrations can directly induce ferroptosis, and such BA-induced ferroptosis can add to the cytotoxic effects of anticancer drugs sorafenib, doxorubicin and cisplatin. These observations suggest that BA could be exploited as a chemo-sensitizer agent in order to overcome cancer drug resistance in selected conditions. However, the possibility of reaching suitably high concentrations of BA in the tumor microenvironment will need to be further investigated.
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Affiliation(s)
- Alessandro Corti
- Department of Translational Research NTMS, University of Pisa Medical School, Pisa, Italy
| | - Silvia Dominici
- Department of Translational Research NTMS, University of Pisa Medical School, Pisa, Italy
| | - Simona Piaggi
- Department of Translational Research NTMS, University of Pisa Medical School, Pisa, Italy
| | - Alfonso Pompella
- Department of Translational Research NTMS, University of Pisa Medical School, Pisa, Italy
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Radu ER, Semenescu A, Voicu SI. Recent Advances in Stimuli-Responsive Doxorubicin Delivery Systems for Liver Cancer Therapy. Polymers (Basel) 2022; 14:5249. [PMID: 36501642 PMCID: PMC9738136 DOI: 10.3390/polym14235249] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/21/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022] Open
Abstract
Doxorubicin (DOX) is one of the most commonly used drugs in liver cancer. Unfortunately, the traditional chemotherapy with DOX presents many limitations, such as a systematic release of DOX, affecting both tumor tissue and healthy tissue, leading to the apparition of many side effects, multidrug resistance (MDR), and poor water solubility. Furthermore, drug delivery systems' responsiveness has been intensively studied according to the influence of different internal and external stimuli on the efficiency of therapeutic drugs. In this review, we discuss both internal stimuli-responsive drug-delivery systems, such as redox, pH and temperature variation, and external stimuli-responsive drug-delivery systems, such as the application of magnetic, photo-thermal, and electrical stimuli, for the controlled release of Doxorubicin in liver cancer therapy, along with the future perspectives of these smart delivery systems in liver cancer therapy.
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Affiliation(s)
- Elena Ruxandra Radu
- Department of Analytical Chemistry and Environmental Engineering, University Politehnica of Bucharest, 011061 Bucharest, Romania
- Advanced Polymers Materials Group, University Politehnica of Bucharest, 011061 Bucharest, Romania
| | - Augustin Semenescu
- Faculty of Materials Science, University Politehnica of Bucharest, Splaiul Independentei 313, 060042 Bucharest, Romania
- Academy of Romanian Scientists, Splaiul Independentei 54, 030167 Bucharest, Romania
| | - Stefan Ioan Voicu
- Department of Analytical Chemistry and Environmental Engineering, University Politehnica of Bucharest, 011061 Bucharest, Romania
- Advanced Polymers Materials Group, University Politehnica of Bucharest, 011061 Bucharest, Romania
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He M, Gu W, Gao Y, Liu Y, Liu J, Li Z. Molecular subtypes and a prognostic model for hepatocellular carcinoma based on immune- and immunogenic cell death-related lncRNAs. Front Immunol 2022; 13:1043827. [PMID: 36479122 PMCID: PMC9720162 DOI: 10.3389/fimmu.2022.1043827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 11/04/2022] [Indexed: 11/22/2022] Open
Abstract
Background Accumulating evidence shows that immunogenic cell death (ICD) enhances immunotherapy effectiveness. In this study, we aimed to develop a prognostic model combining ICD, immunity, and long non-coding RNA biomarkers for predicting hepatocellular carcinoma (HCC) outcomes. Methods Immune- and immunogenic cell death-related lncRNAs (IICDLs) were identified from The Cancer Genome Atlas and Ensembl databases. IICDLs were extracted based on the results of differential expression and univariate Cox analyses and used to generate molecular subtypes using ConsensusClusterPlus. We created a prognostic signature based on IICDLs and a nomogram based on risk scores. Clinical characteristics, immune landscapes, immune checkpoint blocking (ICB) responses, stemness, and chemotherapy responses were also analyzed for different molecular subtypes and risk groups. Result A total of 81 IICDLs were identified, 20 of which were significantly associated with overall survival (OS) in patients with HCC. Cluster analysis divided patients with HCC into two distinct molecular subtypes (C1 and C2), with patients in C1 having a shorter survival time than those in C2. Four IICDLs (TMEM220-AS1, LINC02362, LINC01554, and LINC02499) were selected to develop a prognostic model that was an independent prognostic factor of HCC outcomes. C1 and the high-risk group had worse OS (hazard ratio > 1.5, p < 0.01), higher T stage (p < 0.05), higher clinical stage (p < 0.05), higher pathological grade (p < 0.05), low immune cell infiltration (CD4+ T cells, B cells, macrophages, neutrophils, and myeloid dendritic cells), low immune checkpoint gene expression, poor response to ICB therapy, and high stemness. Different molecular subtypes and risk groups showed significantly different responses to several chemotherapy drugs, such as doxorubicin (p < 0.001), 5-fluorouracil (p < 0.001), gemcitabine (p < 0.001), and sorafenib (p < 0.01). Conclusion Our study identified molecular subtypes and a prognostic signature based on IICDLs that could help predict the clinical prognosis and treatment response in patients with HCC.
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Affiliation(s)
- Mingang He
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Wenchao Gu
- Department of Pulmonary and Critical Care Medicine, Shanghai Pudong New Area People’s Hospital, Shanghai, China
| | - Yang Gao
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Ying Liu
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jie Liu
- Cancer Center, Shandong Public Health Clinical Center, Public Health Clinical Center Affiliated to Shandong University, Jinan, China,*Correspondence: Jie Liu, ; Zengjun Li,
| | - Zengjun Li
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China,*Correspondence: Jie Liu, ; Zengjun Li,
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Jia W, Han Y, Mao X, Xu W, Zhang Y. Nanotechnology strategies for hepatocellular carcinoma diagnosis and treatment. RSC Adv 2022; 12:31068-31082. [PMID: 36349046 PMCID: PMC9621307 DOI: 10.1039/d2ra05127c] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/20/2022] [Indexed: 10/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy threatening human health, and existing diagnostic and therapeutic techniques are facing great challenges. In the last decade or so, nanotechnology has been developed and improved for tumor diagnosis and treatment. For example, nano-intravenous injections have been approved for malignant perivascular epithelioid cell tumors. This article provides a comprehensive review of the applications of nanotechnology in HCC in recent years: (I) in radiological imaging, magnetic resonance imaging (MRI), fluorescence imaging (FMI) and multimodality imaging. (II) For diagnostic applications in HCC serum markers. (III) As embolic agents in transarterial chemoembolization (TACE) or directly as therapeutic drugs. (IV) For application in photothermal therapy and photodynamic therapy. (V) As carriers of chemotherapeutic drugs, targeted drugs, and natural plant drugs. (VI) For application in gene and immunotherapy. Compared with the traditional methods for diagnosis and treatment of HCC, nanoparticles have high sensitivity, reduce drug toxicity and have a long duration of action, and can also be combined with photothermal and photodynamic multimodal combination therapy. These summaries provide insights for the further development of nanotechnology applications in HCC.
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Affiliation(s)
- WeiLu Jia
- Medical School, Southeast University Nanjing 210009 China
| | - YingHui Han
- Outpatient Department, The Second Affiliated Hospital of Nanjing Medical University Nanjing 210009 China
| | - XinYu Mao
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University Nanjing 210009 China
| | - WenJing Xu
- Medical School, Southeast University Nanjing 210009 China
| | - YeWei Zhang
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University Nanjing 210009 China
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Chaudhary A, Bhardwaj SK, Khan A, Srivastava A, Sinha KK, Ali M, Haque R. Combinatorial Effect of Arsenic and Herbal Compounds in Telomerase-Mediated Apoptosis Induction in Liver Cancer. Biol Trace Elem Res 2022; 201:3300-3310. [PMID: 36192614 DOI: 10.1007/s12011-022-03430-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 09/17/2022] [Indexed: 11/25/2022]
Abstract
Tumour illness and its resistance against existing anticancer therapies pose a serious health concern globally despite the progressive advancement of therapeutic options. The prevailing treatment of HCC using numerous antitumor agents has inflated long-lived complete remissions, but a percentage of individuals still die due to disease recurrence, indicating a need for further exploration of possible anti-tumour regimes. We aim to boost the effectiveness of the HCC treatment by conducting current investigations evaluating the effect of arsenic trioxide (ATO) with different herbal compounds like quercetin and aloe-emodin against liver tumour via inhibition of telomerase, a pro-cancer enzyme. The anticancer activity of ATO with herbal compounds was investigated in human control liver cell line (Wrl-68) and cancer liver cell line (HepG2) at different time intervals. Viability and cytotoxicity in response to combinatorial drugs were assessed in vitro by trypan blue dye exclusion assay and MTT and WST assay. Apoptosis was analysed by annexin V/PI assay, and the expression of telomerase and apoptosis-regulating proteins was evaluated by immunoblotting and qRT-PCR. Arsenic trioxide in combination with quercetin and aloe-emodin reduced cell viability in cancerous cells compared to normal cells by inducing apoptosis, downregulating telomerase and Bcl-2 (anti-apoptotic protein) and upregulating the expression of Bax (pro-apoptotic protein). ATO exhibited significant anticancer effects due to the synergistic effects of quercetin and aloe-emodin in liver tumour cells. The current study data collectively suggest that a successful inhibition of cancer growth by the combination of ATO and tested herbal medicines against liver tumour growth is via the inhibition of telomerase activity.
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Affiliation(s)
- Archana Chaudhary
- Department of Biotechnology, School of Earth Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India
| | - Sadhan Kumar Bhardwaj
- Department of Biotechnology, School of Earth Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India
| | - Azmi Khan
- Department of Life Sciences, School of Earth Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India
| | - Amrita Srivastava
- Department of Life Sciences, School of Earth Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India
| | - Kislay Kumar Sinha
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Hajipur, Bihar, India
| | - Mehboob Ali
- Toxicology Invivotek, Genesis Biotech Company Hamilton, Hamilton Township, NJ, 08691, USA
| | - Rizwanul Haque
- Department of Biotechnology, School of Earth Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India.
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Identification and Validation of Two Heterogeneous Molecular Subtypes and a Prognosis Predictive Model for Hepatocellular Carcinoma Based on Pyroptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8346816. [PMID: 36071875 PMCID: PMC9441383 DOI: 10.1155/2022/8346816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 06/27/2022] [Accepted: 08/09/2022] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is a worldwide malignant cancer with high incidence and mortality. Considering the high heterogeneity of HCC, clarifying molecular characteristics associated with HCC development could help improve patients' outcomes. Pyroptosis is a novel form of cell death and is noted to be implicated in HCC pathogenesis whereas its molecular feature in HCC is unclear. Thus, we intended to clarify the molecular characteristic as well as the clinical significance of pyroptosis for HCC. A systematic bioinformatics analysis was conducted among 40 pyroptosis-related genes based on The Cancer Genome Atlas, the International Cancer Genome Consortium, and the Gene Expression Omnibus databases. A total of 12 HCC-associated pyroptosis-related genes (HPRGs) were identified to be overexpressed in HCC tissues and significantly connected to patients' poor survival. Through consensus clustering based on the HPRGs' expression, we found patients could be stratified into two distinctive pyroptosis subtypes, PyLow and PyHigh. The PyHigh group owned a notable lower survival rate and a higher high-grade proportion compared with the PyLow subtype. Besides, patients' sensitivities to chemotherapeutic drugs also presented distinctive differences between the two subtypes. Indicated by pathway enrichment analysis and immune characteristic difference analysis, the distinctions between the pyroptosis subtypes may be related to tumor immunity. Further, a five-gene risk model composed of BAK1, CHMP4A, CHMP4B, DHX9, and GSDME was established. Subsequent analyses demonstrated that the model could credibly classify patients as low or high risk and was an independent prognostic indicator for HCC. Abnormal expressions of the five genes were validated by biological experiments and new bioinformatics analysis. In conclusion, this study recognized and verified two heterogeneous pyroptosis subtypes and a predictable prognosis model for HCC. Our work may help facilitate the clinical management and treatment of HCC and understand the functions of pyroptosis in oncology.
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Nour MA, Kheradmand F, Rasmi Y, Baradaran B. Alpha7 nicotinic acetylcholine receptor expression in Sorafenib-resistant Hepatocellular carcinoma cells. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:165. [PMID: 35972579 DOI: 10.1007/s12032-022-01745-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/04/2022] [Indexed: 11/28/2022]
Abstract
Hepatocellular carcinoma (HCC), the most prevalent kind of liver cancer, remains one of the world's main causes of death. The alpha7 nicotinic acetylcholine receptor (α7nAchR) has been recognized to be overexpressed in malignancies and chemoresistance. Since little is known about the role of α7nAchR expression in drug-resistant cells, this study was designed to investigate the effect of α7nAchR suppression in combination with Sorafenib (SOR) on SOR-resistant HCC cells. First, SOR-resistant HCC cells were generated. To suppress the expression of α7nAchR, cells were treated with SOR following siRNA transfection. qRT-PCR was used to examine the expression of α7nAchR and apoptotic genes by evaluating the IC50 of SOR and the combination of α7nAchR siRNA and SOR on the survival of resistant cells. Moreover, apoptosis, autophagy, and cell cycle analysis for resistant HCC cells were performed using flow cytometry. Cell migration and colony formation assays were also used for further confirmation. Our results suggest that inhibiting α7nAchR can lead resistant HCC cells to become sensitive. Furthermore, when siRNA and SOR were treated together, HCC-resistant cells showed a considerable reduction in α7nAchR mRNA gene expression. In addition, when α7nAchR was downregulated in combination with SOR, migration and colony formation were inhibited. Apoptosis was triggered by modulating the expression of apoptotic target genes, and cell cycle arrest was observed in the G2-M and subG1 phases. Overexpression of α7nAchR in SOR-resistant HCC cells suggests that it might be a therapeutic target for HCC cell resistance therapy.
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Affiliation(s)
- Mina Afrashteh Nour
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Fatemeh Kheradmand
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
| | - Yousef Rasmi
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. .,Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, 516615731, Iran.
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Becer E, Mutlu Altundag E, Başer KHC, Vatansever HS. Cytotoxic activity and antioxidant effects of Origanum onites essential oil and its two major contents, carvacrol and p-cymene on human colorectal (HCT116) and hepatocelluler carcinoma (HepG2) cell lines. JOURNAL OF ESSENTIAL OIL RESEARCH 2022. [DOI: 10.1080/10412905.2022.2107101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Affiliation(s)
- Eda Becer
- Department of Biochemistry, Faculty of Pharmacy, Near East University, Nicosia, Turkey
- DESAM Institute, Near East University, Nicosia, Turkey
| | - Ergül Mutlu Altundag
- Department of Biochemistry, Faculty of Medicine, Eastern Mediterranean University, Famagusta, Turkey
| | - K. Hüsnü Can Başer
- Department of Pharmacognosy, Faculty of Pharmacy, Near East University, Nicosia, Turkey
| | - Hafize Seda Vatansever
- DESAM Institute, Near East University, Nicosia, Turkey
- Department of Histology and Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
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47
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Yang S, Wang J, Wang S, Zhou A, Zhao G, Li P. Roles of small extracellular vesicles in the development, diagnosis and possible treatment strategies for hepatocellular carcinoma (Review). Int J Oncol 2022; 61:91. [PMID: 35674180 PMCID: PMC9262158 DOI: 10.3892/ijo.2022.5381] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/24/2022] [Indexed: 11/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common malignancy of hepatocytes accounting for 75-85% of primary hepatic carcinoma cases. Small extracellular vesicles (sEVs), previously known as exosomes with a diameter of 30-200 nm, can transport a variety of biological molecules between cells, and have been proposed to function in physiological and pathological processes. Recent studies have indicated that the cargos of sEVs are implicated in intercellular crosstalk among HCC cells, paratumor cells and the tumor microenvironment. sEV-encapsulated substances (including DNA, RNA, proteins and lipids) regulate signal transduction pathways in recipient cells and contribute to cancer initiation and progression in HCC. In addition, the differential expression of sEV cargos between patients facilitates the potential utility of sEVs in the diagnosis and prognosis of patients with HCC. Furthermore, the intrinsic properties of low immunogenicity and high stability render sEVs ideal vehicles for targeted drug delivery in the treatment of HCC. The present review article summarizes the carcinogenic and anti-neoplastic capacities of sEVs and discusses the potential and prospective diagnostic and therapeutic applications of sEVs in HCC.
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Affiliation(s)
- Shuyue Yang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Jiaxin Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Shidong Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Anni Zhou
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Guiping Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
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48
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Qin Y, Wang CJ, Ye HL, Ye GX, Wang S, Pan DB, Wang J, Shen HJ, Xu SQ. WWP2 overexpression inhibits the antitumor effects of doxorubicin in hepatocellular carcinoma. Cell Biol Int 2022; 46:1682-1692. [PMID: 35880837 DOI: 10.1002/cbin.11856] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 05/12/2022] [Accepted: 06/20/2022] [Indexed: 11/07/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common liver cancer that accounts for 90% of cases. Doxorubicin exhibits a broad spectrum of antitumor activity and is one of the most active agents in HCC. WW domain-containing protein 2 (WWP2) is highly expressed in HCC tissues and activates protein kinase B (AKT) signaling pathway to enhance tumor metastasis. However, the role of WWP2 in the glycolysis and antitumor effects of doxorubicin and the epigenetic alterations of WWP2 in HCC remain to be elucidated. The levels of WWP2 and N6-methyladenosine methyltransferase-like 3 (METTL3) in clinical samples and cells were investigated. WWP2 were silenced or overexpressed to study the role of WWP2 in regulating cell proliferation, colony formation, and glycolysis. RNA immunoprecipitation was performed to test m6 A levels. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blot were used to measure mRNA and protein, respectively. WWP2 silencing inhibits cell proliferation, colony formation, and glycolysis, while WWP2 overexpression has the inverse effects via the AKT signaling pathway. Silencing WWP2 enhances doxorubicin's antitumor effect, while WWP2 overexpression suppresses doxorubicin's antitumor effect. Data also support that METTL3 mediates WWP2 m6A modification, and m6A reader, IGF2BP2, binds to the methylated WWP2 to promote the stability of WWP2, leading to upregulation of WWP2. METTL3 mediates WWP2 m6A modification, which can be recognized and bound by IGF2BP2 to increase the stability of WWP2, leading to WWP2 overexpression which inhibits the antitumor effects of doxorubicin through METTL3/WWP2/AKT/glycolysis axis.
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Affiliation(s)
- Yong Qin
- Department of Hepatobiliary Surgery, People Hospital of LiShui, The Sixth Affiliated Hospital of Wenzhou Medical University, The First Affiliated Hospital of LiShui University, Lishui, China
| | - Chao-Jun Wang
- Department of Hepatobiliary Surgery, People Hospital of LiShui, The Sixth Affiliated Hospital of Wenzhou Medical University, The First Affiliated Hospital of LiShui University, Lishui, China
| | - Hai-Lin Ye
- Department of Hepatobiliary Surgery, People Hospital of LiShui, The Sixth Affiliated Hospital of Wenzhou Medical University, The First Affiliated Hospital of LiShui University, Lishui, China
| | - Guan-Xiong Ye
- Department of Hepatobiliary Surgery, People Hospital of LiShui, The Sixth Affiliated Hospital of Wenzhou Medical University, The First Affiliated Hospital of LiShui University, Lishui, China
| | - Shi Wang
- Department of Hepatobiliary Surgery, People Hospital of LiShui, The Sixth Affiliated Hospital of Wenzhou Medical University, The First Affiliated Hospital of LiShui University, Lishui, China
| | - De-Biao Pan
- Department of Hepatobiliary Surgery, People Hospital of LiShui, The Sixth Affiliated Hospital of Wenzhou Medical University, The First Affiliated Hospital of LiShui University, Lishui, China
| | - Jun Wang
- Department of Hepatobiliary Surgery, People Hospital of LiShui, The Sixth Affiliated Hospital of Wenzhou Medical University, The First Affiliated Hospital of LiShui University, Lishui, China
| | - He-Juan Shen
- Department of Hepatobiliary Surgery, People Hospital of LiShui, The Sixth Affiliated Hospital of Wenzhou Medical University, The First Affiliated Hospital of LiShui University, Lishui, China
| | - Sheng-Qian Xu
- Department of Hepatobiliary Surgery, People Hospital of LiShui, The Sixth Affiliated Hospital of Wenzhou Medical University, The First Affiliated Hospital of LiShui University, Lishui, China
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49
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Drug Discovery Using Evolutionary Similarities in Chemical Binding to Inhibit Patient-Derived Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms23147971. [PMID: 35887321 PMCID: PMC9322808 DOI: 10.3390/ijms23147971] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/14/2022] [Accepted: 07/18/2022] [Indexed: 12/15/2022] Open
Abstract
Drug resistance causes therapeutic failure in refractory cancer. Cancer drug resistance stems from various factors, such as patient heterogeneity and genetic alterations in somatic cancer cells, including those from identical tissues. Generally, resistance is intrinsic for cancers; however, cancer resistance becomes common owing to an increased drug treatment. Unfortunately, overcoming this issue is not yet possible. The present study aimed to evaluate a clinical approach using candidate compounds 19 and 23, which are sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) inhibitors, discovered using the evolutionary chemical binding similarity method. mRNA sequencing indicated SERCA as the dominant marker of patient-derived anti-cancer drug-resistant hepatocellular carcinoma (HCC), but not of patient-derived anti-cancer drug-sensitive HCC. Candidate compounds 19 and 23 led to significant tumor shrinkage in a tumor xenograft model of anti-cancer drug-resistant patient-derived HCC cells. Our results might be clinically significant for the development of novel combinatorial strategies that selectively and efficiently target highly malignant cells such as drug-resistant and cancer stem-like cells.
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50
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The Efficacy of Combined Therapy of Regorafenib with Detoxicating and Stasis Softening Chinese Herbal Spleen Tonics in Mid-/Late-Stage Hepatocellular Carcinoma. CONTRAST MEDIA & MOLECULAR IMAGING 2022; 2022:9316873. [PMID: 35800233 PMCID: PMC9192279 DOI: 10.1155/2022/9316873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/12/2022] [Accepted: 05/18/2022] [Indexed: 11/27/2022]
Abstract
Objective To explore the efficacy of combined therapy of Regorafenib with detoxicating and stasis softening Chinese herbal spleen tonics (DSS-splenic tonics) in mid-/late-stage hepatocellular carcinoma. Methods Retrospective observational data of 120 patients were obtained, 60 of which received combined therapy of DSS-splenic tonics and regorafenib. Adverse event, overall survival (OS), and time-to-progress (TTP) were analyzed. Synergistic effect of DSS-spleen tonics was found and validated in human hepatocellular carcinoma HCCLM3 cell line and xenograft mouse models. Results Combination of regorafenib and DSS-splenic tonics also slightly extended the TTP and OS compared with treatment of regorafenib alone, suggesting DSS-splenic tonics has synergistic effect with regorafenib. Both Regorafenib and DSS-spleen tonics exerted inhibitory effect on cell viability and invasion capability of HCCLM3 cells, and combining both could enhance the antitumor effect. At molecular level, we found that VEGF, HIF-1α, MVD, and VEGF2 were all suppressed by regorafenib and DSS-splenic tonics. These results suggest that DSS-spleen tonics function synergistically with regorafenib in HCC by enhancing the regulation of regorafenib on VEGF, MMP-2, HIF-1α, and MVD, and may diminish angiogenesis during HCC progression. Conclusion DSS-spleen tonics could exert synergistic antitumor effect with regorafenib via targeting VEGF.
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