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Xie Q, Luo M, Liu M, Xie Y, Li D, Dai H, Chen X. Discovery of potential VEGFR-2 inhibitors from natural products by virtual screening and molecular dynamics simulation. Phys Chem Chem Phys 2025; 27:3732-3747. [PMID: 39878700 DOI: 10.1039/d4cp03575e] [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: 01/31/2025]
Abstract
Hepatocellular carcinoma (HCC) is the most common cancer worldwide and vascular endothelial growth factor receptor-2 (VEGFR-2) is an important target in the development of inhibitors for the treatment of liver cancer. So far, however, there are no effective drugs targeting VEGFR-2 to achieve complete treatment of liver cancer. In this study, we employed molecular docking, molecular dynamics simulations, molecular mechanics generalized Born surface area (MM-GBSA) method, quantum mechanics/molecular mechanics (QM/MM) calculations and steered molecular dynamics simulations to discover the potential inhibitors from COCONUT database targeting VEGFR-2. The molecular docking analyses of 13 743 natural compounds targeting VEGFR-2 identified 96 molecules as promising candidates. Our molecular dynamics simulations revealed that only 5 candidate-docking systems remained stable over 100 ns of production run. Then, steered molecular dynamics simulations showed that CNP0076764, CNP0028810, CNP0177683 and CNP0107283 had higher mean force values than that of sorafenib, reflecting the high potential of candidate molecules. A detailed analysis of the binding modes revealed that Leu840, Val848, Lys868, Glu885, Leu889, Val899, Val916, Leu1035, Cys1045, Asp1046 and Phe1047 play key roles in binding the inhibitors. Overall, this study shows evidence that the four natural products obtained from the COCONUT database could be further used as anti-cancer inhibitors, which provides theoretical guidance for designing new drugs.
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Affiliation(s)
- Qiong Xie
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
| | - Mengshi Luo
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
| | - Mingyan Liu
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
| | - Yuxin Xie
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
| | - Di Li
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
| | - Hongjing Dai
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
- School of Chemistry and Chemical Engineering, Qiannan Normal University for Nationalities, Duyun 558000, P. R. China
| | - Xiaohua Chen
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
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2
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Nagy A, Börzsei D, Hoffmann A, Török S, Veszelka M, Almási N, Varga C, Szabó R. A Comprehensive Overview on Chemotherapy-Induced Cardiotoxicity: Insights into the Underlying Inflammatory and Oxidative Mechanisms. Cardiovasc Drugs Ther 2024:10.1007/s10557-024-07574-0. [PMID: 38492161 DOI: 10.1007/s10557-024-07574-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/05/2024] [Indexed: 03/18/2024]
Abstract
While oncotherapy has made rapid progress in recent years, side effects of anti-cancer drugs and treatments have also come to the fore. These side effects include cardiotoxicity, which can cause irreversible cardiac damages with long-term morbidity and mortality. Despite the continuous in-depth research on anti-cancer drugs, an improved knowledge of the underlying mechanisms of cardiotoxicity are necessary for early detection and management of cardiac risk. Although most reviews focus on the cardiotoxic effect of a specific individual chemotherapeutic agent, the aim of our review is to provide comprehensive insight into various agents that induced cardiotoxicity and their underlying mechanisms. Characterization of these mechanisms are underpinned by research on animal models and clinical studies. In order to gain insight into these complex mechanisms, we emphasize the role of inflammatory processes and oxidative stress on chemotherapy-induced cardiac changes. A better understanding and identification of the interplay between chemotherapy and inflammatory/oxidative processes hold some promise to prevent or at least mitigate cardiotoxicity-associated morbidity and mortality among cancer survivors.
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Affiliation(s)
- András Nagy
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Denise Börzsei
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Alexandra Hoffmann
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Szilvia Török
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Médea Veszelka
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Nikoletta Almási
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Csaba Varga
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Renáta Szabó
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary.
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Zhou XQ, Li YP, Dang SS. Precision targeting in hepatocellular carcinoma: Exploring ligand-receptor mediated nanotherapy. World J Hepatol 2024; 16:164-176. [PMID: 38495282 PMCID: PMC10941735 DOI: 10.4254/wjh.v16.i2.164] [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: 12/20/2023] [Revised: 01/10/2024] [Accepted: 01/18/2024] [Indexed: 02/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and poses a major challenge to global health due to its high morbidity and mortality. Conventional chemotherapy is usually targeted to patients with intermediate to advanced stages, but it is often ineffective and suffers from problems such as multidrug resistance, rapid drug clearance, nonspecific targeting, high side effects, and low drug accumulation in tumor cells. In response to these limitations, recent advances in nanoparticle-mediated targeted drug delivery technologies have emerged as breakthrough approaches for the treatment of HCC. This review focuses on recent advances in nanoparticle-based targeted drug delivery systems, with special attention to various receptors overexpressed on HCC cells. These receptors are key to enhancing the specificity and efficacy of nanoparticle delivery and represent a new paradigm for actively targeting and combating HCC. We comprehensively summarize the current understanding of these receptors, their role in nanoparticle targeting, and the impact of such targeted therapies on HCC. By gaining a deeper understanding of the receptor-mediated mechanisms of these innovative therapies, more effective and precise treatment of HCC can be achieved.
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Affiliation(s)
- Xia-Qing Zhou
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Ya-Ping Li
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Shuang-Suo Dang
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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4
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Zhao H, Sun M, Zhang Y, Kong W, Fan L, Wang K, Xu Q, Chen B, Dong J, Shi Y, Wang Z, Wang S, Zhuang X, Li Q, Lin F, Yao X, Zhang W, Kong C, Zhang R, Feng D, Zhao X. Connecting the Dots: The Cerebral Lymphatic System as a Bridge Between the Central Nervous System and Peripheral System in Health and Disease. Aging Dis 2024; 15:115-152. [PMID: 37307828 PMCID: PMC10796102 DOI: 10.14336/ad.2023.0516] [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: 02/12/2023] [Accepted: 05/16/2023] [Indexed: 06/14/2023] Open
Abstract
As a recently discovered waste removal system in the brain, cerebral lymphatic system is thought to play an important role in regulating the homeostasis of the central nervous system. Currently, more and more attention is being focused on the cerebral lymphatic system. Further understanding of the structural and functional characteristics of cerebral lymphatic system is essential to better understand the pathogenesis of diseases and to explore therapeutic approaches. In this review, we summarize the structural components and functional characteristics of cerebral lymphatic system. More importantly, it is closely associated with peripheral system diseases in the gastrointestinal tract, liver, and kidney. However, there is still a gap in the study of the cerebral lymphatic system. However, we believe that it is a critical mediator of the interactions between the central nervous system and the peripheral system.
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Affiliation(s)
- Hongxiang Zhao
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
| | - Meiyan Sun
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
| | - Yue Zhang
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
| | - Wenwen Kong
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
| | - Lulu Fan
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
| | - Kaifang Wang
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
| | - Qing Xu
- Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Baiyan Chen
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
| | - Jianxin Dong
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
| | - Yanan Shi
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
| | - Zhengyan Wang
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
| | - ShiQi Wang
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
| | - Xiaoli Zhuang
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Qi Li
- Department of Anesthesiology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Feihong Lin
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
| | - Xinyu Yao
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - WenBo Zhang
- Department of Neurosurgery, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
| | - Chang Kong
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China.
| | - Rui Zhang
- Department of Anesthesiology, Affiliated Hospital of Weifang Medical University, Weifang, China.
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
| | - Dayun Feng
- Department of neurosurgery, Tangdu hospital, Fourth Military Medical University, Xi'an, China.
| | - Xiaoyong Zhao
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
- Department of Anesthesiology, Affiliated Hospital of Weifang Medical University, Weifang, China.
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, China.
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Demenkov PS, Antropova EA, Adamovskaya AV, Mishchenko EL, Khlebodarova TM, Ivanisenko TV, Ivanisenko NV, Venzel AS, Lavrik IN, Ivanisenko VA. Prioritization of potential pharmacological targets for the development of anti-hepatocarcinoma drugs modulating the extrinsic apoptosis pathway: the reconstruction and analysis of associative gene networks help. Vavilovskii Zhurnal Genet Selektsii 2023; 27:784-793. [PMID: 38213696 PMCID: PMC10777304 DOI: 10.18699/vjgb-23-91] [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: 07/26/2023] [Revised: 08/25/2023] [Accepted: 08/28/2023] [Indexed: 01/13/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common severe type of liver cancer characterized by an extremely aggressive course and low survival rates. It is known that disruptions in the regulation of apoptosis activation are some of the key features inherent in most cancer cells, which determines the pharmacological induction of apoptosis as an important strategy for cancer therapy. The computer design of chemical compounds capable of specifically regulating the external signaling pathway of apoptosis induction represents a promising approach for creating new effective ways of therapy for liver cancer and other oncological diseases. However, at present, most of the studies are devoted to pharmacological effects on the internal (mitochondrial) apoptosis pathway. In contrast, the external pathway induced via cell death receptors remains out of focus. Aberrant gene methylation, along with hepatitis C virus (HCV) infection, are important risk factors for the development of hepatocellular carcinoma. The reconstruction of gene networks describing the molecular mechanisms of interaction of aberrantly methylated genes with key participants of the extrinsic apoptosis pathway and their regulation by HCV proteins can provide important information when searching for pharmacological targets. In the present study, 13 criteria were proposed for prioritizing potential pharmacological targets for developing anti-hepatocarcinoma drugs modulating the extrinsic apoptosis pathway. The criteria are based on indicators of the structural and functional organization of reconstructed gene networks of hepatocarcinoma, the extrinsic apoptosis pathway, and regulatory pathways of virus-extrinsic apoptosis pathway interaction and aberrant gene methylation-extrinsic apoptosis pathway interaction using ANDSystem. The list of the top 100 gene targets ranked according to the prioritization rating was statistically significantly (p-value = 0.0002) enriched for known pharmacological targets approved by the FDA, indicating the correctness of the prioritization method. Among the promising potential pharmacological targets, six highly ranked genes (JUN, IL10, STAT3, MYC, TLR4, and KHDRBS1) are likely to deserve close attention.
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Affiliation(s)
- P S Demenkov
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Kurchatov Genomic Center of ICG SB RAS, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia
| | - E A Antropova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - A V Adamovskaya
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia
| | - E L Mishchenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Kurchatov Genomic Center of ICG SB RAS, Novosibirsk, Russia
| | - T M Khlebodarova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Kurchatov Genomic Center of ICG SB RAS, Novosibirsk, Russia
| | - T V Ivanisenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Kurchatov Genomic Center of ICG SB RAS, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia
| | - N V Ivanisenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - A S Venzel
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Kurchatov Genomic Center of ICG SB RAS, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia
| | - I N Lavrik
- Medical Faculty, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - V A Ivanisenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Kurchatov Genomic Center of ICG SB RAS, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia
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6
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Eissa IH, Yousef RG, Elkady H, Elkaeed EB, Alsfouk AA, Husein DZ, Ibrahim IM, Elhendawy MA, Godfrey M, Metwaly AM. Design, semi-synthesis, anti-cancer assessment, docking, MD simulation, and DFT studies of novel theobromine-based derivatives as VEGFR-2 inhibitors and apoptosis inducers. Comput Biol Chem 2023; 107:107953. [PMID: 37673011 DOI: 10.1016/j.compbiolchem.2023.107953] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/21/2023] [Accepted: 08/28/2023] [Indexed: 09/08/2023]
Abstract
A group of theobromine derivatives was designed based on the key pharmacophoric characteristics of VEGFR-2 inhibitors. HepG2 and MCF-7 cancer cell lines were used to test the obtained compounds for their in vitro anti-proliferative activities. Compound 15 (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(4-(1-(2-(4-hydroxybenzoyl)hydrazono)ethyl) phenyl)acetamide) was the most potent cytotoxic member against MCF-7 (IC50 = 0.42 µM) and HepG2 (IC50 = 0.22 µM). The effectiveness of VEGFR-2 inhibition was assessed for compound 15, and its IC50 value was calculated to be 0.067 µM. Additional cellular mechanistic investigations showed that compound 15 dramatically increased the population of apoptotic HepG2 cells in both early and late apoptosis. The investigation of apoptotic markers confirmed that compound 15 upregulated the levels of BAX (2.26-fold) and downregulated the levels of Bcl-2 (4.4-fold). The molecular docking investigations, MM-GPSA, PLIP studies, and MD simulations validated the potential of compound 15 to be a VEGFR-2 inhibitor. DFT calculations have been completed to comprehend how the electrical charge is distributed within compound 15 and to predict how it would bond to VEGFR-2. Lastly, ADMET prediction showed that the designed members have drug-like characteristics and minimal levels of toxicity. In conclusion, our in vitro and in silico investigations showed that compound 15 exhibited promising apoptotic anticancer potential through the suppression of VEGFR-2.
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Affiliation(s)
- Ibrahim H Eissa
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
| | - Reda G Yousef
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt
| | - Hazem Elkady
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt
| | - Eslam B Elkaeed
- Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh 13713, Saudi Arabia
| | - Aisha A Alsfouk
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Dalal Z Husein
- Chemistry Department, Faculty of Science, New Valley University, El-Kharja 72511, Egypt
| | - Ibrahim M Ibrahim
- Biophysics Department, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Mostafa A Elhendawy
- Department of Chemistry and Biochemistry, University of Mississippi, University, MS 38677, USA; Department of Agriculture Chemistry, Faculty of Agriculture, Damietta University, Damietta, Egypt
| | - Murrell Godfrey
- Department of Chemistry and Biochemistry, University of Mississippi, University, MS 38677, USA
| | - Ahmed M Metwaly
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt; Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.
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Yu S, Zhao R, Zhang B, Lai C, Li L, Shen J, Tan X, Shao J. Research progress and application of the CRISPR/Cas9 gene-editing technology based on hepatocellular carcinoma. Asian J Pharm Sci 2023; 18:100828. [PMID: 37583709 PMCID: PMC10424087 DOI: 10.1016/j.ajps.2023.100828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 04/17/2023] [Accepted: 07/10/2023] [Indexed: 08/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is now a common cause of cancer death, with no obvious change in patient survival over the past few years. Although the traditional therapeutic modalities for HCC patients mainly involved in surgery, chemotherapy, and radiotherapy, which have achieved admirable achievements, challenges are still existed, such as drug resistance and toxicity. The emerging gene therapy of clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9-based (CRISPR/Cas9), as an alternative to traditional treatment methods, has attracted considerable attention for eradicating resistant malignant tumors and regulating multiple crucial events of target gene-editing. Recently, advances in CRISPR/Cas9-based anti-drugs are presented at the intersection of science, such as chemistry, materials science, tumor biology, and genetics. In this review, the principle as well as statues of CRISPR/Cas9 technique were introduced first to show its feasibility. Additionally, the emphasis was placed on the applications of CRISPR/Cas9 technology in therapeutic HCC. Further, a broad overview of non-viral delivery systems for the CRISPR/Cas9-based anti-drugs in HCC treatment was summarized to delineate their design, action mechanisms, and anticancer applications. Finally, the limitations and prospects of current studies were also discussed, and we hope to provide comprehensively theoretical basis for the designing of anti-drugs.
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Affiliation(s)
- Shijing Yu
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Ruirui Zhao
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Bingchen Zhang
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Chunmei Lai
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Linyan Li
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Jiangwen Shen
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Xiarong Tan
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Jingwei Shao
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou 350108, China
- College of Materials and Chemical Engineering, Minjiang University, Fuzhou 350108, China
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Scherrer D, Barrett N, Teyton L, Pearce T, Nitcheu J, Pouletty P, Santo J, Ehrlich HJ. Demonstration of the Antitumor Activity of the iNKT Agonist ABX196, a Novel Enhancer of Cancer Immunotherapy, in Melanoma and Hepatocarcinoma Mouse Models. Mol Cancer Ther 2022; 21:1788-1797. [PMID: 36198025 PMCID: PMC9716246 DOI: 10.1158/1535-7163.mct-22-0183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/26/2022] [Accepted: 09/28/2022] [Indexed: 01/12/2023]
Abstract
Immune checkpoint blockers (ICB) provide a promising approach to antitumor immunotherapy through blockade of immunosuppressive pathways. The synthetic glycolipid, ABX196, is a potent stimulator of invariant natural killer T cells (iNKT), a small subset of regulatory lymphocytes, which are powerful enhancers of immunity when activated. ABX196 was investigated alone and in combination with chemotherapy and ICBs in a melanoma B16F10 tumor cell-bearing and an orthotopic Hepa 1-6 hepatocarcinoma (HCC) cell-bearing C57BL/6 mice model. In the melanoma model, immune response evaluation included immunofluorescence staining and detection by flow cytometry to identify anti-CD45, anti-CD8, anti-CD4, anti-CD3, anti-CD19, anti-FoxP3, CD1d tetramer, and anti-programmed cell death protein 1 (PD-1) markers. Analysis by MRI, liver weight, and IHC staining to detect CD4, CD8, F4/80, PD-1, programmed death-ligand 1, Ki67, and FoxP3 markers were used to measure antitumor response in the HCC model. Combination treatment with ABX196 and anti-PD-1 resulted in significant synergistic antitumor effects, reflected by the increase of CD8+ cells in the tumor and an increased ratio of CD8+ effector cells to FoxP3+ regulatory T cells (Treg) in mice with melanomas. ABX196 monotherapy and combination therapy resulted in antitumor effects in the HCC model. No significant differences in survival were demonstrated between monotherapy and combination therapy due to high response levels with either treatment. A synergistic combination effect was apparent when IFNγ was measured in peripheral blood, indicating sustained activation of iNKT cells. In both models, the antitumor effects were associated with a generation of a more advantageous T-effector to Treg cell ratio within the tumor, which could lead to in the proliferation and accumulation of cells that would otherwise be anergized. SYNOPSIS Using melanoma and HCC tumor models in mice, this study demonstrates the potential of ABX196, alone and in combination with anti-PD-1 antibody, as a novel strategy to overcome the immunosuppressive microenvironment and to produce antitumor activity.
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Affiliation(s)
| | - Noel Barrett
- Independent Consultant, c/o Abivax, Paris, France
| | - Luc Teyton
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California
| | | | | | | | - Julien Santo
- Abivax, Montpellier, France.,Corresponding Author: Julien Santo, Abivax, 1919 Route de Mende, Montpellier 34293, France. Phone: 434-359-596; E-mail:
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Ali G, Omar H, Hersi F, Abo-Youssef A, Ahmed O, Mohamed W. The Protective Role of Etoricoxib Against Diethylnitrosamine/2-acetylaminofluorene- Induced Hepatocarcinogenesis in Wistar Rats: The Impact of NF-κB/COX-2/PGE2 Signaling. Curr Mol Pharmacol 2022; 15:252-262. [PMID: 34238176 DOI: 10.2174/1874467214666210708103752] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/19/2021] [Accepted: 05/19/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Liver cancer ranks as the 7th and 5th leading cause of cancer morbidity worldwide in men and women, respectively. Hepatocellular Carcinoma (HCC) is the most common type of liver cancer and is associated with an increasing global burden of Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH). OBJECTIVE The present study aimed to investigate the possible chemopreventive effect of etoricoxib on diethylnitrosamine (DENA) and 2-acetylaminofluorene (2AAF)-induced HCC in male Wistar rats. METHODS HCC was induced by DENA (150 mg/kg/week; i.p) for 2 weeks, then 2AAF (20 mg/kg; p.o) every other day for three successive weeks. Etoricoxib (0.6 mg/kg, p.o.) was given to DENA/ 2AAF-administered rats for 20 weeks. RESULTS Etoricoxib significantly suppressed alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19.9) as liver tumor biomarkers. It also decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin levels while increased serum albumin levels. Besides, it alleviated DENA/2AAF-induced histopathological abrasions and inflammatory cell infiltration. Furthermore, etoricoxib showed a potent antioxidant effect, supported by a significant lipid peroxide reduction and elevation in superoxide dismutase activity and GSH content. In addition, Etoricoxib significantly down-regulated the protein expression of interleukin 1 beta (IL-1β), tumor necrosis factor α (TNFα), nuclear Factor-kappa B (NF-κB), phosphorylated nuclear Factor-kappa B (p-NF-κB), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2). CONCLUSION In conclusion, the current results proved that etoricoxib possesses an anticarcinogenic effect via its antioxidant, anti-inflammatory, and modulation of NF-κB/COX-2/PGE2 signaling.
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Affiliation(s)
- Gaber Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514,Egypt
| | - Hany Omar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514,Egypt
| | - Fatema Hersi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272 ,United Arab Emirates
| | - Amira Abo-Youssef
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514,Egypt
| | - Osama Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521,Egypt
| | - Wafaa Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514,Egypt
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10
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Silverman RB. Inactivators of Ornithine Aminotransferase for the Treatment of Hepatocellular Carcinoma. ACS Med Chem Lett 2021; 13:38-49. [PMID: 35059122 PMCID: PMC8762738 DOI: 10.1021/acsmedchemlett.1c00526] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/22/2021] [Indexed: 01/16/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second or third leading cause of cancer mortality worldwide (depending on which statistics are used), yet there is no effective treatment. Currently, there are nine FDA-approved drugs for HCC, five monoclonal antibodies and four tyrosine kinase inhibitors. Ornithine aminotransferase (OAT) has been validated as a target in preclinical studies, which demonstrates that it is a potential target to treat HCC. Currently, there are no OAT inactivators in clinical trials for HCC. This Innovation describes evidence to support inhibition of OAT as a novel approach for HCC tumor growth inhibition. After the mechanism of OAT is discussed, the origins of our involvement in OAT inactivation, based on our previous work on mechanism-based inactivation of GABA-AT, are described. Once it was demonstrated that OAT inactivation does lead to HCC tumor growth inhibition, new selective OAT inactivators were designed and their inactivation mechanisms were elucidated. A summary of these mechanistic studies is presented. Inactivators of OAT provide the potential for treatment of HCC, targeting the Wnt/β-catenin pathway.
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11
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Hazem NM, ElKashef WF, El-Sherbiny IM, Emam AA, Shaalan D, Sobh M. Anticarcinogenic Effects of Capsaicin-Loaded Nanoparticles on In vitro Hepatocellular Carcinoma. CURRENT CHEMICAL BIOLOGY 2021; 15:188-201. [DOI: 10.2174/2212796814999201116211648] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 09/20/2020] [Accepted: 09/27/2020] [Indexed: 01/03/2025]
Abstract
Background::
Hepatocellular Carcinoma (HCC) is the fifth most frequent cancer worldwide
with a low overall survival due to high metastasis and recurrence rates. The aim of this study
is to assess and compare the possible anti-neoplastic effect of capsaicin and nanoformulated capsaicin
on in vitro HCC human cell line HepG2. The source of the cell line, including when and
from where it was obtained. Whether the cell line has recently been authenticated and by what
method. Whether the cell line has recently been tested for mycoplasma contamination.
Materials and Methods::
Capsaicin-loaded Trimethyl Chitosan Nanoparticles (CL TMCS NPs)
were synthesized by ionotropic gelation of cationic TMCS with capsaicin. The synthesized nanoparticles
were characterized through TEM, and zeta analyzer. Human hepatocarcinoma HepG2 cell
lines were cultured and treated with 50, 75 & 100 μM of Capsaicin (CAP), plain TMCS NPs and
CL-NPs as well as ethanol (control) for 24h and 48h. The induced effects were investigated by
flow cytometry, immunocytochemistry assay for Bcl-2, Bax, and caspase proteins and evaluating
gene expression levels of Bcl-2, Bax, and MDR-1 mRNA by real-time PCR.
Results::
Our results demonstrated that capsaicin- loaded NPs had the potential to significantly increase
capsaicin bioactivity compared with the plain capsaicin formulation either in inducing apoptosis
through altering expression of apoptotic regulators or modifying MDR-1 expression.
Conclusions::
TMCs nanoparticles investigated in this study may be a good drug delivery vehicle
for capsaicin. Application of capsaicin-loaded NPs in HCC management as an adjunct therapeutic
approach may be a novel strategy to improve the treatment efficacy and resistance of the conventionally
used chemotherapy.
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Affiliation(s)
- Noha M Hazem
- Department of Medical Biochemistry, Faculty of Medicine, Mansoura University,Egypt
| | - Wagdi F ElKashef
- Pathology Department, Faculty of Medicine, Mansoura University,Egypt
| | | | - Ahmed A Emam
- Medical Experimental Research Center, Faculty of Medicine, Mansoura University,Egypt
| | - Dalia Shaalan
- Department of Medical Biochemistry, Faculty of Medicine, Mansoura University,Egypt
| | - Mohamed Sobh
- Medical Experimental Research Center, Faculty of Medicine, Mansoura University,Egypt
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12
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Petrov RA, Mefedova SR, Yamansarov EY, Maklakova SY, Grishin DA, Lopatukhina EV, Burenina OY, Lopukhov AV, Kovalev SV, Timchenko YV, Ondar EE, Ivanenkov YA, Evteev SA, Vaneev AN, Timoshenko RV, Klyachko NL, Erofeev AS, Gorelkin PV, Beloglazkina EK, Majouga AG. New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma. Mol Pharm 2020; 18:461-468. [PMID: 33264010 DOI: 10.1021/acs.molpharmaceut.0c00980] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In this work, we have developed covalent and low molecular weight docetaxel delivery systems based on conjugation with N-acetyl-d-galactosamine and studied their properties related to hepatocellular carcinoma cells. The resulting glycoconjugates have an excellent affinity to the asialoglycoprotein receptor (ASGPR) in the nanomolar range of concentrations and a high cytotoxicity level comparable to docetaxel. Likewise, we observed the 21-75-fold increase in water solubility in comparison with parent docetaxel and prodrug lability to intracellular conditions with half-life values from 25.5 to 42 h. We also found that the trivalent conjugate possessed selective toxicity against hepatoma cells vs control cell lines (20-35 times). The absence of such selectivity in the case of monovalent conjugates indicates the effect of ligand valency. Specific ASGPR-mediated cellular uptake of conjugates was proved in vitro using fluorescent-labeled analogues. In addition, we showed an enhanced generation of reactive oxygen species in the HepG2 cells, which could be inhibited by the natural ligand of ASGPR. Overall, the obtained results highlight the potential of ASGPR-directed cytostatic taxane drugs for selective therapy of hepatocellular carcinoma.
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Affiliation(s)
- Rostislav A Petrov
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) of the Ufa Federal Research Centre, Oktyabrya Prospekt 71, Ufa 450054, Russian Federation
| | - Sofiia R Mefedova
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Emil Yu Yamansarov
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation
| | - Svetlana Yu Maklakova
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation
| | - Dmitrii A Grishin
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Elena V Lopatukhina
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Olga Y Burenina
- Skolkovo Institute of Science and Technology, 3 Nobel str., Skolkovo 143026, Russian Federation
| | - Anton V Lopukhov
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Sergey V Kovalev
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Yury V Timchenko
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Evgenia E Ondar
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Yan A Ivanenkov
- Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) of the Ufa Federal Research Centre, Oktyabrya Prospekt 71, Ufa 450054, Russian Federation.,Moscow Institute of Physics and Technology (State University), 9 Institutskiy Lane, Dolgoprudny City, Moscow 141700, Russian Federation
| | - Sergei A Evteev
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Alexander N Vaneev
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation
| | - Roman V Timoshenko
- National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation
| | - Natalia L Klyachko
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,Skolkovo Institute of Science and Technology, 3 Nobel str., Skolkovo 143026, Russian Federation
| | - Alexander S Erofeev
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation
| | - Petr V Gorelkin
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation
| | - Elena K Beloglazkina
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Alexander G Majouga
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation.,Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow 125047, Russian Federation
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13
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Abstract
The incidence and mortality related to hepatocellular carcinoma (HCC) continue to increase in the United States, with most patients presenting at advanced stages where curative therapy and long-term survival is unlikely. Fortunately, significant progress has been made in identifying the landscape of HCC mutations due to advances in whole genome expression profiling. Drug development has also evolved in recent years with multiple first- and second-line systemic chemotherapy agents approved for HCC for the first time in over a decade. However, despite advances in molecular profiling, mutations that were identified at the highest frequency were not amenable to drug development, and curative therapy for advanced HCC remains elusive. This review focuses on the current understanding of HCC genomics and the limitations of translating the current HCC molecular profiling into clinical practice and examines the effectiveness and benefits of approved systemic therapies for advanced HCC.
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14
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Shangguan AJ, Zhou K, Yang J, Eresen A, Wang B, Sun C, Pan L, Hu S, Khan AT, Mouli SK, Yaghmai V, Zhang Z. Intraprocedural Transcatheter Intraarterial Perfusion (TRIP)-MRI for Evaluation of Irreversible Electroporation Therapy Response in a Rabbit Liver Tumor Model. Clin Exp Gastroenterol 2020; 13:543-553. [PMID: 33192084 PMCID: PMC7654546 DOI: 10.2147/ceg.s269163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 09/24/2020] [Indexed: 12/22/2022] Open
Abstract
Purpose Irreversible electroporation (IRE) is a promising new ablation method for hepatocellular carcinoma (HCC) treatment with few side-effects; however, tissue perfusion and differentiation between treatment zones have not been sufficiently studied. In this project, we analyzed HCC tumor perfusion changes immediately after IRE treatment using transcatheter intraarterial perfusion (TRIP)-MRI to monitor treatment zone margins. Materials and Methods All protocols were approved by the institutional animal care and use committee. A total of 34 rabbits were used for this prospective study: tumor liver group (n=17), normal liver group (n=14), and 3 for growing VX2 tumors. All procedures and imaging were performed under anesthesia. VX2 tumors were grown by injection of VX2 cells into rabbit hindlimbs. Liver tumors were induced by percutaneous US-guided injection of VX2 tumor fragments into liver. For digital subtraction angiography (DSA), a 2F catheter was advanced through left hepatic artery via femoral artery access, followed by contrast injection. All rabbits underwent baseline anatomic MRI, then IRE procedure or IRE probe placement only, and lastly post-procedure anatomic and TRIP-MRI. Liver tissues were dissected immediately after imaging for histology. All statistical analyses were performed on GraphPad Prism, with P<0.05 considered significant. Results IRE generated central IRE zone and peripheral reversible electroporation (RE) zone on anatomic MRI for both normal liver and liver tumor tissues. The semiquantitative analysis showed that IRE zone had the lowest AUC, PE, WIS, Ktrans, ve , and vp as well as the highest TTP, followed by RE zone, then untreated tissues. Receiver operating characteristic analysis showed that WIS and AUC60 had the highest AUCROC. Histologic analysis showed a positive correlation in viable area fraction between MRI and histologic measurements. IRE zone had the highest %apoptosis and lowest CD31+ staining. Conclusion Our results demonstrated that intraprocedural TRIP-MRI can effectively differentiate IRE and RE zones after IRE ablation in normal liver and liver tumor tissues.
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Affiliation(s)
- Anna J Shangguan
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Kang Zhou
- Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, People's Republic of China
| | - Jia Yang
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Aydin Eresen
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Bin Wang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, People's Republic of China
| | - Chong Sun
- Department of Orthopedics, Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Liang Pan
- Department of Radiology, Third Affiliated Hospital of Suzhou University, Changzhou, Jiangsu, People's Republic of China
| | - Su Hu
- Department of Radiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Ali T Khan
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Samdeep K Mouli
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Vahid Yaghmai
- Department of Radiological Sciences, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Zhuoli Zhang
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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15
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Abdel-Mohsen HT, Abd El-Meguid EA, El Kerdawy AM, Mahmoud AEE, Ali MM. Design, synthesis, and molecular docking of novel 2-arylbenzothiazole multiangiokinase inhibitors targeting breast cancer. Arch Pharm (Weinheim) 2020; 353:e1900340. [PMID: 32045054 DOI: 10.1002/ardp.201900340] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/18/2020] [Accepted: 01/20/2020] [Indexed: 12/31/2022]
Abstract
A novel series of 2-arylbenzothiazoles 9, 10, and 12 were designed and synthesized as VEGFR-2/FGFR-1/PDGFR-β multiangiokinase inhibitors targeting breast cancer. Structural elongation of the known 2-phenylbenzothiazole scaffold (type I protein kinase inhibitor [PKI]), was carried out to afford series of type II PKIs 9, 10, and 12. Compounds 9d, 9f, 9i, and 9k exhibited potent multikinase inhibitory activity with IC50 values of 0.19, 0.18, 0.17, and 0.13 μM, respectively, against VEGFR-2; IC50 values of 0.28, 0.37, 0.19, and 0.27 μM, respectively, against FGFR-1; and IC50 values of 0.07, 0.04, 0.08, and 0.14 μM, respectively, against PDGFR-β. Moreover, the synthesized benzothiazoles demonstrated promising cytotoxic activity against the MCF-7 cell line. The most potent benzothiazoles 9d and 9i exhibited IC50 values of 7.83 and 6.58 μM, respectively, on the MCF-7 cell line in comparison to sorafenib (III), which showed IC50 = 4.33 μM. Additionally, 9d and 9i showed VEGFR-2 inhibitory activity in MCF-7 cells of 81% and 83% when compared with sorafenib (III), which showed 88% inhibition. Molecular docking of the designed compounds in the VEGFR-2 and FGFR-1 active sites showed the accommodation of the 2-phenylbenzothiazole moiety, as reported, in the hinge region of the receptor tyrosine kinase (RTK)-binding site, while the amide moiety is involved in hydrogen bond interactions with the key amino acids in the gate area; this in turn directs the aryl group to the hydrophobic allosteric back pocket of the RTKs in a type II-like binding mode. The synthesized benzothiazoles showed satisfactory ADME properties for further optimization in drug discovery.
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Affiliation(s)
- Heba T Abdel-Mohsen
- Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt
| | - Eman A Abd El-Meguid
- Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt
| | - Ahmed M El Kerdawy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.,Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, Cairo, Egypt
| | - Abeer E E Mahmoud
- Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, Cairo, Egypt
| | - Mamdouh M Ali
- Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, Cairo, Egypt
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16
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Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles. Molecules 2020; 25:molecules25040770. [PMID: 32053964 PMCID: PMC7071059 DOI: 10.3390/molecules25040770] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/05/2020] [Accepted: 02/08/2020] [Indexed: 12/24/2022] Open
Abstract
In this study, a novel series of 1,2-disubstituted benzo[d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is two-fold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC50 = 1.98 μM in comparison to sorafenib (IC50 = 10.99 μM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds 17a and 6 showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of 17a on the HepG2 cell cycle demonstrated that 17a arrested the cell cycle at the G2/M phase and induced a dose-dependent apoptotic effect. Molecular docking studies of the synthesized 1,2-disubstituted benzimidazoles in the VEGFR-2 active site displayed their ability to accomplish the essential hydrogen bonding and hydrophobic interactions for optimum inhibitory activity.
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17
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Poojari R, Sawant AV, Kini S, Srivastava R, Panda D. Antihepatoma activity of multifunctional polymeric nanoparticles via inhibition of microtubules and tyrosine kinases. Nanomedicine (Lond) 2020; 15:381-396. [PMID: 31990235 DOI: 10.2217/nnm-2019-0349] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 12/10/2019] [Indexed: 12/19/2022] Open
Abstract
Aim: Synthesis of poly-L-lactic acid nanoparticles comprising of microtubule-inhibitor docetaxel and tyrosine kinase inhibitor sorafenib (PLDS NPs) for hepatoma treatment. Materials & methods: PLDS NPs were prepared by the emulsion solvent evaporation method and the anticancer activity was evaluated in Huh7 hepatoma cells. Results: Real-time imaging of quantum dots incorporating poly-L-lactic acid nanoparticles showed a rapid internalization of the nanoparticles in Huh7 cells. PLDS NPs exerted stronger antiproliferative, apoptotic and antiangiogenic effects than free single drug counterparts. They strongly promoted microtubule bundling, multinucleation and increased mitotic index in Huh7 cells. They also inhibited the expression of pERK1/2, pAKT and cyclin D1. Conclusion: We developed a single-nanoscale platform for dual drug delivery and high-sensitivity quantum dots imaging for hepatoma treatment. [Formula: see text].
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Affiliation(s)
- Radhika Poojari
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Avishkar V Sawant
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Sudarshan Kini
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
- Nitte University Centre for Science Education & Research, Nitte (Deemed to be University), Paneer Campus, Deralakatte, Mangaluru, 575018, India
| | - Rohit Srivastava
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Dulal Panda
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
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18
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Yu M, Zeng M, Pan Z, Wu F, Guo L, He G. Discovery of novel akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma cells. Eur J Med Chem 2020; 189:112076. [PMID: 32007668 DOI: 10.1016/j.ejmech.2020.112076] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 01/08/2020] [Accepted: 01/15/2020] [Indexed: 02/08/2023]
Abstract
In this study, a series of thieno [2,3-d]pyrimidine derivatives were designed, synthesized and evaluated as novel AKT1 inhibitors. In vitro antitumor assay results showed that compounds 9d-g and 9i potently suppressed the enzymatic activities of AKT1 and potently inhibited the proliferation of HepG2, Hep3B, Huh-7 and SMMC-7721 cancer cell lines. Among these derivatives, the compound 9f demonstrated the best inhibitory activities on AKT1 (IC50 = 0.034 μM) and Huh-7 cell (IC50 = 0.076 μM). A panel of biological assays showed that compound 9f suppressed the cellular proliferation of Huh-7 through Akt/mTOR signaling pathway mediated autophagy mechanism. Furthermore, the antitumor capacity of 9f was validated in the subcutaneous Huh-7 xenograft models. Together, our results demonstrate that a novel small-molecule Akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma, which may afford a potential drug candidate for targeted cancer therapy.
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Affiliation(s)
- Meng Yu
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, PR China
| | - Minghui Zeng
- Department of Pharmacy, Qionglai Medical Center Hospital of Sichuan Province, Chengdu, Sichuan, 611530, PR China
| | - Zhaoping Pan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, PR China
| | - Fengbo Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, PR China
| | - Li Guo
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, PR China
| | - Gu He
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, PR China.
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19
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Exploring receptor tyrosine kinases-inhibitors in Cancer treatments. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2019. [DOI: 10.1186/s43042-019-0035-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
AbstractBackgroundReceptor tyrosine kinases (RTKs) are signaling enzymes responsible for the transfer of Adenosine triphosphate (ATP) γ-phosphate to the tyrosine residues substrates. RTKs demonstrate essential roles in cellular growth, metabolism, differentiation, and motility. Anomalous expression of RTK customarily leads to cell growth dysfunction, which is connected to tumor takeover, angiogenesis, and metastasis. Understanding the structure, mechanisms of adaptive and acquired resistance, optimizing inhibition of RTKs, and eradicating cum minimizing the havocs of quiescence cancer cells is paramount.MainTextTyrosine kinase inhibitors (TKIs) vie with RTKs ATP-binding site for ATP and hitherto reduce tyrosine kinase phosphorylation, thus hampering the growth of cancer cells. TKIs can either be monoclonal antibodies that compete for the receptor’s extracellular domain or small molecules that inhibit the tyrosine kinase domain and prevent conformational changes that activate RTKs. Progression of cancer is related to aberrant activation of RTKs due to due to mutation, excessive expression, or autocrine stimulation.ConclusionsUnderstanding the modes of inhibition and structures of RTKs is germane to the design of novel and potent TKIs. This review shed light on the structures of tyrosine kinases, receptor tyrosine kinases, tyrosine kinase inhibitors, minimizing imatinib associated toxicities, optimization of tyrosine kinase inhibition in curtailing quiescence in cancer cells and the prospects of receptor tyrosine kinase based treatments.
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Lai SC, Su YT, Chi CC, Kuo YC, Lee KF, Wu YC, Lan PC, Yang MH, Chang TS, Huang YH. DNMT3b/OCT4 expression confers sorafenib resistance and poor prognosis of hepatocellular carcinoma through IL-6/STAT3 regulation. J Exp Clin Cancer Res 2019; 38:474. [PMID: 31771617 PMCID: PMC6878666 DOI: 10.1186/s13046-019-1442-2] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 10/10/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The inflammatory cytokine interleukin-6 (IL-6) is critical for the expression of octamer-binding transcription factor 4 (OCT4), which is highly associated with early tumor recurrence and poor prognosis of hepatocellular carcinomas (HCC). DNA methyltransferase (DNMT) family is closely linked with OCT4 expression and drug resistance. However, the underlying mechanism regarding the interplay between DNMTs and IL-6-induced OCT4 expression and the sorafenib resistance of HCC remains largely unclear. METHODS HCC tissue samples were used to examine the association between DNMTs/OCT4 expression levels and clinical prognosis. Serum levels of IL-6 were detected using ELISA assays (n = 144). Gain- and loss-of-function experiments were performed in cell lines and mouse xenograft models to determine the underlying mechanism in vitro and in vivo. RESULTS We demonstrate that levels of DNA methyltransferase 3 beta (DNMT3b) are significantly correlated with the OCT4 levels in HCC tissues (n = 144), and the OCT4 expression levels are positively associated with the serum IL-6 levels. Higher levels of IL-6, DNMT3b, or OCT4 predicted early HCC recurrence and poor prognosis. We show that IL-6/STAT3 activation increases DNMT3b/1 and OCT4 in HCC. Activated phospho-STAT3 (STAT-Y640F) significantly increased DNMT3b/OCT4, while dominant negative phospho-STAT3 (STAT-Y705F) was suppressive. Inhibiting DNMT3b with RNA interference or nanaomycin A (a selective DNMT3b inhibitor) effectively suppressed the IL-6 or STAT-Y640F-induced increase of DNMT3b-OCT4 and ALDH activity in vitro and in vivo. The fact that OCT4 regulates the DNMT1 expressions were further demonstrated either by OCT4 forced expression or DNMT1 silence. Additionally, the DNMT3b silencing reduced the OCT4 expression in sorafenib-resistant Hep3B cells with or without IL-6 treatment. Notably, targeting DNMT3b with nanaomycin A significantly increased the cell sensitivity to sorafenib, with a synergistic combination index (CI) in sorafenib-resistant Hep3B cells. CONCLUSIONS The DNMT3b plays a critical role in the IL-6-mediated OCT4 expression and the drug sensitivity of sorafenib-resistant HCC. The p-STAT3 activation increases the DNMT3b/OCT4 which confers the tumor early recurrence and poor prognosis of HCC patients. Findings from this study highlight the significance of IL-6-DNMT3b-mediated OCT4 expressions in future therapeutic target for patients expressing cancer stemness-related properties or sorafenib resistance in HCC.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Cell Line, Tumor
- DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors
- DNA (Cytosine-5-)-Methyltransferases/biosynthesis
- DNA (Cytosine-5-)-Methyltransferases/genetics
- DNA (Cytosine-5-)-Methyltransferases/metabolism
- Disease Models, Animal
- Drug Resistance, Neoplasm
- Female
- Hep G2 Cells
- Heterografts
- Humans
- Interleukin-6/blood
- Interleukin-6/genetics
- Interleukin-6/metabolism
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Mice
- Mice, Inbred BALB C
- Mice, Inbred NOD
- Mice, Nude
- Mice, SCID
- Middle Aged
- Octamer Transcription Factor-3/biosynthesis
- Octamer Transcription Factor-3/genetics
- Prognosis
- STAT3 Transcription Factor/metabolism
- Sorafenib/pharmacology
- DNA Methyltransferase 3B
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Affiliation(s)
- Ssu-Chuan Lai
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031 Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031 Taiwan
| | - Yu-Ting Su
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031 Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031 Taiwan
- TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, 11031 Taiwan
| | - Ching-Chi Chi
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Taoyuan, 33305 Taiwan
- College of Medicine, Chang Gung University, Taoyuan, 33302 Taiwan
| | - Yung-Che Kuo
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031 Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031 Taiwan
- TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, 11031 Taiwan
| | - Kam-Fai Lee
- Department of Pathology, Chang Gung Memorial Hospital, Chiayi, 61363 Taiwan
| | - Yu-Chih Wu
- TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, 11031 Taiwan
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, 11031 Taiwan
| | - Pei-Chi Lan
- TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, 11031 Taiwan
| | - Muh-Hwa Yang
- Institute of Clinical Medicine, College of Medicine, National Yang Ming University, Taipei, 11221 Taiwan
- Division of Medical Oncology, Taipei Veterans General Hospital, Taipei, 11217 Taiwan
| | - Te-Sheng Chang
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, 33382 Taiwan
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi, 61363 Taiwan
| | - Yen-Hua Huang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031 Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031 Taiwan
- TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, 11031 Taiwan
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, 11031 Taiwan
- Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031 Taiwan
- Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031 Taiwan
- Comprehensive Cancer Center of Taipei Medical University, Taipei, 11031 Taiwan
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Ma X, Qin X, Shang X, Liu M, Wang X. Organic anion transport polypeptide 1b2 selectively affects the pharmacokinetic interaction between paclitaxel and sorafenib in rats. Biochem Pharmacol 2019; 169:113612. [DOI: 10.1016/j.bcp.2019.08.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 08/16/2019] [Indexed: 01/27/2023]
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Tracking Dynamics of Spontaneous Tumors in Mice Using Photon-Counting Computed Tomography. iScience 2019; 21:68-83. [PMID: 31655257 PMCID: PMC6820243 DOI: 10.1016/j.isci.2019.10.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/30/2019] [Accepted: 10/02/2019] [Indexed: 12/20/2022] Open
Abstract
Computed tomography is a powerful medical imaging modality for longitudinal studies in cancer to follow neoplasia progression and evaluate anticancer therapies. Here, we report the generation of a photon-counting micro-computed tomography (PC-CT) method based on hybrid pixel detectors with enhanced sensitivity and precision of tumor imaging. We then applied PC-CT for longitudinal imaging in a clinically relevant liver cancer model, the Alb-R26Met mice, and found a remarkable heterogeneity in the dynamics for tumors at the initiation phases. Instead, the growth curve of evolving tumors exhibited a comparable exponential growth, with a constant doubling time. Furthermore, longitudinal PC-CT imaging in mice treated with a combination of MEK and BCL-XL inhibitors revealed a drastic tumor regression accompanied by a striking remodeling of macrophages in the tumor microenvironment. Thus, PC-CT is a powerful system to detect cancer initiation and progression, and to monitor its evolution during treatment.
Development of photon-counting micro-computed tomography (PC-CT) with hybrid pixels PC-CT allows longitudinal imaging of tumor dynamics in mouse cancer models RTK-driven tumors are heterogeneous at onset, but grow steadily during progression MEK + BCL-XL targeting leads to tumor regression and microenvironment remodeling
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Baidoo SA, Sarkodie EK, Boakye-Yiadom KO, Kesse S. Nanomedicinal delivery systems for intelligent treatment of hepatocellular carcinoma. J Drug Deliv Sci Technol 2019. [DOI: 10.1016/j.jddst.2019.101152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Palomba F, Genovese D, Rampazzo E, Zaccheroni N, Prodi L, Morbidelli L. PluS Nanoparticles Loaded with Sorafenib: Synthetic Approach and Their Effects on Endothelial Cells. ACS OMEGA 2019; 4:13962-13971. [PMID: 31497714 PMCID: PMC6714606 DOI: 10.1021/acsomega.9b01699] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 07/18/2019] [Indexed: 05/24/2023]
Abstract
Silica nanostructures are widely investigated for theranostic applications since relatively mild and easy synthetic methods allow the fabrication of multicompartment nanoparticles (NPs) and fine modulation of their properties. Here, we report the optimization of a synthetic strategy leading to brightly fluorescent silica NPs with a high loading ability, up to 45 molecules per NP, of Sorafenib, a small molecule acting as an antiangiogenic drug. We demonstrate that these NPs can efficiently release the drug and they are able to inhibit endothelial cell proliferation and migration and network formation. Their lyophilization can endow them with long shelf stability, whereas, once in solution, they show a much slower release compared to analogous micellar systems. Interestingly, Sorafenib released from Pluronic silica NPs completely prevented endothelial cell responses and postreceptor mitogen-activated protein kinase signaling ignited by vascular endothelial growth factor, one of the major players of tumor angiogenesis. Our results indicate that these theranostic systems represent a promising structure for anticancer applications since NPs alone have no cytotoxic effect on cultured endothelial cells, a cell type to which drugs and exogenous material are always in contact once delivered.
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Affiliation(s)
- Francesco Palomba
- Dipartimento
di Chimica “Giacomo Ciamician”, Alma Mater Studiorum, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
| | - Damiano Genovese
- Dipartimento
di Chimica “Giacomo Ciamician”, Alma Mater Studiorum, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
| | - Enrico Rampazzo
- Dipartimento
di Chimica “Giacomo Ciamician”, Alma Mater Studiorum, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
| | - Nelsi Zaccheroni
- Dipartimento
di Chimica “Giacomo Ciamician”, Alma Mater Studiorum, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
| | - Luca Prodi
- Dipartimento
di Chimica “Giacomo Ciamician”, Alma Mater Studiorum, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
| | - Lucia Morbidelli
- Dipartimento
di Scienze della Vita, Università
di Siena, Via A. Moro
2, 53100 Siena, Italy
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25
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Supplementary Sorafenib Therapies for Hepatocellular Carcinoma-A Systematic Review and Meta-Analysis: Supplementary Sorafenib for Liver Cancer. J Clin Gastroenterol 2019; 53:486-494. [PMID: 30939505 DOI: 10.1097/mcg.0000000000001175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third deadliest cancer worldwide. Sorafenib is considered a supplementary treatment to surgical or locoregional therapies for improving outcomes. We evaluated the efficacy of sorafenib as a supplementary therapy for HCC. METHODS We conducted a meta-analysis including 11 randomized controlled trials. Patients with HCC and studies in which sorafenib was administered alone and compared with placebo or those in which sorafenib was administered in combination with another treatment and compared with that treatment alone were included. The overall effects (OEs) on overall survival and time to progression were pooled as hazard ratios. RESULTS The OEs of sorafenib as a first-line therapy versus placebo for unresectable HCC were 0.62 [95% confidence interval (CI): 0.50-0.77] and 0.58 (95% CI: 0.47-0.70), respectively. The OEs of sorafenib as a second-line therapy versus placebo for progressive HCC were 0.73 (95% CI: 0.47-1.13) and 0.54 (95% CI: 0.30-0.97), respectively. The OEs of sorafenib as an adjuvant therapy versus placebo for early HCC were 1.00 (95% CI: 0.76-1.30) and 0.89 (95% CI: 0.74-1.08), respectively. The OEs of sorafenib combined with transarterial chemoemboliztion (TACE) versus placebo combined with TACE were 0.80 (95% CI: 0.54-1.21) and 0.85 (95% CI: 0.70-1.04), respectively. The OEs of sorafenib as an adjuvant to TACE versus placebo as an adjuvant to TACE for intermediate HCC were 1.06 (95% CI: 0.69-1.64) and 0.65 (95% CI: 0.31-1.36), respectively. CONCLUSIONS Sorafenib was effective as a first-line therapy for unresectable HCC, but it was ineffective as a second-line or adjuvant therapy. Sorafenib did not increase the efficacy of TACE.
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Liang Q, Kong L, Du Y, Zhu X, Tian J. Antitumorigenic and antiangiogenic efficacy of apatinib in liver cancer evaluated by multimodality molecular imaging. Exp Mol Med 2019; 51:1-11. [PMID: 31285418 PMCID: PMC6802662 DOI: 10.1038/s12276-019-0274-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/18/2019] [Accepted: 03/28/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality worldwide. Sorafenib is the standard first-line treatment for advanced HCC, but its efficacy is limited. Apatinib is a small-molecule tyrosine kinase inhibitor that has shown promising antitumor effects in gastric and non-small cell lung cancers in clinical trials, but there have been only a few studies reporting its anti-HCC effects in vitro and in HCC xenograft models. Hence, our present study systemically investigated and compared the antitumorigenic and antiangiogenic efficacy of apatinib and sorafenib in HCC in vitro and in vivo using multimodality molecular imaging, including bioluminescence imaging (BLI), bioluminescence tomography (BLT), fluorescence molecular imaging (FMI), and computed tomography angiography (CTA). Moreover, the safety and side effects of the two drugs were systemically evaluated. We found that apatinib showed a comparable therapeutic efficacy to sorafenib for the inhibition of HCC. The drug safety evaluation revealed that both of these drugs caused hypertension and mild liver and kidney damage. Sorafenib caused diarrhea, rash, and weight loss in mice, but these effects were not observed in mice treated with apatinib. In conclusion, apatinib has similar antitumorigenic and antiangiogenic efficacy as sorafenib in HCC with less toxicity. These findings may provide preclinical evidence supporting the potential application of apatinib for the treatment of HCC patients.
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Affiliation(s)
- Qian Liang
- CAS Key Laboratory of Molecular Imaging, the State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, 100190, Beijing, China
- University of Chinese Academy of Sciences, 100080, Beijing, China
- Beijing Key Laboratory of Molecular Imaging, 100190, Beijing, China
| | - Lingxin Kong
- CAS Key Laboratory of Molecular Imaging, the State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, 100190, Beijing, China
- University of Chinese Academy of Sciences, 100080, Beijing, China
- Beijing Key Laboratory of Molecular Imaging, 100190, Beijing, China
| | - Yang Du
- CAS Key Laboratory of Molecular Imaging, the State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, 100190, Beijing, China.
- University of Chinese Academy of Sciences, 100080, Beijing, China.
- Beijing Key Laboratory of Molecular Imaging, 100190, Beijing, China.
| | - Xu Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University School of Oncology, No. 52 Fucheng Road, Haidian District, 100142, Beijing, China.
| | - Jie Tian
- CAS Key Laboratory of Molecular Imaging, the State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, 100190, Beijing, China.
- University of Chinese Academy of Sciences, 100080, Beijing, China.
- Beijing Key Laboratory of Molecular Imaging, 100190, Beijing, China.
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine, Beihang University, 100191, Beijing, China.
- Engineering Research Center of Molecular and Neuro Imaging of Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710126, Shaanxi, China.
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Abdel-Mohsen HT, Omar MA, El Kerdawy AM, Mahmoud AEE, Ali MM, El Diwani HI. Novel potent substituted 4-amino-2-thiopyrimidines as dual VEGFR-2 and BRAF kinase inhibitors. Eur J Med Chem 2019; 179:707-722. [PMID: 31284081 DOI: 10.1016/j.ejmech.2019.06.063] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 06/12/2019] [Accepted: 06/21/2019] [Indexed: 12/23/2022]
Abstract
In the present study, we report the discovery of a novel class of substituted 4-amino-2-thiopyrimidines as antiangiogenic and antiproliferative agents. Structural hybridization between 4-substituted aminopyrimidines (VEGFR-2 inhibitors) and 2-thioxopyrimidines (BRAF inhibitors) was carried out to afford substituted 4-amino-2-thiopyrimidines as type II dual VEGFR-2/BRAF inhibitors. Our design strategy was tailored such that the 4-amino-2-thiopyrimidine scaffold is to be accommodated in the central gate area of the inactive DFG-out conformation of both enzymes. On one side, the hydrophobic substituent on the 4-amino group would occupy the hydrophobic back pocket and on the other side the substituent on the sulfide moiety should extend to fit in the hinge region (front pocket). Molecular docking simulations confirmed the ability of the designed compounds to accomplish the key interactions in VEGFR-2 and BRAF active sites. Most of the synthesized substituted 4-amino-2-thiopyrimidines demonstrated potent VEGFR-2 inhibitory activity at submicromolar concentrations. Compounds 8a, 8d, 9c and 9e showed IC50 = 0.17, 0.12, 0.17 and 0.19 μM, respectively against VEGFR-2 in comparison to sorafenib (I) IC50 = 0.10 μM and regorafenib (II) IC50 = 0.005 μM. While compounds 9c, 9d and 10a showed IC50 = 0.15, 0.22 and 0.11 μM, respectively against BRAF-WT. At 10 μM concentration 9c revealed promising in vitro broad-spectrum antiproliferative activity against cancer cell lines with growth inhibition percent ranging from 10 to 90%. Moreover, compounds 7b, 8d, 9a, 9b, 9c and 9d showed potent activity against MCF7 cell line (IC50 = 17.18, 17.20, 19.98, 19.61, 13.02 and 16.54 μM, respectively). On the other hand, compounds 9c, 9d and 10d were found to be the most potent compounds against T-47D cell line (IC50 = 2.18, 8.09 and 4.36 μM, respectively). Studying the effect of the most potent compounds on VEGFR-2 level in MCF7 cell line revealed that 9c and 9d showed inhibition percent of 84 and 80%, respectively, in comparison to sorafenib (I) (% inhibition = 90%).
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Affiliation(s)
- Heba T Abdel-Mohsen
- Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Dokki, Cairo, Egypt.
| | - Mohamed A Omar
- Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Dokki, Cairo, Egypt
| | - Ahmed M El Kerdawy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Molecular Modeling Unit, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, New Giza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt
| | - Abeer E E Mahmoud
- Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, Cairo, Egypt
| | - Mamdouh M Ali
- Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, Cairo, Egypt
| | - Hoda I El Diwani
- Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Dokki, Cairo, Egypt
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Kieckhaefer JE, Maina F, Wells R, Wangensteen KJ. Liver Cancer Gene Discovery Using Gene Targeting, Sleeping Beauty, and CRISPR/Cas9. Semin Liver Dis 2019; 39:261-274. [PMID: 30912094 PMCID: PMC7485130 DOI: 10.1055/s-0039-1678725] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a devastating and prevalent cancer with limited treatment options. Technological advances have enabled genetic screens to be employed in HCC model systems to characterize genes regulating tumor initiation and growth. Relative to traditional methods for studying cancer biology, such as candidate gene approaches or expression analysis, genetic screens have several advantages: they are unbiased, with no a priori selection; can directly annotate gene function; and can uncover gene-gene interactions. In HCC, three main types of screens have been conducted and are reviewed here: (1) transposon-based mutagenesis screens, (2) knockdown screens using RNA interference (RNAi) or the CRISPR/Cas9 system, and (3) overexpression screens using CRISPR activation (CRISPRa) or cDNAs. These methods will be valuable in future genetic screens to delineate the mechanisms underlying drug resistance and to identify new treatments for HCC.
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Affiliation(s)
- Julia E. Kieckhaefer
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA
| | - Flavio Maina
- Aix Marseille University, CNRS, Developmental Biology Institute of Marseille (IBDM), Parc Scientifique de Luminy, Marseille, France
| | - Rebecca Wells
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA
- Pathology and Laboratory Medicine and Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Kirk J. Wangensteen
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA
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29
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Pottakkat B, Ashokachakkaravarthy K. Sorafenib resistance and autophagy in hepatocellular carcinoma: A concealed threat. JOURNAL OF CANCER RESEARCH AND PRACTICE 2019. [DOI: 10.4103/jcrp.jcrp_6_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Taniai T, Shirai Y, Shiba H, Sakamoto T, Furukawa K, Yanaga K. Spontaneous Pathological Complete Regression of Hepatocellular Carcinoma. Case Rep Gastroenterol 2018; 12:653-659. [PMID: 30519151 PMCID: PMC6276737 DOI: 10.1159/000494551] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 10/15/2018] [Indexed: 01/27/2023] Open
Abstract
Several possible mechanisms for spontaneous regression of hepatocellular carcinoma (HCC) have been reported. Spontaneous complete regression of HCC is extremely rare. We herein report a case of spontaneous pathological complete regression of HCC following decrement of elevated serum alpha-fetoprotein (AFP). The serum AFP of a 74-year-old man who underwent hepatic resection for HCC twice increased up to 7,529 ng/mL and then spontaneously decreased to 404 ng/mL in 2 months. Computed tomography, magnetic resonance imaging, and angiography revealed a liver tumor in segment 7 without early enhancement. With a diagnosis of recurrent HCC, partial hepatic resection was performed. The resected specimens revealed no HCC macroscopically, and pathological examination revealed only a small area with cell dysplasia. The patient remains well with normal serum AFP and protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels for 29 months after the third hepatic resection without recurrence of HCC. We describe a case of spontaneous pathological complete regression of HCC following decrement of elevated serum AFP. Further studies are needed to identify the mechanism(s) of spontaneous regression of HCC.
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Affiliation(s)
- Tomohiko Taniai
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Yoshihiro Shirai
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiroaki Shiba
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Taro Sakamoto
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Kenei Furukawa
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Katsuhiko Yanaga
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
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31
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Dai N, Ye R, He Q, Guo P, Chen H, Zhang Q. Capsaicin and sorafenib combination treatment exerts synergistic anti‑hepatocellular carcinoma activity by suppressing EGFR and PI3K/Akt/mTOR signaling. Oncol Rep 2018; 40:3235-3248. [PMID: 30272354 PMCID: PMC6196646 DOI: 10.3892/or.2018.6754] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 09/17/2018] [Indexed: 02/06/2023] Open
Abstract
Capsaicin (8‑methyl N‑vanillyl‑6 nonenamide) is a natural plant extract that has antitumor properties and induces apoptosis and autophagy in various types of malignancies, including hepatocellular carcinoma (HCC). Sorafenib is a multi‑kinase inhibitor that improves the survival of patients with advanced HCC. In the present study, capsaicin and sorafenib were found to inhibit the growth of LM3, Hep3B and HuH7 cells. In addition, the combination of capsaicin and sorafenib exerted a synergistic inhibitory effect on HCC cell growth. In LM3 cells, capsaicin and sorafenib combination treatment achieved a markedly stronger induction of apoptosis by increasing caspase‑3, Bax and poly(ADP‑ribose) polymerase activity and inhibiting Bcl‑2, and induction of autophagy by upregulating the levels of beclin‑1 and LC3A/B II, enhancing P62 degradation. The combination of capsaicin and sorafenib also inhibited cell invasion and metastasis via upregulation of E‑cadherin and downregulation of N‑cadherin, vimentin, matrix metalloproteinase (MMP)2 and MMP9. Additional studies suggested an association between the abovementioned anticancer activities and inhibition of the epidermal growth factor receptor/phosphoinositide 3 kinase/Akt/mammalian target of rapamycin pathway. Taken together, these data confirm that capsaicin and sorafenib combination treatment inhibits the growth, invasion and metastasis of HCC cells and induces autophagy in a synergistic manner, supporting its potential as a therapeutic option for HCC.
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Affiliation(s)
- Ninggao Dai
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Ruifan Ye
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Qikuan He
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Pengyi Guo
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Hao Chen
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Qiyu Zhang
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
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Badawi M, Kim J, Dauki A, Sutaria D, Motiwala T, Reyes R, Wani N, Kolli S, Jiang J, Coss CC, Jacob ST, Phelps MA, Schmittgen TD. CD44 positive and sorafenib insensitive hepatocellular carcinomas respond to the ATP-competitive mTOR inhibitor INK128. Oncotarget 2018; 9:26032-26045. [PMID: 29899840 PMCID: PMC5995255 DOI: 10.18632/oncotarget.25430] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 04/26/2018] [Indexed: 12/18/2022] Open
Abstract
The mTOR pathway is activated in about 50% of patients with hepatocellular carcinoma (HCC). In an effort to identify new pathways and compounds to treat advanced HCC, we considered the ATP-competitive mTOR inhibitor INK128. ATP-competitive mTOR inhibitors attenuate both mTORC1 and mTORC2. INK128 was evaluated in sorafenib sensitive and insensitive HCC cell lines, CD44low and CD44high HCC and those cell lines with acquired sorafenib resistance. CD44 was significantly increased in Huh7 cells made resistant to sorafenib. Forced expression of CD44 enhanced cellular proliferation and migration, and rendered the cells more sensitive to the anti-proliferative effects of INK128. INK128 suppressed CD44 expression in HCC cells while allosteric mTOR inhibitors did not. CD44 inhibition correlated with 4EBP1 phosphorylation status. INK128 showed better anti-proliferative and anti-migration effects on the mesenchymal-like HCC cells, CD44high HCC cells compared to the allosteric mTOR inhibitor everolimus. Moreover, a combination of INK128 and sorafenib showed improved anti-proliferative effects in CD44high HCC cells. INK128 was efficacious at reducing tumor growth in CD44high SK-Hep1 xenografts in mice when given as monotherapy or in combination with sorafenib. Since the clinical response to sorafenib is highly variable, our findings suggest that ATP-competitive mTOR inhibitors may be effective in treating advanced, CD44-expressing HCC patients who are insensitive to sorafenib.
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Affiliation(s)
- Mohamed Badawi
- College of Pharmacy, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Jihye Kim
- College of Pharmacy, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Anees Dauki
- College of Pharmacy, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Dhruvitkumar Sutaria
- College of Pharmacy, College of Medicine, The Ohio State University, Columbus, OH, USA
- College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Tasneem Motiwala
- Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Ryan Reyes
- Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Nissar Wani
- Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Shamalatha Kolli
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Jinmai Jiang
- College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Christopher C. Coss
- College of Pharmacy, College of Medicine, The Ohio State University, Columbus, OH, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Samson T. Jacob
- Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Mitch A. Phelps
- College of Pharmacy, College of Medicine, The Ohio State University, Columbus, OH, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
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Lei XF, Ke Y, Bao TH, Tang HR, Wu XS, Shi ZT, Lin J, Zhang ZX, Gu H, Wang L. Effect and safety of sorafenib in patients with intermediate hepatocellular carcinoma who received transarterial chemoembolization: A retrospective comparative study. World J Clin Cases 2018; 6:74-83. [PMID: 29774219 PMCID: PMC5955731 DOI: 10.12998/wjcc.v6.i5.74] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 03/04/2018] [Accepted: 03/20/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To evaluate the safety and efficacy of sorafenib plus transarterial chemoembolization (TACE) treatment for intermediate hepatocellular carcinoma (HCC).
METHODS Sixty-seven patients with intermediate-stage [Barcelona Clinic liver cancer stage B (BCLC-B)] HCC who were treated with sorafenib plus TACE or TACE alone between 2009 and 2011 were included in the study. Follow-up was until 2014 or patient death. Two groups were defined in the experiment: The experimental group, treated with sorafenib plus TACE, and the control group, treated with standard TACE alone.
RESULTS The Kaplan-Meier survival analysis showed that the median overall survival (mOS) of the experimental group was 35.2 mo, while that of the control group was 22.0 mo (P < 0.05). Sorafenib plus TACE showed higher incidence rates of rash, hand-foot syndrome (HFS), and hypertension (P < 0.05) than TACE treatment alone.
CONCLUSION Sorafenib plus TACE treatment for BCLC-B HCC significantly prolonged the mOS of patients compared to TACE treatment alone. The most common toxicities with sorafenib were rash (31.6%), HFS (39.5%) and hypertension (31.6%), but there were no intolerable adverse events. The Cox multivariate analysis showed that the survival of patients with BCLC-B HCC depended on the Child-Pugh classification, tumor diameter, and treatment with sorafenib plus TACE compared to TACE alone.
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Affiliation(s)
- Xue-Fen Lei
- Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Yang Ke
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Tian-Hao Bao
- The Mental Health Center of Kunming Medical University, Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Hao-Ran Tang
- Department of Gastroenterological Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Xue-Song Wu
- Department of Gastroenterological Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Zhi-Tian Shi
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University; Kunming 650101, Yunnan Province, China
| | - Jie Lin
- Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Zhi-Xian Zhang
- Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Hou Gu
- Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University; Kunming 650101, Yunnan Province, China
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Wang X, Zou F, Zhong J, Yue L, Wang F, Wei H, Yang G, Jin T, Dong X, Li J, Xiu P. Secretory Clusterin Mediates Oxaliplatin Resistance via the Gadd45a/PI3K/Akt Signaling Pathway in Hepatocellular Carcinoma. J Cancer 2018; 9:1403-1413. [PMID: 29721050 PMCID: PMC5929085 DOI: 10.7150/jca.23849] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 02/25/2018] [Indexed: 12/12/2022] Open
Abstract
Purpose: Systemic therapy has often been used for patients with advanced hepatocellular carcinoma (HCC). However, due to drug resistance, the use of cytotoxic chemotherapy in the treatment of patients with advanced HCC has typically demonstrated low response rates. Secretory clusterin (sCLU) is expressed in aggressive late-stage tumors and associated with resistance to chemotherapy, including that in HCC cases. The present research aimed to investigate the biological role of sCLU in HCC. Methods: sCLU expression in HCC and normal tissues was examined using immunohistochemical staining, followed by analysis of the correlation between sCLU expression and clinical indicators. In addition, the role and internal mechanism of sCLU in cell proliferation and apoptosis were investigated in HCC cells. Results: sCLU expression was significantly upregulated in HCC tissues; and was associated with histological grade and poor overall survival. The levels of sCLU were significantly increased in Bel7402, SMMC7721 and resistant HCC cells (Bel7404-OR). Inhibiting the activity of sCLU enhanced the chemosensitivity of Bel7402 and SMMC7721 cells. Downregulation of sCLU could increase the expression of Gadd45a in HCC cells. Overexpression of sCLU contributed to drug resistance in Bel7402, SMMC7721 and Bel7404-OR cells; whereas, overexpression of Gadd45a alone overcame drug resistance in the cells above. No significant expression changes of sCLU and Gadd45a were observed in HCC cells after the interference of a selective inhibitor of the PI3K/Akt signaling pathway. However, regulation of the expression of Gadd45a could influence the phosphorylation level of Akt; and further regulate the expression of Bcl-2 and Bax proteins involved in the mitochondrial apoptosis pathways. Conclusions: The results demonstrate that sCLU/Gadd45a/PI3K/Akt signaling represents a novel pathway that could regulate drug resistance in a one-way manner in HCC cells.
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Affiliation(s)
- Xin Wang
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China
| | - Fang Zou
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China.,Department of Emergency Surgery, The People's Hospital of Linyi City, Linyi 276000, China
| | - Jingtao Zhong
- Department of General Surgery, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academic of Medicine Science, Jinan 250117, Shandong, China
| | - Longtao Yue
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China
| | - Fuhai Wang
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China
| | - Honglong Wei
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China
| | - Guangsheng Yang
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China
| | - Tao Jin
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China
| | - Xiaofeng Dong
- Department of Hepatobiliary Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China
| | - Jie Li
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China
| | - Peng Xiu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China
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Hameed S, Bhattarai P, Dai Z. Nanotherapeutic approaches targeting angiogenesis and immune dysfunction in tumor microenvironment. SCIENCE CHINA-LIFE SCIENCES 2018; 61:380-391. [PMID: 29607461 DOI: 10.1007/s11427-017-9256-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 12/19/2017] [Indexed: 12/23/2022]
Abstract
Tumor microenvironment (TME) comprising cellular and non-cellular components is a major source of cancer hallmarks. Notably, angiogenesis responsible for normal physiological remodeling process can otherwise harness vessel abnormalities during tumorigenesis eliciting severe therapeutic inefficiency. Currently, FDA approved antiangiogenic drugs have only shown modest clinical success owing to tumor hypoxia, antiangiogenic therapeutic resistance, and limited knowledge in understanding TME. In order to overcome these limitations, targeting angiogenesis combined with immunosuppressive TME could offer potential therapeutic opportunities. Indeed, these therapeutic approaches can be further revisited with the advent of nanotechnology that can target the key cellular components of TME and tumor cells more precisely. Synergetic targeting without eliciting systemic toxicity achieved by integration of antiangiogenic and immunotherapy in a single nanoplatform is vital for therapeutic success. In this review, we will discuss the most promising nanotechnological advancements oriented to modulate the immunosuppressive TME in association with antiangiogenic therapy that has gained immense popularity in cancer treatment.
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Affiliation(s)
- Sadaf Hameed
- Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, 100871, China
| | - Pravin Bhattarai
- Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, 100871, China
| | - Zhifei Dai
- Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, 100871, China.
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Yan H, Jung KH, Kim J, Rumman M, Oh MS, Hong SS. Artemisia capillaris extract AC68 induces apoptosis of hepatocellular carcinoma by blocking the PI3K/AKT pathway. Biomed Pharmacother 2018; 98:134-141. [DOI: 10.1016/j.biopha.2017.12.043] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 12/05/2017] [Accepted: 12/13/2017] [Indexed: 02/07/2023] Open
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Li X, Zhang D, Guan S, Ye W, Liu L, Lou L. Efficacy of anti-VEGF agents in the treatment of elderly hepatocellular carcinoma: a systematic review. Oncotarget 2017; 8:93179-93185. [PMID: 29190987 PMCID: PMC5696253 DOI: 10.18632/oncotarget.21452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 07/12/2017] [Indexed: 11/25/2022] Open
Abstract
Purpose We aimed to investigate the role of anti-vascular endothelial growth factor (VEGF) agents, including tyrosine-kinase inhibitors or monoclonal anti-bodies, in the treatment of elderly hepatocellular carcinoma (HCC) patients. Materials and Methods Databases from PubMed, Web of Science and abstracts presented at ASCO meeting up to March 31, 2017 were searched to identify relevant studies. The endpoints were overall survival (OS) and progression-free survival (PFS). Data were examined using age cutoffs of 65 years. Results A total of 1,309 elderly (aged ≥ 65 years) HCC patients from seven trials were included for analysis. Our results demonstrated that the use of anti-VEGF agents MTAs in patients aged ≥ 65 years significantly improved PFS (HR 0.65, 95% CI: 0.55–0.76, p < 0.001) but not for OS (HR 0.87, 95% CI: 0.73–1.05, p = 0.15). Sub-group analysis according to treatment line showed that the use of anti-VEGF agents as second-line treatment significantly improved PFS (HR 0.55, 95% CI: 0.45–0.67, p < 0.001) and marginally improved OS (HR 0.83, 95% CI: 0.68–1.01, p = 0.061). Additionally, no survival benefits were observed in elderly HCC received first-line anti-VEGF treatments in terms of PFS (HR 0.87, 95% CI: 0.67–1.13, p = 0.29) and OS (HR 1.19, 95% CI: 0.74–1.36, p = 0.47). No publication bias was detected by Begg's and Egger's tests for OS. Conclusions The findings of this study show that elderly HCC patients who relapsed after a first-line sorafenib treatment obtains a survival benefits from anti-VEGF agents rechallenge. Further studies are recommended to search for predictors of good responders in these patients received anti-VEGF agents.
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Affiliation(s)
- Xiaofei Li
- Department of Infectious Diseases, Yi Wu Central Hospital, Zhejiang Province, 322000, China
| | - Daofu Zhang
- Liao Cheng City People's Hospital, Shandong Province, 252000, China
| | - Shan Guan
- Department of Infectious Diseases, Liaocheng People's Hospital, Shandong Province, 252000, China
| | - Weiwei Ye
- Department of Infectious Diseases, Yi Wu Central Hospital, Zhejiang Province, 322000, China
| | - Liwen Liu
- Department of Infectious Diseases, Yi Wu Central Hospital, Zhejiang Province, 322000, China
| | - Lianqing Lou
- Department of Infectious Diseases, Yi Wu Central Hospital, Zhejiang Province, 322000, China
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Chettiar ST, Malek R, Annadanam A, Nugent KM, Kato Y, Wang H, Cades JA, Taparra K, Belcaid Z, Ballew M, Manmiller S, Proia D, Lim M, Anders RA, Herman JM, Tran PT. Ganetespib radiosensitization for liver cancer therapy. Cancer Biol Ther 2017; 17:457-66. [PMID: 26980196 PMCID: PMC4910914 DOI: 10.1080/15384047.2016.1156258] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33–1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies.
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Affiliation(s)
- Sivarajan T Chettiar
- a Department of Radiation Oncology and Molecular Radiation Sciences , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Reem Malek
- a Department of Radiation Oncology and Molecular Radiation Sciences , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Anvesh Annadanam
- a Department of Radiation Oncology and Molecular Radiation Sciences , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Katriana M Nugent
- a Department of Radiation Oncology and Molecular Radiation Sciences , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Yoshinori Kato
- b The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine , Baltimore , MD , USA.,c Department of Oncology , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Hailun Wang
- a Department of Radiation Oncology and Molecular Radiation Sciences , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Jessica A Cades
- a Department of Radiation Oncology and Molecular Radiation Sciences , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Kekoa Taparra
- a Department of Radiation Oncology and Molecular Radiation Sciences , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA.,d Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Zineb Belcaid
- e Department of Neurosurgery , Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Matthew Ballew
- a Department of Radiation Oncology and Molecular Radiation Sciences , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Sarah Manmiller
- a Department of Radiation Oncology and Molecular Radiation Sciences , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - David Proia
- f Synta Pharmaceuticals Corp. , Lexington , MD , USA
| | - Michael Lim
- c Department of Oncology , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA.,e Department of Neurosurgery , Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Robert A Anders
- g Department of Pathology , Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Joseph M Herman
- a Department of Radiation Oncology and Molecular Radiation Sciences , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA.,c Department of Oncology , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Phuoc T Tran
- a Department of Radiation Oncology and Molecular Radiation Sciences , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA.,c Department of Oncology , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA.,d Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine , Baltimore , MD , USA.,h Department of Urology , Johns Hopkins University School of Medicine , Baltimore , MD , USA
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Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model. PLoS One 2017; 12:e0181944. [PMID: 28829785 PMCID: PMC5567696 DOI: 10.1371/journal.pone.0181944] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/10/2017] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the 2nd leading cause of cancer-related deaths every year globally. The most common form of treatment, hepatic arterial infusion (HAI), involves the direct injection of doxorubicin (DOX) into the hepatic artery. It is plagued with limited therapeutic efficacy and the occurrence of severe toxicities (e.g. cardiotoxicity). We aim to improve the therapeutic index of DOX delivered via HAI by loading the drug onto generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands. DOX is attached to the surface of G5 molecules via two different enzyme-sensitive linkages, L3 or L4, to achieve controllable drug release inside hepatic cancer cells. We previously reported on P1 and P2 particles that resulted from the combination of NAcGal-targeting with L3- or L4-DOX linkages, respectively, and showed controllable DOX release and toxicity towards hepatic cancer cells comparable to free DOX. In this study, we demonstrate that while the intratumoral delivery of free DOX (1 mg/kg) into HCC-bearing nod scid gamma (NSG) mice achieves a 2.5-fold inhibition of tumor growth compared to the saline group over 30 days, P1 and P2 particles delivered at the same DOX dosage achieve a 5.1- and 4.4-fold inhibition, respectively. Incubation of the particles with human induced pluripotent stem cell derived cardiomyocytes (hiPSC CMs) showed no effect on monolayer viability, apoptosis induction, or CM electrophysiology, contrary to the effect of free DOX. Moreover, magnetic resonance imaging revealed that P1- and P2-treated mice maintained cardiac function after intraperitoneal administration of DOX at 1 mg/kg for 21 days, unlike the free DOX group at an equivalent dosage, confirming that P1/P2 can avoid DOX-induced cardiotoxicity. Taken together, these results highlight the ability of P1/P2 particles to improve the therapeutic index of DOX and offer a replacement therapy for clinical HCC treatment.
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Le Grazie M, Biagini MR, Tarocchi M, Polvani S, Galli A. Chemotherapy for hepatocellular carcinoma: The present and the future. World J Hepatol 2017; 9:907-920. [PMID: 28824742 PMCID: PMC5545136 DOI: 10.4254/wjh.v9.i21.907] [Citation(s) in RCA: 144] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 06/20/2017] [Accepted: 07/03/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it’s still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatin- and gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.
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Ting CT, Cheng YY, Tsai TH. Herb-Drug Interaction between the Traditional Hepatoprotective Formulation and Sorafenib on Hepatotoxicity, Histopathology and Pharmacokinetics in Rats. Molecules 2017; 22:E1034. [PMID: 28640225 PMCID: PMC6152211 DOI: 10.3390/molecules22071034] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2017] [Accepted: 06/19/2017] [Indexed: 12/12/2022] Open
Abstract
Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC). In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT) and with two cytochrome P450 3A4 (CYP3A4) inhibitors, grapefruit juice and ketoconazole. Liver enzyme levels and histopathology of liver slices were used to evaluate sorafenib-induced hepatotoxicity and the potential hepatoprotective effects of the LDXGT formulation on subjects treated with the combination of sorafenib and the herbal medicine. In this study, a validated HPLC-photodiode array analytical system was developed for the pharmacokinetic study of sorafenib in rats. As the result of the pharmacokinetic data, pretreatment with the LDXGT formulation did not significantly interact with sorafenib compared with sorafenib oral administration alone. Furthermore, grapefruit juice and ketoconazole did not significantly affect sorafenib metabolism. Furthermore, pretreatment with variable, single or repeat doses of the LDXGT formulation did not suppress or exacerbate the sorafenib-induced hepatotoxicity and histopathological alterations. According to these results, the LDXGT formulation is safe, but has no beneficial effects on sorafenib-induced hepatotoxicity. A detailed clinical trial should be performed to further evaluate the efficacy or adverse effects of the LDXGT formulation in combination with sorafenib in humans.
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Affiliation(s)
- Chin-Tsung Ting
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
- Division of Gastrointestinal Surgery, Department of Surgery, Ren-Ai Branch, Taipei City Hospital, Taipei 10629, Taiwan.
| | - Yung-Yi Cheng
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
| | - Tung-Hu Tsai
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
- Graduate Institute of Acupuncture Science, China Medical University, Taichung 40402, Taiwan.
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Department of Chemical Engineering, National United University, Miaoli 36063, Taiwan.
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Ziogas IA, Tsoulfas G. Evolving role of Sorafenib in the management of hepatocellular carcinoma. World J Clin Oncol 2017; 8:203-213. [PMID: 28638790 PMCID: PMC5465010 DOI: 10.5306/wjco.v8.i3.203] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/03/2017] [Accepted: 04/23/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide and comes third in cancer-related mortality. Although there is a broad spectrum of treatment options to choose from, only a few patients are eligible candidates to receive a curative therapy according to their stage of disease, and thus palliative treatment is implemented in the majority of the patients suffering from liver cancer. Sorafenib, a multikinase inhibitor, is the only currently approved agent for systemic therapy in patients with advanced stage HCC and early stage liver disease. It has been shown to improve the overall survival, but with various side effects, while its cost is not negligible. Sorafenib has been in the market for a decade and has set the stage for personalized targeted therapy. Its role during this time has ranged from monotherapy to neoadjuvant and adjuvant treatment with surgical resection, liver transplantation and chemoembolization or even in combination with other chemotherapeutic agents. In this review our aim is to highlight in depth the current position of Sorafenib in the armamentarium against HCC and how that has evolved over time in its use either as a single agent or in combination with other therapies.
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Sakamaki A, Kamimura K, Abe S, Tsuchiya A, Takamura M, Kawai H, Yamagiwa S, Terai S. Spontaneous regression of hepatocellular carcinoma: A mini-review. World J Gastroenterol 2017; 23:3797-3804. [PMID: 28638219 PMCID: PMC5467065 DOI: 10.3748/wjg.v23.i21.3797] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 03/22/2017] [Accepted: 05/04/2017] [Indexed: 02/06/2023] Open
Abstract
Spontaneous tumor regression is an extremely rare phenomenon in the oncology field. However, there are several case reports resulted in the regression of hepatocellular carcinoma (HCC) and the accumulation of clinical information and analyses of the mechanism can contribute to the development of a novel therapy. For this purpose, we have carefully reviewed 23 cases of spontaneously regressed HCC published in recent 5 years and our case. The information regarding the tumor size, tumor marker, treatments, etc., have been summarized. The mechanism of spontaneous regression has been discussed to date and presumed to be due to many factors, including hypoxia and immunological reactions. In this careful review of the 24 cases based on the clinical information, hypoxia, systemic inflammation, and both upon spontaneous regression were seen in 3, 8, and 4 cases, respectively among the 15 cases for which the information regarding the proposed mechanisms are available. Recent development of immunotherapeutic approaches in oncology shows promising results, therefore, accumulation of additional cases and analysis of mechanisms underlying the spontaneous regression of HCC are essential and could lead to the development of a new generation of immunotherapies including antibodies directed against immune reactions.
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Matrone A, Valerio L, Pieruzzi L, Giani C, Cappagli V, Lorusso L, Agate L, Puleo L, Viola D, Bottici V, Del Re M, Molinaro E, Danesi R, Elisei R. Protein kinase inhibitors for the treatment of advanced and progressive radiorefractory thyroid tumors: From the clinical trials to the real life. Best Pract Res Clin Endocrinol Metab 2017; 31:319-334. [PMID: 28911728 DOI: 10.1016/j.beem.2017.06.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The last ten years have been characterized by the introduction in the clinical practice of new drugs named tyrosine kinase inhibitors for the treatment of several human tumors. After the positive conclusion of two international multicentric, randomized phase III clinical trials, two of these drugs, sorafenib and lenvatinib, have been recently approved and they are now available for the treatment of advanced and progressive radioiodine refractory thyroid tumors. We have been involved in most clinical trials performed with different tyrosine kinase inhibitors in different histotypes of thyroid cancer thus acquiring a lot of experience in the management of both drugs and their adverse events. Aim of this review is to give an overview of both the rationale for the use of these inhibitors in thyroid cancer and the major results of the clinical trials. Some suggestions for the management of treated patients in the real life are also provided.
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Affiliation(s)
- Antonio Matrone
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - Laura Valerio
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - Letizia Pieruzzi
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - Carlotta Giani
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - Virginia Cappagli
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - Loredana Lorusso
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - Laura Agate
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - Luciana Puleo
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - David Viola
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - Valeria Bottici
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - Marzia Del Re
- Unit of Pharmacology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - Eleonora Molinaro
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - Romano Danesi
- Unit of Pharmacology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy
| | - Rossella Elisei
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy.
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Yan Y, Wang L, He J, Liu P, Lv X, Zhang Y, Xu X, Zhang L, Zhang Y. Synergy with interferon-lambda 3 and sorafenib suppresses hepatocellular carcinoma proliferation. Biomed Pharmacother 2017; 88:395-402. [PMID: 28122304 DOI: 10.1016/j.biopha.2017.01.077] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 01/11/2017] [Accepted: 01/12/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common and fatal malignancy of the liver. Sorafenib is a small molecule multikinase inhibitor that acts against different cancer cell lines and is used for the treatment of HCC. However, some advanced HCC patients fail to respond to sorafenib, and those who do lack a meaningful clinical benefit. Interferon-lambda 3 (IFN-λ3) is a type III interferon with antiviral, antiproliferative, and immunomodulatory functions. Here, we evaluated the use of IFN-λ3 as an adjuvant treatment with sorafenib in HCC. In the present study, CCK-8 and colony formation assay results showed that treatment with a combination of IFN-λ3 and sorafenib suppresses the viability of HepG2 and SMMC7721 liver cancer cell lines more than treatment with either alone. In addition, flow cytometry results confirmed that treatment with a combination of IFN-λ3 and sorafenib promotes the loss of mitochondrial membrane potential and induces the production of ROS more than treatment with either alone. Furthermore, using a subcutaneous SMMC7721 tumor model, treatment with a combination of IFN-λ3 and sorafenib significantly reduced the tumor growth/volume and induced apoptosis compared to treatment with sorafenib alone. These results show that combined treatment with IFN-λ3 and sorafenib facilitates a synergistic effect on suppressing HCC cancer growth and promoting cell apoptosis in vitro and in vivo. Thus, IFN-λ3 in combination with sorafenib might prove to be a useful adjunctive strategy for the clinical treatment of HCC.
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Affiliation(s)
- Yuke Yan
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China
| | - Liang Wang
- Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China; Division of Liver Disease, Lanzhou University Second Hospital, Lanzhou 730030, PR China
| | - Jingjing He
- Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China; Division of Liver Disease, Lanzhou University Second Hospital, Lanzhou 730030, PR China
| | - Pengcheng Liu
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China
| | - Xi Lv
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China
| | - Yawu Zhang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China
| | - Xiaodong Xu
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China
| | - Lingyi Zhang
- Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China; Division of Liver Disease, Lanzhou University Second Hospital, Lanzhou 730030, PR China
| | - Youcheng Zhang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China.
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Su CL, Tseng CL, Ramesh C, Liu HS, Huang CYF, Yao CF. Using gene expression database to uncover biology functions of 1,4-disubstituted 1,2,3-triazole analogues synthesized via a copper (I)-catalyzed reaction. Eur J Med Chem 2017; 132:90-107. [PMID: 28342400 DOI: 10.1016/j.ejmech.2017.03.034] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 03/14/2017] [Accepted: 03/15/2017] [Indexed: 12/18/2022]
Abstract
We have synthesized bioactive 1,4-disubstituted 1,2,3-triazole analogues containing 2H-1,4-benzoxazin-3-(4H)-one derivatives via 1,3-dipolar cycloaddition in the presence of CuI. All the reactions proceeded smoothly and afforded its desired products in excellent yields. Among these analogues, 3y exhibited a better cytotoxic effect on human hepatocellular carcinoma (HCC) Hep 3B cells and displayed less cytotoxicity on normal human umbilical vein endothelial cells, compared with Sorafenib, a targeted therapy for advanced HCC. 3y also induced stronger apoptosis and autophagy. Addition of curcumin enhanced 3y-induced cytotoxicity by further induction of autophagy. Using gene expression signatures of 3y to query Connectivity Map, a glycogen synthase kinase-3 inhibitor (AR-A014418) was predicted to display similar molecular action of 3y. Experiments further demonstrate that AR-A014418 acted like 3y, and vice versa. Overall, our data suggest the chemotherapeutic potential of 3y on HCC.
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Affiliation(s)
- Chun-Li Su
- Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan.
| | - Chia-Ling Tseng
- Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan
| | - Chintakunta Ramesh
- Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan
| | - Hsiao-Sheng Liu
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Center of Infectious Disease and Signaling Research Center, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Chi-Ying F Huang
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan; Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Ching-Fa Yao
- Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan.
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Lin ZY, Chuang WL. Contrary influence of clinically applied sorafenib concentrations among hepatocellular carcinoma patients. Biomed Pharmacother 2017; 86:27-31. [PMID: 27936391 DOI: 10.1016/j.biopha.2016.11.144] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 11/25/2016] [Accepted: 11/30/2016] [Indexed: 12/13/2022] Open
Abstract
The treatment responses of sorafenib in hepatocellular carcinoma are modest which may be due to different characteristics of cancer cells or insufficient therapeutic concentrations. This study was to clarify this issue. The anti-proliferative effects and differential expressions of 8 genes related to sorafenib anti-cancer mechanisms (tyrosine kinase receptor genes: KDR, PDGFRB; RAF cascade: RAF1, BRAF, MAP2K1, MAP2K2, MAPK1, MAPK3) were investigated in primary cultured hepatocellular carcinoma cells collected from 8 patients using clinically applied sorafenib concentrations (5, 10μg/mL). The anti-proliferative effects of sorafenib at either 5 or 10μg/mL, which were related to down-regulations of KDR, PDGFRB and/or genes in the RAF cascade, were achieved only in one patient (HCC38/KMUH). However, either 5 or 10μg/mL sorafenib promoted proliferation in 4 patients (HCC29/KMUH, HCC62/KMUH, HCC87/KMUH, HCC98/KMUH). Among them, the RAF cascade, PDGFRB and/or KDR were up-regulated in 3 patients but no gene was differentially expressed in the remaining one patient (HCC87/KMUH). Increase the sorafenib concentration to 10μg/mL paradoxically up-regulated and/or obliterated the previously down-regulated genes in the RAF cascade and/or KDR in 4 patients (HCC29/KMUH, HCC76/KMUH, HCC87/KMUH, HCC98/KMUH). Significant down-regulations of the RAF cascade and PDGFRB by sorafenib but without anti-proliferative effects were detected in one patient (HCC54/KMUH). In conclusion, influence of sorafenib on proliferation is not simply through the RAF cascade. The responses of KDR, PDGFRB and the RAF cascade to sorafenib among patients are diverse or even contrary. Increase the sorafenib concentration has potential to up-regulate genes favored angiogenesis and proliferation.
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Affiliation(s)
- Zu-Yau Lin
- Division of Hepatobiliary Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Wan-Long Chuang
- Division of Hepatobiliary Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Luo SC, Wu CC, Jheng SB, Huang ZY. Spontaneous remission of hepatocellular carcinoma without any treatment. JOURNAL OF CANCER RESEARCH AND PRACTICE 2016. [DOI: 10.1016/j.jcrpr.2016.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
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Omar HA, Tolba MF, Hung JH, Al-Tel TH. OSU-2S/Sorafenib Synergistic Antitumor Combination against Hepatocellular Carcinoma: The Role of PKCδ/p53. Front Pharmacol 2016; 7:463. [PMID: 27965580 PMCID: PMC5127788 DOI: 10.3389/fphar.2016.00463] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 11/16/2016] [Indexed: 12/19/2022] Open
Abstract
Background: Sorafenib (Nexavar®) is an FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, the low efficacy and adverse effects at high doses limit the clinical application of sorafenib and strongly recommend its combination with other agents aiming at ameliorating its drawbacks. OSU-2S, a PKCδ activator, was selected as a potential candidate anticancer agent to be combined with sorafenib to promote the anti-cancer activity through synergistic interaction. Methods: The antitumor effects of sorafenib, OSU-2S and their combination were assessed by MTT assay, caspase activation, Western blotting, migration/invasion assays in four different HCC cell lines. The synergistic interactions were determined by Calcusyn analysis. PKCδ knockdown was used to elucidate the role of PKCδ activation as a mechanism for the synergy. The knockdown/over-expression of p53 was used to explain the differential sensitivity of HCC cell lines to sorafenib and/or OSU-2S. Results: OSU-2S synergistically enhanced the anti-proliferative effects of sorafenib in the four used HCC cell lines with combination indices <1. This effect was accompanied by parallel increases in caspase 3/7 activity, PARP cleavage, PKCδ activation and inhibition of HCC cell migration/invasion. In addition, PKCδ knockdown abolished the synergy between sorafenib and OSU-2S. Furthermore, p53 restoration in Hep3B cells through the over-expression rendered them more sensitive to both agents while p53 knockdown from HepG2 cells increased their resistance to both agents. Conclusion: OSU-2S augments the anti-proliferative effect of sorafenib in HCC cell lines, in part, through the activation of PKCδ. The p53 status in HCC cells predicts their sensitivity toward both sorafenib and OSU-2S. The proposed combination represents a therapeutically relevant approach that can lead to a new HCC therapeutic protocol.
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Affiliation(s)
- Hany A Omar
- Sharjah Institute for Medical Research and College of Pharmacy, University of SharjahSharjah, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef UniversityBeni-Suef, Egypt
| | - Mai F Tolba
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams UniversityCairo, Egypt; School of Pharmacy, Chapman University, IrvineCA, USA
| | - Jui-Hsiang Hung
- Department of Biotechnology, Chia Nan University of Pharmacy and Science Tainan, Taiwan
| | - Taleb H Al-Tel
- Sharjah Institute for Medical Research and College of Pharmacy, University of Sharjah Sharjah, United Arab Emirates
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50
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Mani SKK, Zhang H, Diab A, Pascuzzi PE, Lefrançois L, Fares N, Bancel B, Merle P, Andrisani O. EpCAM-regulated intramembrane proteolysis induces a cancer stem cell-like gene signature in hepatitis B virus-infected hepatocytes. J Hepatol 2016; 65:888-898. [PMID: 27238755 PMCID: PMC5289705 DOI: 10.1016/j.jhep.2016.05.022] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 05/02/2016] [Accepted: 05/17/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatocytes in which the hepatitis B virus (HBV) is replicating exhibit loss of the chromatin modifying polycomb repressive complex 2 (PRC2), resulting in re-expression of specific, cellular PRC2-repressed genes. Epithelial cell adhesion molecule (EpCAM) is a PRC2-repressed gene, normally expressed in hepatic progenitors, but re-expressed in hepatic cancer stem cells (hCSCs). Herein, we investigated the functional significance of EpCAM re-expression in HBV-mediated hepatocarcinogenesis. METHODS Employing molecular approaches (transfections, fluorescence-activated cell sorting, immunoblotting, qRT-PCR), we investigated the role of EpCAM-regulated intramembrane proteolysis (RIP) in HBV replicating cells in vitro, and in liver tumors from HBV X/c-myc mice and chronically HBV infected patients. RESULTS EpCAM undergoes RIP in HBV replicating cells, activating canonical Wnt signaling. Transfection of Wnt-responsive plasmid expressing green fluorescent protein (GFP) identified a GFP + population of HBV replicating cells. These GFP+/Wnt+ cells exhibited cisplatin- and sorafenib-resistant growth resembling hCSCs, and increased expression of pluripotency genes NANOG, OCT4, SOX2, and hCSC markers BAMBI, CD44 and CD133. These genes are referred as EpCAM RIP and Wnt-induced hCSC-like gene signature. Interestingly, this gene signature is also overexpressed in liver tumors of X/c-myc bitransgenic mice. Clinically, a group of HBV-associated hepatocellular carcinomas was identified, exhibiting elevated expression of the hCSC-like gene signature and associated with reduced overall survival post-surgical resection. CONCLUSIONS The hCSC-like gene signature offers promise as prognostic tool for classifying subtypes of HBV-induced HCCs. Since EpCAM RIP and Wnt signaling drive expression of this hCSC-like signature, inhibition of these pathways can be explored as therapeutic strategy for this subtype of HBV-associated HCCs. LAY SUMMARY In this study, we provide evidence for a molecular mechanism by which chronic infection by the hepatitis B virus results in the development of poor prognosis liver cancer. Based on this mechanism our results suggest possible therapeutic interventions.
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Affiliation(s)
- Saravana Kumar Kailasam Mani
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, United States; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States
| | - Hao Zhang
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, United States; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States
| | - Ahmed Diab
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, United States; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States
| | - Pete E Pascuzzi
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States; Purdue University Libraries, Purdue University, West Lafayette, IN 47907, United States
| | - Lydie Lefrançois
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052 - CNRS 5286, Lyon Cedex 03, France
| | - Nadim Fares
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052 - CNRS 5286, Lyon Cedex 03, France
| | - Brigitte Bancel
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052 - CNRS 5286, Lyon Cedex 03, France
| | - Philippe Merle
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052 - CNRS 5286, Lyon Cedex 03, France
| | - Ourania Andrisani
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, United States; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
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