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1
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Huang C, Li Y, Zhang F, Zhang C, Ding Z. Advancements in elucidating the mechanisms of Sorafenib resistance in hepatocellular carcinoma. Int J Surg 2025; 111:2990-3005. [PMID: 39992113 DOI: 10.1097/js9.0000000000002294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 01/17/2025] [Indexed: 02/25/2025]
Abstract
Primary liver cancer is a major global health challenge, of which hepatocellular carcinoma is the most common. For patients with advanced liver cancer, Sorafenib is a first-line targeted drug that occupies a dominant position in clinical applications. Sorafenib is a multi-kinase inhibitor commonly used in clinical practice, which can effectively inhibit tumor cell proliferation, promote cell apoptosis, and inhibit angiogenesis. However, the emergence of drug resistance has hindered the development of treatment programs, which is an urgent problem to be solved. Recent studies have revealed many mechanisms and influencing factors of Sorafenib resistance (such as epigenetic regulation, programmed cell death, metabolic reprogramming, and tumor microenvironment changes). This review not only summarizes the above mechanisms, but also summarizes the combined application of Sorafenib with other drugs (such as molecular targeted drugs, other anti-angiogenesis drugs, cytotoxic drugs, immunotherapy drugs, etc .). Finally, potential strategies and research directions to overcome drug resistance (such as targeting epigenetic pathways or metabolic reprogramming) are discussed to provide suggestions for future in-depth research and clinical applications.
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Affiliation(s)
- Chen Huang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yangqian Li
- Frontiers Science Center for Disease-related Molecular Network, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fengmei Zhang
- Frontiers Science Center for Disease-related Molecular Network, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chenliang Zhang
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhenyu Ding
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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2
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Heumann P, Albert A, Gülow K, Tümen D, Müller M, Kandulski A. Insights in Molecular Therapies for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1831. [PMID: 38791911 PMCID: PMC11120383 DOI: 10.3390/cancers16101831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/03/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
We conducted a comprehensive review of the current literature of published data and clinical trials (MEDLINE), as well as published congress contributions and active recruiting clinical trials on targeted therapies in hepatocellular carcinoma. Combinations of different agents and medical therapy along with radiological interventions were analyzed for the setting of advanced HCC. Those settings were also analyzed in combination with adjuvant situations after resection or radiological treatments. We summarized the current knowledge for each therapeutic setting and combination that currently is or has been under clinical evaluation. We further discuss the results in the background of current treatment guidelines. In addition, we review the pathophysiological mechanisms and pathways for each of these investigated targets and drugs to further elucidate the molecular background and underlying mechanisms of action. Established and recommended targeted treatment options that already exist for patients are considered for systemic treatment: atezolizumab/bevacizumab, durvalumab/tremelimumab, sorafenib, lenvatinib, cabozantinib, regorafenib, and ramucirumab. Combination treatment for systemic treatment and local ablative treatment or transarterial chemoembolization and adjuvant and neoadjuvant treatment strategies are under clinical investigation.
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Affiliation(s)
- Philipp Heumann
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany (K.G.); (D.T.)
| | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany (K.G.); (D.T.)
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3
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Pessino G, Scotti C, Maggi M, Immuno-Hub Consortium. Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets. Cancers (Basel) 2024; 16:901. [PMID: 38473265 DOI: 10.3390/cancers16050901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include surgical options, systemic chemotherapy, and kinase inhibitors, like sorafenib and regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint inhibitors, such as atezolizumab and pembrolizumab, show efficacy, and combination therapies enhance clinical responses. Despite this, the treatment of hepatocellular carcinoma (HCC) remains a challenge, as the complex tumor ecosystem and the immunosuppressive microenvironment associated with it hamper the efficacy of the available therapeutic approaches. This review explores current and advanced approaches to treat HCC, considering both known and new potential targets, especially derived from proteomic analysis, which is today considered as the most promising approach. Exploring novel strategies, this review discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), and engineered antibodies. It then reports a systematic analysis of the main ligand/receptor pairs and molecular pathways reported to be overexpressed in tumor cells, highlighting their potential and limitations. Finally, it discusses TGFβ, one of the most promising targets of the HCC microenvironment.
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Affiliation(s)
- Greta Pessino
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Claudia Scotti
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Maristella Maggi
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Immuno-Hub Consortium
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
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4
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Takao S, Fukushima H, King AP, Kato T, Furusawa A, Okuyama S, Kano M, Choyke PL, Escorcia FE, Kobayashi H. Near-infrared photoimmunotherapy in the models of hepatocellular carcinomas using cetuximab-IR700. Cancer Sci 2023; 114:4654-4663. [PMID: 37817415 PMCID: PMC10727998 DOI: 10.1111/cas.15965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/22/2023] [Accepted: 09/01/2023] [Indexed: 10/12/2023] Open
Abstract
Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in many cancers, and overexpression of EGFR is frequently observed in hepatocellular carcinomas (HCCs). Near-infrared photoimmunotherapy (NIR-PIT) is a new anticancer treatment that selectively damages the cell membrane of cancer cells after NIR light-induced photochemical reaction of IR700, which is bound to a targeting antibody on the cell membrane. NIR-PIT using cetuximab-IR700 has already been approved in Japan, is under review by the US Food and Drug Administration (FDA) for advanced head and neck cancers, and its safety has been established. However, EGFR has not been investigated as a target in NIR-PIT in HCCs. Here, we investigate the application of NIR-PIT using cetuximab-IR700 to HCCs using xenograft mouse models of EGFR-expressing HCC cell lines, Hep3B, HuH-7, and SNU-449. In vitro NIR-PIT using EGFR-targeted cetuximab-IR700 killed cells in a NIR light dose-dependent manner. In vivo NIR-PIT resulted in a delayed growth compared with untreated controls. In addition, in vivo NIR-PIT in both models showed histological signs of cancer cell damage, such as cytoplasmic vacuolation and nuclear dysmorphism. A significant decrease in Ki-67 positivity was also observed after NIR-PIT, indicating decreased cancer cell proliferation. This study suggests that NIR-PIT using cetuximab-IR700 has potential for the treatment of EGFR-expressing HCCs.
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Affiliation(s)
- Seiichiro Takao
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Hiroshi Fukushima
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - A. Paden King
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Takuya Kato
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Aki Furusawa
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Shuhei Okuyama
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Makoto Kano
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Peter L. Choyke
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Freddy E. Escorcia
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Hisataka Kobayashi
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
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5
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Kim DH, Kim MJ, Kim NY, Lee S, Byun JK, Yun JW, Lee J, Jin J, Kim J, Chin J, Cho SJ, Lee IK, Choi YK, Park KG. DN200434, an orally available inverse agonist of estrogen-related receptor γ, induces ferroptosis in sorafenib-resistant hepatocellular carcinoma. BMB Rep 2022; 55:547-552. [PMID: 36016501 PMCID: PMC9712702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Indexed: 12/14/2022] Open
Abstract
Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERRγ with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinduced ferroptosis and showed significantly higher ERRγ levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically, DN200434 increased mitochondrial ROS generation by reducing glutathione/glutathione disulfide levels, which subsequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results indicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib. [BMB Reports 2022; 55(11): 547-552].
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Affiliation(s)
- Dong-Ho Kim
- Department of Biomedical Science, Kyungpook National University, Daegu 41566, Korea
| | - Mi-Jin Kim
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Korea,Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Na-Young Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Seunghyeong Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Jun-Kyu Byun
- BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea
| | - Jae Won Yun
- Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul 05368, Korea
| | - Jaebon Lee
- Sungkyunkwan University School of Medicine, Seoul 16419, Korea
| | - Jonghwa Jin
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Jina Kim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea
| | - Jungwook Chin
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea
| | - Sung Jin Cho
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Korea
| | - In-Kyu Lee
- Department of Biomedical Science, Kyungpook National University, Daegu 41566, Korea,Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Korea,Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Yeon-Kyung Choi
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Korea,Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, Korea,Corresponding authors. Keun-Gyu Park, Tel: +82-53-200-5505; Fax: +82-53-426-2046; E-mail: ; Yeon-Kyung Choi, Tel: +82-53-200-3869; Fax: +82-53-200-3870; E-mail:
| | - Keun-Gyu Park
- Department of Biomedical Science, Kyungpook National University, Daegu 41566, Korea,Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Korea,Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea,Corresponding authors. Keun-Gyu Park, Tel: +82-53-200-5505; Fax: +82-53-426-2046; E-mail: ; Yeon-Kyung Choi, Tel: +82-53-200-3869; Fax: +82-53-200-3870; E-mail:
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6
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Kim DH, Kim MJ, Kim NY, Lee S, Byun JK, Yun JW, Lee J, Jin J, Kim J, Chin J, Cho SJ, Lee IK, Choi YK, Park KG. DN200434, an orally available inverse agonist of estrogen-related receptor γ, induces ferroptosis in sorafenib-resistant hepatocellular carcinoma. BMB Rep 2022; 55:547-552. [PMID: 36016501 PMCID: PMC9712702 DOI: 10.5483/bmbrep.2022.55.11.089] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/20/2022] [Accepted: 08/01/2022] [Indexed: 07/21/2023] Open
Abstract
Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERRγ with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinduced ferroptosis and showed significantly higher ERRγ levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically, DN200434 increased mitochondrial ROS generation by reducing glutathione/glutathione disulfide levels, which subsequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results indicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib. [BMB Reports 2022; 55(11): 547-552].
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Affiliation(s)
- Dong-Ho Kim
- Department of Biomedical Science, Kyungpook National University, Daegu 41566, Korea
| | - Mi-Jin Kim
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Na-Young Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Seunghyeong Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Jun-Kyu Byun
- BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea
| | - Jae Won Yun
- Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul 05368, Korea
| | - Jaebon Lee
- Sungkyunkwan University School of Medicine, Seoul 16419, Korea
| | - Jonghwa Jin
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Jina Kim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea
| | - Jungwook Chin
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea
| | - Sung Jin Cho
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Korea
| | - In-Kyu Lee
- Department of Biomedical Science, Kyungpook National University, Daegu 41566, Korea
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Yeon-Kyung Choi
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, Korea
| | - Keun-Gyu Park
- Department of Biomedical Science, Kyungpook National University, Daegu 41566, Korea
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
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7
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Natu A, Singh A, Gupta S. Hepatocellular carcinoma: Understanding molecular mechanisms for defining potential clinical modalities. World J Hepatol 2021; 13:1568-1583. [PMID: 34904030 PMCID: PMC8637668 DOI: 10.4254/wjh.v13.i11.1568] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/12/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year. The diagnosis of hepatocellular carcinoma (HCC) has relied on scanning techniques and serum-based markers such as α-fetoprotein. These measures have limitations due to their detection limits and asymptomatic conditions during the early stages, resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is offered. However, the aid of conventional therapy for patients in the advanced stage of HCC has limited outcomes. Thus, it is essential to seek a new treatment strategy and improve the diagnostic techniques to manage the disease. Researchers have used the omics profile of HCC patients for sub-classification of tissues into different groups, which has helped us with prognosis. Despite these efforts, a promising target for treatment has not been identified. The hurdle in this situation is genetic and epigenetic variations in the tumor, leading to disparities in response to treatment. Understanding reversible epigenetic changes along with clinical traits help to define new markers for patient categorization and design personalized therapy. Many clinical trials of inhibitors of epigenetic modifiers (also known as epi-drugs) are in progress. Epi-drugs like azacytidine or belinostat are already approved for other cancer treatments. Furthermore, epigenetic changes have also been observed in drug-resistant HCC tumors. In such cases, combinatorial treatment of epi-drugs with systemic therapy or trans-arterial chemoembolization might re-sensitize resistant cells.
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Affiliation(s)
- Abhiram Natu
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, Maharashtra, India
| | - Anjali Singh
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, Maharashtra, India
| | - Sanjay Gupta
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, Maharashtra, India
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Anti-Hepatocellular Carcinoma Biomolecules: Molecular Targets Insights. Int J Mol Sci 2021; 22:ijms221910774. [PMID: 34639131 PMCID: PMC8509806 DOI: 10.3390/ijms221910774] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/25/2021] [Accepted: 09/26/2021] [Indexed: 12/15/2022] Open
Abstract
This report explores the available curative molecules directed against hepatocellular carcinoma (HCC). Limited efficiency as well as other drawbacks of existing molecules led to the search for promising potential alternatives. Understanding of the cell signaling mechanisms propelling carcinogenesis and driven by cell proliferation, invasion, and angiogenesis can offer valuable information for the investigation of efficient treatment strategies. The complexity of the mechanisms behind carcinogenesis inspires researchers to explore the ability of various biomolecules to target specific pathways. Natural components occurring mainly in food and medicinal plants, are considered an essential resource for discovering new and promising therapeutic molecules. Novel biomolecules normally have an advantage in terms of biosafety. They are also widely diverse and often possess potent antioxidant, anti-inflammatory, and anti-cancer properties. Based on quantitative structure-activity relationship studies, biomolecules can be used as templates for chemical modifications that improve efficiency, safety, and bioavailability. In this review, we focus on anti-HCC biomolecules that have their molecular targets partially or completely characterized as well as having anti-cancer molecular mechanisms that are fairly described.
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9
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Hu CT, Mandal JP, Wu WS. Regulation on tumor metastasis by Raf kinase inhibitory protein: New insight with reactive oxygen species signaling. Tzu Chi Med J 2021; 33:332-338. [PMID: 34760627 PMCID: PMC8532577 DOI: 10.4103/tcmj.tcmj_296_20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/19/2021] [Accepted: 02/18/2021] [Indexed: 12/12/2022] Open
Abstract
Targeted therapy aiming at the metastatic signal pathway, such as that triggered by receptor tyrosine kinase (RTK), for the prevention of tumor progression is promising. However, RTK-based targeted therapy frequently suffered from drug resistance due to the co-expression of multiple growth factor receptors that may raise compensatory secondary signaling and acquired mutations after treatment. One alternative strategy is to manipulate the common negative regulators of the RTK signaling. Among them, Raf kinase inhibitory protein (RKIP) is highlighted and focused on this review. RKIP can associate with Raf-1, thus suppressing the downstream mitogen-activated protein kinase (MAPK) cascade. RKIP also negatively regulates other metastatic signal molecules including NF-κB, STAT3, and NOTCH1. In general, RKIP achieves this task via associating and blocking the activity of the critical molecules on upstream of the aforementioned pathways. One novel RKIP-related signaling involves reactive oxygen species (ROS). In our recent report, we found that PKCδ-mediated ROS generation may interfere with the association of RKIP with heat shock protein 60 (HSP60)/MAPK complex via oxidation of HSP60 triggered by the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. The departure of RKIP may impact the downstream MAPK in two aspects. One is to trigger the Mt→cytosol translocation of HSP60 coupled with MAPKs. The other is to change the conformation of HSP60, favoring more efficient activation of the associated MAPK by upstream kinases in cytosol. It is worthy of investigating whether various RTKs capable of generating ROS can drive metastatic signaling via affecting RKIP in the same manner.
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Affiliation(s)
- Chi-Tan Hu
- Division of Gastroenterology, Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Research Centre for Hepatology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | | | - Wen-Sheng Wu
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan
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10
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Mahgoub S, Abosalem H, Emara M, Kotb N, Maged A, Soror S. Restoring NK cells functionality via cytokine activation enhances cetuximab-mediated NK-cell ADCC: A promising therapeutic tool for HCC patients. Mol Immunol 2021; 137:221-227. [PMID: 34284214 DOI: 10.1016/j.molimm.2021.07.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/08/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022]
Abstract
Natural Killer (NK) cells are considered the first line of defense against viral infections and tumors. Several factors affect NK cytotoxic activity rendering it dysfunctional and thereby impeding the ability to scavenge abnormal cells as a part of immune escaping mechanisms induced by different types of cancers. NK cells play a crucial role augmenting the activity of various types of anticancer mAb since dysfunctional NK cells are the main reason for the low response to these therapies. To this light, we examined the phenotypic characters of the circulating NK cells isolated from HCC patients compared to healthy controls. Then, dysfunctional NK cells, from HCC patients, were reactivated with cytokines cocktail and their cytotoxic activity with the anti-EGFR mAb "cetuximab" was investigated. This showed a downregulation of patients NK cells activating receptors (NKP30, NKP46, NKG2D and CD16) as well as CD56 and up-regulation of NKG2A inhibitory receptor. We also reported an increase in aberrant CD56- NK cells subset in peripheral blood of HCC patients compared to healthy controls. Thus, confirming the dysfunctionality of peripheral NK cells isolated from HCC patients. Cytokines re-activation of those NK cells lead to upregulation of NK activating receptors and downregulation of inhibitory receptor. Moreover, the percentage of aberrant CD56- NK cells subset was reduced. Here, we proved that advanced HCC patients have an increased percentage of more immature and noncytotoxic NK cell subsets in their peripheral blood, which might account for the low cytotoxicity noticed in those patients. A significant improvement in the cytotoxicity against HCC was noticed upon using reactivated NK cells combined with cetuximab. Therefore, this study highlights the potential recruitment of NK immune cells along with cetuximab to enhance cytotoxicity against HCC.
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Affiliation(s)
- Shahenda Mahgoub
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Ein-Helwan, Cairo, 11795, Egypt.
| | - Hadeer Abosalem
- Deputy of Technical Manager, Biotechnology Unit, Egyptian Drug Authority (EDA), Giza, 12654, Egypt.
| | - Mohamed Emara
- Department of Microbiology and Immunology, Faculty of Pharmacy, Helwan University, Ein-Helwan, Cairo, 11795, Egypt.
| | - Nahla Kotb
- Manager of Blood Derivative Unit, Egyptian Drug Authority (EDA), Giza, 12654, Egypt.
| | - A Maged
- National Hepatology and Tropical Medicine Research Institute (NHTMRI), 11441, Cairo, Egypt.
| | - Sameh Soror
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Ein-Helwan, Cairo, 11795, Egypt.
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11
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Wang Y, Zhang M, Gong Y, Wu Q, Zhang L, Jiao S. Bioinformatic Analysis of Hepatocellular Carcinoma Cell Lines to the Efficacy of Nimotuzumab. Int J Gen Med 2021; 14:2611-2621. [PMID: 34168487 PMCID: PMC8217909 DOI: 10.2147/ijgm.s312770] [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: 03/25/2021] [Accepted: 05/28/2021] [Indexed: 11/23/2022] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) continues to be a cancer with rising incidence, high mortality, and recurrence rate. The therapeutic effects on HCC are not satisfactory currently. Epidermal growth factor receptor (EGFR) is an important factor, while anti-EGFR agencies have not shown ideal results in HCC. Materials and Methods We tested efficacy of nimotuzumab and EGFR expression on cell surface in six HCC cell lines (Hep 3B2.1–7, Li-7, PLC/PRF/5, SK-HEP-1, SNU-182, and SNU-387). Then, we analyzed RNA sequences of every cell line and performed a bioinformatic analysis. Differentially expressed genes (DEGs) were analyzed. The data, TCGA-LIHC from The Cancer Genome Atlas (TCGA) and GSE102079 from Gene Expression Omnibus (GEO), were used to analyse DEGs of Hoshida subclass. Results Hep 3B2.1–7 and PLC/PRF/5 were sensitive to nimotuzumab whereas Li-7, SK-HEP-1, SNU-182, and SNU-387 cell lines were resistant. Then, we compared the DEGs between sensitive and resistant group cell lines. We enriched DEGs in GO and KEGG and performed GSEA in each group. Genes in two groups did not show obvious different expressions in EGFR pathways, while Hoshida subclass of HCC seemed to associate with the efficacy of nimotuzumab in that S2 and S3 showed better therapeutic effect than S1. Therefore, we analyzed genes in human tumor samples which were from TCGA-LIHC and GSE102079. We found that COL1A1, COL1A2, COL3A1, and MMP9 were the focus DEGs of S1 and S2 & S3 related to EGFR. Conclusion The efficacy of nimotuzumab in HCC did not show direct relevance with EGFR protein expression and EGFR-related pathway. However, efficacy could associate with Hoshida subclass of HCC. Three ECM genes (COL1A1, COL1A2, COL3A1) and MMP9 were paid attention, as they might play important roles in the curative effect of nimotuzumab in HCC.
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Affiliation(s)
- Yu Wang
- Department of Oncology, Oncology Faculty, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Meng Zhang
- Department of Research and Development, Beijing DCTY® Biotech Co.,Ltd, Beijing, People's Republic of China.,Department of Hepatobiliary Surgery, PLA Rocket Force Characteristic Medical Center, Beijing, People's Republic of China
| | - Yixin Gong
- Department of Research and Development, Beijing DCTY® Biotech Co.,Ltd, Beijing, People's Republic of China
| | - Qiyan Wu
- Department of Oncology, Oncology Faculty, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Lijun Zhang
- Department of Oncology, Oncology Faculty, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Shunchang Jiao
- Department of Oncology, Oncology Faculty, Chinese PLA General Hospital, Beijing, People's Republic of China
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12
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Wang T, Zhang Q, Wang N, Liu Z, Zhang B, Zhao Y. Research Progresses of Targeted Therapy and Immunotherapy for Hepatocellular Carcinoma. Curr Med Chem 2021; 28:3107-3146. [PMID: 33050856 DOI: 10.2174/0929867327666201013162144] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/25/2020] [Accepted: 09/01/2020] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with nearly one million new cases and deaths every year. Owing to the complex pathogenesis, hidden early symptoms, rapidly developing processes, and poor prognosis, the morbidity and mortality of HCC are increasing yearly. With the progress being made in modern medicine, the treatment of HCC is no longer limited to traditional methods. Targeted therapy and immunotherapy have emerged to treat advanced and metastatic HCC in recent years. Since Sorafenib is the first molecular targeting drug against angiogenesis, targeted drugs for HCC are continually emerging. Moreover, immunotherapy plays a vital role in clinical trials. In particular, the application of immune checkpoint inhibitors, which have received increasing attention in the field of cancer treatment, is a possible research path. Interestingly, these two therapies generally complement each other at some stages of HCC, bringing new hope for patients with advanced HCC. In this paper, we discuss the research progress of targeted therapy and immunotherapy for HCC in recent years, which will provide a reference for the further development of drugs for HCC.
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Affiliation(s)
- Tao Wang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Qiting Zhang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Ning Wang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Ziqi Liu
- Department of Pharmacy, the PLA Rocket Force Characteristic Medical Center, Beijing 100088, China
| | - Bin Zhang
- Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, Department of Marine Pharmacy, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Yufen Zhao
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
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13
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Abosalema H, Mahgoub S, Emara M, Kotb N, Soror S. Interrupted crosstalk between natural killer cells and anti-epidermal growth factor receptor: a possible role in hepatocellular carcinoma treatment failure. Curr Cancer Drug Targets 2021; 21:601-607. [PMID: 34011259 DOI: 10.2174/1568009621666210519105203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 02/20/2021] [Accepted: 02/23/2021] [Indexed: 11/22/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide. Most patients are diagnosed for the first time at late stages; this leads to a very poor prognosis. It is challenging to discover strategies for treatment at these advanced stages. Recently, monoclonal antibodies (mAbs) targeting specific cellular signaling pathways in HCC have been developed. Unfortunately, they still have a low survival rate, and some of them failed clinically to produce effective responses even if they showed very good results against HCC in preclinical studies. This review focuses on and discusses the possible causes for the failure of mAbs, precisely anti-Epidermal Growth Factor Receptor (EGFR) mAb and the crosstalk between this mAb and patients' NK cells.
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Affiliation(s)
- Hadeer Abosalema
- Deputy of Technical Mmanager, Biotechnology Unit, Egyptian Drug Authority (EDA), Giza, 12654, Egypt
| | - Shahenda Mahgoub
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo,11795, Egypt
| | - Mohamed Emara
- Department of Microbiology and Immunology, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo,11795, Egypt
| | - Nahla Kotb
- Manager of Blood Derivative Unite, Egyptian Drug Authority (EDA), 12654, Egypt
| | - Sameh Soror
- Department of Biochemistry and molecular biology, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo,11795, Egypt
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14
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Lee SR, Lee JG, Heo JH, Jo SL, Ryu J, Kim G, Yon JM, Lee MS, Lee GS, An BS, Shin HJ, Woo DC, Baek IJ, Hong EJ. Loss of PGRMC1 Delays the Progression of Hepatocellular Carcinoma via Suppression of Pro-Inflammatory Immune Responses. Cancers (Basel) 2021; 13:cancers13102438. [PMID: 34069911 PMCID: PMC8157610 DOI: 10.3390/cancers13102438] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/13/2021] [Accepted: 05/15/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Progesterone receptor membrane component 1 (PGRMC1) and epidermal growth factor receptor (EGFR) are highly expressed in various cancers. Here, we first analyzed two sets of clinical data and found that the levels of PGRMC1 and EGFR in hepatocellular carcinomas (HCCs) were both inversely correlated with the survival of HCC patients. Accordingly, by using a carcinogen-induced mouse model of HCC, we found that Pgrmc1 knockout suppressed HCC development and extended the lifespan of HCC-bearing mice. In the acute setting of high-dose carcinogen administration, Pgrmc1 knockout was associated with increases in hepatic necrosis and decreases in the production of the pro-inflammatory cytokine IL-6. Indeed, silencing of Pgrmc1 in murine macrophages suppressed IL-6 production and NF-κB activity, and this process was significantly mediated by EGFR. Our study shows that Pgrmc1 affects the development of HCCs by regulating the EGFR-mediated inflammatory responses. Pgrmc1 may serve as a biomarker and a therapeutic target of HCC. Abstract Pgrmc1 is a non-canonical progesterone receptor related to the lethality of various types of cancer. PGRMC1 has been reported to exist in co-precipitated protein complexes with epidermal growth factor receptor (EGFR), which is considered a useful therapeutic target in hepatocellular carcinoma (HCC). Here, we investigated whether Pgrmc1 is involved in HCC progression. In clinical datasets, PGRMC1 transcription level was positively correlated with EGFR levels; importantly, PGRMC1 level was inversely correlated with the survival duration of HCC patients. In a diethylnitrosamine (DEN)-induced murine model of HCC, the global ablation of Pgrmc1 suppressed the development of HCC and prolonged the survival of HCC-bearing mice. We further found that increases in hepatocyte death and suppression of compensatory proliferation in the livers of DEN-injured Pgrmc1-null mice were concomitant with decreases in nuclear factor κB (NF-κB)-dependent production of interleukin-6 (IL-6). Indeed, silencing of Pgrmc1 in murine macrophages led to reductions in NF-κB activity and IL-6 production. We found that the anti-proinflammatory effect of Pgrmc1 loss was mediated by reductions in EGFR level and its effect was not observed after exposure of the EGFR inhibitor erlotinib. This study reveals a novel cooperative role of Pgrmc1 in supporting the EGFR-mediated development of hepatocellular carcinoma, implying that pharmacological suppression of Pgrmc1 may be a useful strategy in HCC treatment.
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Affiliation(s)
- Sang R. Lee
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea; (S.R.L.); (J.H.H.); (S.L.J.); (J.R.); (H.-J.S.)
| | - Jong Geol Lee
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (J.G.L.); (G.K.); (J.-M.Y.); (D.-C.W.)
| | - Jun H. Heo
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea; (S.R.L.); (J.H.H.); (S.L.J.); (J.R.); (H.-J.S.)
| | - Seong Lae Jo
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea; (S.R.L.); (J.H.H.); (S.L.J.); (J.R.); (H.-J.S.)
| | - Jihoon Ryu
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea; (S.R.L.); (J.H.H.); (S.L.J.); (J.R.); (H.-J.S.)
| | - Globinna Kim
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (J.G.L.); (G.K.); (J.-M.Y.); (D.-C.W.)
| | - Jung-Min Yon
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (J.G.L.); (G.K.); (J.-M.Y.); (D.-C.W.)
| | - Myeong Sup Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Geun-Shik Lee
- College of Veterinary Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Korea;
| | - Beum-Soo An
- Department of Biomaterials Science, College of Natural Resources & Life Science, Pusan National University, Miryang, Gyeongsangnam 50463, Korea;
| | - Hyun-Jin Shin
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea; (S.R.L.); (J.H.H.); (S.L.J.); (J.R.); (H.-J.S.)
| | - Dong-Cheol Woo
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (J.G.L.); (G.K.); (J.-M.Y.); (D.-C.W.)
| | - In-Jeoung Baek
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (J.G.L.); (G.K.); (J.-M.Y.); (D.-C.W.)
- Correspondence: (I.-J.B.); (E.-J.H.); Tel.: +82-2-3010-2798 (I.-J.B.); +82-42-821-6781 (E.-J.H.); Fax: +82-2-3010-4197 (I.-J.B.); +82-42-821-8903 (E.-J.H.)
| | - Eui-Ju Hong
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea; (S.R.L.); (J.H.H.); (S.L.J.); (J.R.); (H.-J.S.)
- Correspondence: (I.-J.B.); (E.-J.H.); Tel.: +82-2-3010-2798 (I.-J.B.); +82-42-821-6781 (E.-J.H.); Fax: +82-2-3010-4197 (I.-J.B.); +82-42-821-8903 (E.-J.H.)
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15
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Luo XY, Wu KM, He XX. Advances in drug development for hepatocellular carcinoma: clinical trials and potential therapeutic targets. J Exp Clin Cancer Res 2021; 40:172. [PMID: 34006331 PMCID: PMC8130401 DOI: 10.1186/s13046-021-01968-w] [Citation(s) in RCA: 130] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/27/2021] [Indexed: 02/06/2023] Open
Abstract
Although hepatocellular carcinoma (HCC) is one of the deadliest health burdens worldwide, few drugs are available for its clinical treatment. However, in recent years, major breakthroughs have been made in the development of new drugs due to intensive fundamental research and numerous clinical trials in HCC. Traditional systemic therapy schemes and emerging immunotherapy strategies have both advanced. Between 2017 and 2020, the United States Food and Drug Administration (FDA) approved a variety of drugs for the treatment of HCC, including multikinase inhibitors (regorafenib, lenvatinib, cabozantinib, and ramucirumab), immune checkpoint inhibitors (nivolumab and pembrolizumab), and bevacizumab combined with atezolizumab. Currently, there are more than 1000 ongoing clinical trials involving HCC, which represents a vibrant atmosphere in the HCC drug research and development field. Additionally, traditional Chinese medicine approaches are being gradually optimized. This review summarizes FDA-approved agents for HCC, elucidates promising agents evaluated in clinical phase I/II/III trials and identifies emerging targets for HCC treatment. In addition, we introduce the development of HCC drugs in China. Finally, we discuss potential problems in HCC drug therapy and possible future solutions and indicate future directions for the development of drugs for HCC treatment.
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Affiliation(s)
- Xiang-Yuan Luo
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Kong-Ming Wu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xing-Xing He
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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16
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Pan Z, Liu C, Zhi Y, Xie Z, Wu L, Jiang M, Zhang Y, Zhou R, Zhao L. LIMK1 nuclear translocation promotes hepatocellular carcinoma progression by increasing p-ERK nuclear shuttling and by activating c-Myc signalling upon EGF stimulation. Oncogene 2021; 40:2581-2595. [PMID: 33686242 DOI: 10.1038/s41388-021-01736-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 02/19/2021] [Accepted: 02/24/2021] [Indexed: 12/23/2022]
Abstract
LIM kinase 1 (LIMK1) is a serine/threonine and tyrosine kinase that is predominantly located in the cytoplasm. In our study, nuclear translocation of LIMK1 in clinical hepatocellular carcinoma (HCC) samples was demonstrated for the first time, especially in samples from those with intravascular tumour thrombus. LIMK1 was overexpressed in HCC tissues, and nuclear LIMK1 expression was associated with poor prognosis in HCC patients. Although the effects of cytoplasmic LIMK1 on cofilin phosphorylation and actin filament dynamics have been well studied, the function of nuclear LIMK1 is still unclear. Gain- and loss-of-function experiments were performed both in vitro and in vivo and demonstrated a correlation between nuclear LIMK1 and the enhanced aggressive phenotype of HCC. EGF could drive the nuclear translocation of LIMK1 by activating the interaction of p-ERK and LIMK1 and facilitating their roles in nuclear shuttling. Moreover, nuclear LIMK1 could directly bind to the promoter region of c-Myc and stimulate c-Myc transcription. Although the EGFR monoclonal antibody cetuximab has a poor therapeutic effect on advanced HCC patients, in vivo animal study showed that cetuximab achieved a significant inhibitory effect on the progression of nuclear LIMK1-overexpressing HCC cells. In addition, recent data have demonstrated the potential of cetuximab in combination therapy for HCC patients with LIMK1 nuclear translocation.
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Affiliation(s)
- Zhihua Pan
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Chaoqun Liu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yunfei Zhi
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhiyue Xie
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Ling Wu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Muhong Jiang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yujie Zhang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Rui Zhou
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China. .,Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China. .,Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
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17
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Abstract
Hepatocellular carcinoma (HCC) is increasing in prevalence and is the third leading cause of cancer-related death worldwide. Unlike other malignancies, HCC can be diagnosed with dynamic imaging with very high accuracy, and tissue diagnosis is not needed for cancer therapy. There is a unique role of established as well as developing biomarkers in diagnosis, prognosis, and management of HCC. Sequencing HCC tumors has yielded substantial insights into HCC tumor biology and has raised the possibility of precision oncology in which therapy decisions are guided by cancer genetics. However, it is not ready for prime time yet.
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Affiliation(s)
- Vincent L Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Pratima Sharma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
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18
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Chow AKM, Yau SWL, Ng L. Novel molecular targets in hepatocellular carcinoma. World J Clin Oncol 2020; 11:589-605. [PMID: 32879846 PMCID: PMC7443834 DOI: 10.5306/wjco.v11.i8.589] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 06/04/2020] [Accepted: 06/20/2020] [Indexed: 02/06/2023] Open
Abstract
Globally, hepatocellular carcinoma (HCC) is a leading cause of cancer and cancer-related deaths. The therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low, which results in a poor prognosis. The development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this disease. However, the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control group. Hence, in this review we describe the importance of developing more effective targeted therapies for the management of advanced HCC. Recent investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling pathways. Proteins involved in the Hedgehog and Notch signaling pathways, Polo-like kinase 1, arginine, histone deacetylases and Glypican-3 can be potential targets in the treatment of HCC. Monotherapy has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of chemoresistance. Thus, emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.
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Affiliation(s)
- Ariel Ka-Man Chow
- School of Nursing and Health Studies, The Open University of Hong Kong, Hong Kong, China
| | - Simon Wing-Lung Yau
- School of Nursing and Health Studies, The Open University of Hong Kong, Hong Kong, China
| | - Lui Ng
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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19
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Gong J, Chuang J, Cho M, Toomey K, Hendifar A, Li D. Molecular Targets, Pathways, and Therapeutic Implications for Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:ijms21155232. [PMID: 32718047 PMCID: PMC7432744 DOI: 10.3390/ijms21155232] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/19/2020] [Accepted: 07/21/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents one of the leading causes of cancer mortality worldwide. While significant advances have been made for the treatment of advanced hepatocellular carcinoma in the past few years, the prognosis remains poor and effective biomarkers to guide selection of therapies remain noticeably absent. However, several targeted therapies have been approved in the past few years that have improved the outlook for this disease. In this review, we will highlight the recent therapies approved for the treatment of advanced HCC and discuss promising therapeutic options, targets, and pathways for drug development and consideration for future clinical trials.
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Affiliation(s)
- Jun Gong
- Department of Gastrointestinal Malignancies, Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA 90048, USA;
| | - Jeremy Chuang
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - May Cho
- Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA; (M.C.); (K.T.)
| | - Kyra Toomey
- Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA; (M.C.); (K.T.)
| | - Andrew Hendifar
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Daneng Li
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
- Correspondence:
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20
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Procyanidin B1, a novel and specific inhibitor of Kv10.1 channel, suppresses the evolution of hepatoma. Biochem Pharmacol 2020; 178:114089. [PMID: 32533968 DOI: 10.1016/j.bcp.2020.114089] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/21/2020] [Accepted: 06/08/2020] [Indexed: 01/29/2023]
Abstract
Recently, we and other groups revealed that aberrant expression of Kv10.1 channel, a voltage-gated potassium ion channel, contributes to a variety of tumorigenesis process.Potent and selective inhibitor of Kv10.1 is urgently needed, both as pharmacological tools for studying the physiological functions of this enigmatic channel and as potential leads for development of anti-tumor drugs. In this study, Procyanidin B1, a natural compound extracted from the grape seed, was identified as a potent, specific inhibitor, which can inhibit the Kv10.1 channel in a concentration-dependent manner (IC50 = 10.38 ± 0.87 μM), but has negligible effects on other potassium channels, including Kir2.1, HERG or KCNQ1. It was demonstrated that Procyanidin B1 directly binds to Kv10.1 channel and inhibits its currents, without increasing intracellular Ca2+. Further, three amino acids, I550, T552, and Q557 in the C-linker domain of Kv10.1 were found critical for forming the binding pocket of Procyanidin B1 with Kv10.1 channel.In addition, Procyanidin B1 inhibits migration and proliferation of liver cancer cells (HuH-7 cells, HepG2 cells) through inhibiting Kv10.1, but not in Kv10.1 negatively expressed cell lines. Next, we assayed the tumor suppressing effect of Procyanidin B1 on cell line-derived xenograft mouse model. Our data showed that 15 mg/kg Procyanidin B1 can significantly suppress the growth of the tumor (HepG2) with an inhibition rate of about 60.25%. Compared with cisplatin, Procyanidin B1 has no side effect on the normal metabolismof the mice. The present work indicated that Procyanidin B1 is a proming liver cancer anti-tumor drug, and also confirmed that Kv10.1 can serve as a potential, tumor-specific drug target.
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21
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The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther 2020; 5:87. [PMID: 32532960 PMCID: PMC7292831 DOI: 10.1038/s41392-020-0187-x] [Citation(s) in RCA: 625] [Impact Index Per Article: 125.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/14/2020] [Accepted: 04/26/2020] [Indexed: 02/07/2023] Open
Abstract
Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib is currently an effective first-line therapy. Unfortunately, the development of drug resistance to sorafenib is becoming increasingly common. This study aims to identify factors contributing to resistance and ways to mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated cell death, and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression. This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients.
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22
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Dai Q, Zhang C, Yuan Z, Sun Q, Jiang Y. Current discovery strategies for hepatocellular carcinoma therapeutics. Expert Opin Drug Discov 2020; 15:243-258. [PMID: 31809618 DOI: 10.1080/17460441.2020.1696769] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 11/20/2019] [Indexed: 02/06/2023]
Abstract
Introduction: The global incidence of hepatocellular carcinoma (HCC) is not expected to decline significantly over the next 30 years. And although the latest gene sequencing studies have established its genetic map, the potentially targetable drivers of HCC are, so far, difficult to identify. To date, only seven drugs have been approved by the FDA for unresectable HCC treatment; thus, effective therapeutic breakthroughs are still needed urgently.Areas covered: In this review, the authors discuss both genetic and epigenetic alterations in HCC and introduce the current progress with some of the representative molecular targeting inhibitors, listing some of the approved drugs for the targets of HCC. The structure-activity relationship of molecules (e.g. thalidomide, bortezomil) used for HCC is also discussed.Expert opinion: Effective therapeutic targets and effective drugs for HCC treatment are an urgent unmet need. Better understanding and characterization of genetic and epigenetic alterations, which are important to hepatocarcinogenesis, may help to understand the molecular pathogenesis of HCC, as well as provide novel therapeutic lead compounds for HCC treatment.
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Affiliation(s)
- Qiuzi Dai
- Department of Chemistry, Tsinghua University, Beijing, PR China
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
- Shenzhen Bay Laboratory, Shenzhen, PR China
| | - Cunlong Zhang
- Shenzhen Bay Laboratory, Shenzhen, PR China
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
| | - Zigao Yuan
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
- Shenzhen Bay Laboratory, Shenzhen, PR China
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
| | - Qinsheng Sun
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
- Shenzhen Bay Laboratory, Shenzhen, PR China
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
| | - Yuyang Jiang
- National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, PR China
- Shenzhen Bay Laboratory, Shenzhen, PR China
- Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, P. R. China
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Abou-Alfa GK, Jarnagin W, El Dika I, D'Angelica M, Lowery M, Brown K, Ludwig E, Kemeny N, Covey A, Crane CH, Harding J, Shia J, O'Reilly EM. Liver and Bile Duct Cancer. ABELOFF'S CLINICAL ONCOLOGY 2020:1314-1341.e11. [DOI: 10.1016/b978-0-323-47674-4.00077-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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24
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Ippolito D, Pecorelli A, Querques G, Drago SG, Maino C, Franzesi CT, Hatzidakis A, Sironi S. Dynamic Computed Tomography Perfusion Imaging: Complementary Diagnostic Tool in Hepatocellular Carcinoma Assessment From Diagnosis to Treatment Follow-up. Acad Radiol 2019; 26:1675-1685. [PMID: 30852079 DOI: 10.1016/j.acra.2019.02.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 02/13/2019] [Accepted: 02/13/2019] [Indexed: 02/05/2023]
Abstract
Early diagnosis of HCC is of paramount importance in order to enable the application of curative treatments. Among these, radiofrequency ablation (RFA) is actually considered the most effective ablative therapy for early stage hepatocellular carcinoma (HCC) not suitable for surgery. On the other hand, transarterial chemoembolization (TACE) represents the standard of care for intermediate stage HCC and compensated liver function. Finally, sorafenib, an oral antiangiogenic targeted drug, is the only approved systemic therapy for advanced HCC with vascular invasion, extrahepatic spread, and well-preserved liver function. Beside traditional radiological techniques, new functional imaging tools have been introduced in order to provide not only morphological information but also quantitative functional data. In this review, we analyze perfusion-CT (pCT) from a technical point of view, describing the main different mathematical analytical models for the quantification of tissue perfusion from acquired CT raw data, the most commonly acquired perfusion parameters, and the technical parameters required to perform a standard pCT examination. Moreover, a systematic review of the literature was performed to assess the role of pCT as an emerging imaging biomarker for HCC diagnosis, response evaluation to RFA, TACE, and sorafenib, and we examine its challenges in HCC management.
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Affiliation(s)
- Davide Ippolito
- University of Milano-Bicocca, Milan, Italy; Department of Diagnostic Radiology, San Gerardo Hospital, Via Pergolesi 33 - 20900 Monza, Italy
| | - Anna Pecorelli
- University of Milano-Bicocca, Milan, Italy; Department of Diagnostic Radiology, San Gerardo Hospital, Via Pergolesi 33 - 20900 Monza, Italy.
| | - Giulia Querques
- University of Milano-Bicocca, Milan, Italy; Department of Diagnostic Radiology, San Gerardo Hospital, Via Pergolesi 33 - 20900 Monza, Italy
| | - Silvia Girolama Drago
- University of Milano-Bicocca, Milan, Italy; Department of Diagnostic Radiology, San Gerardo Hospital, Via Pergolesi 33 - 20900 Monza, Italy
| | - Cesare Maino
- University of Milano-Bicocca, Milan, Italy; Department of Diagnostic Radiology, San Gerardo Hospital, Via Pergolesi 33 - 20900 Monza, Italy
| | - Cammillo Talei Franzesi
- University of Milano-Bicocca, Milan, Italy; Department of Diagnostic Radiology, San Gerardo Hospital, Via Pergolesi 33 - 20900 Monza, Italy
| | - Adam Hatzidakis
- Department of Medical Imaging, University Hospital of Heraklion, Greece
| | - Sandro Sironi
- University of Milano-Bicocca, Milan, Italy; Department of Diagnostic Radiology, ASST Papa Giovanni XXIII, Bergamo, Italy
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25
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Erdogan A, Ozkan A. Cetuximab and epirubicin HCl-combined application as a possibility to treat both parental and epirubicin HCl-resistant liver cancer cells. Biol Futur 2019; 70:175-184. [PMID: 34554450 DOI: 10.1556/019.70.2019.22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 07/17/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND AND AIMS Targeted chemotherapeutics such as cetuximab can cause many side effects such as skin toxicity when used in high concentrations. In addition, cancer cells can develop resistance to some of the anticancer agents during treatment. The lack of the desired success in chemotherapy and the development of resistance to chemotherapeutics, such as epirubicin HCl, suggest that there is a need for combined therapies. The combination of targeted chemotherapeutics and conventional chemotherapy drugs may lead to the emergence of new strategies in the treatment of cancer. In this study, cytotoxic, antiproliferative, cell cycle inhibitive, oxidative stress generation, and apoptotic effects and effect mechanisms of cetuximab alone and together with epirubicin HCl on parental liver cancer cells (P-Hep G2) and epirubicin HCl-resistant liver cancer cells (R-Hep G2) were investigated. MATERIALS Cytotoxic effects of cetuximab alone and with epirubicin-HCl on cells were determined by Cell Titer-Blue® Cell Viability and Lactate Dehydrogenase Activity tests. Cell cycle distributions and apoptosis were detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS Cetuximab with epirubicin HCl treatment increased the cytotoxic effect on both cells. Caspase-3/7 activity increased 3 and 1.5 times in comparison with control group in P-Hep G2 and R-Hep G2 cells, respectively, after treating with cetuximab alone, whereas the increase was found to be approximately 4.7 and 2.5 times when cetuximab was treated with epirubicin HCl in P-Hep G2 and R-Hep G2 cells, respectively. Both cetuximab alone and together with epirubicin HCl treatments caused increases in Bax/Bcl-2 ratio in both cells. DISCUSSION Treatment of cetuximab with epirubicin HCl to P-Hep G2 and R-Hep G2 cells was found to be more effective in cytotoxic effect and inducing apoptosis comparison to cetuximab alone treatment. In addition, combination treatment showed different effects on pro-apoptotic/anti-apoptotic genes expression according to cells drug resistance properties.
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Affiliation(s)
- Ayse Erdogan
- Genetic and Bioengineering Department, Faculty of Engineering, Alanya Alaaddin Keykubat University, Antalya, Turkey.
| | - Aysun Ozkan
- Department of Biology, Faculty of Science, Akdeniz University, Antalya, Turkey
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26
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López-Luque J, Bertran E, Crosas-Molist E, Maiques O, Malfettone A, Caja L, Serrano T, Ramos E, Sanz-Moreno V, Fabregat I. Downregulation of Epidermal Growth Factor Receptor in hepatocellular carcinoma facilitates Transforming Growth Factor-β-induced epithelial to amoeboid transition. Cancer Lett 2019; 464:15-24. [PMID: 31465839 PMCID: PMC6853171 DOI: 10.1016/j.canlet.2019.08.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 08/20/2019] [Accepted: 08/22/2019] [Indexed: 12/19/2022]
Abstract
The Epidermal Growth Factor Receptor (EGFR) and the Transforming Growth Factor-beta (TGF-β) are key regulators of hepatocarcinogenesis. Targeting EGFR was proposed as a promising therapy; however, poor success was obtained in human hepatocellular carcinoma (HCC) clinical trials. Here, we describe how EGFR is frequently downregulated in HCC patients while TGF-β is upregulated. Using 2D/3D cellular models, we show that after EGFR loss, TGF-β is more efficient in its pro-migratory and invasive effects, inducing epithelial to amoeboid transition. EGFR knock-down promotes loss of cell-cell and cell-to-matrix adhesion, favouring TGF-β-induced actomyosin contractility and acquisition of an amoeboid migratory phenotype. Moreover, TGF-β upregulates RHOC and CDC42 after EGFR silencing, promoting Myosin II in amoeboid cells. Importantly, low EGFR combined with high TGFB1 or RHOC/CDC42 levels confer poor patient prognosis. In conclusion, this work reveals a new tumour suppressor function for EGFR counteracting TGF-β-mediated epithelial to amoeboid transitions in HCC, supporting a rational for targeting the TGF-β pathway in patients with low EGFR expression. Our work also highlights the relevance of epithelial to amoeboid transition in human tumours and the need to better target this process in the clinic.
EGFR expression is low and heterogeneous in a great percentage of HCC patients. EGFR loss in HCC cells facilitates TGF-β pro-migratory and invasive functions. EGFR silenced HCC cells respond to TGF-β inducing epithelial-amoeboid transition. TGF-β upregulates RHOC and CDC42 and actomyosin contractility in EGFR silenced cells. Low EGFR combined with high TGFB1 or RHOC/CDC42 levels confer poor HCC prognosis.
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Affiliation(s)
- Judit López-Luque
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain.
| | - Esther Bertran
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain.
| | - Eva Crosas-Molist
- Barts Cancer Institute- a Cancer Research UK Centre of Excellence Queen Mary University of London, John Vane Science Building Charterhouse Square, London, EC1M 6BQ, UK.
| | - Oscar Maiques
- Barts Cancer Institute- a Cancer Research UK Centre of Excellence Queen Mary University of London, John Vane Science Building Charterhouse Square, London, EC1M 6BQ, UK.
| | - Andrea Malfettone
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
| | - Laia Caja
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
| | - Teresa Serrano
- Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain; Pathological Anatomy Service, University Hospital of Bellvitge, Barcelona, Spain.
| | - Emilio Ramos
- Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain; Department of Surgery, Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain.
| | - Victoria Sanz-Moreno
- Barts Cancer Institute- a Cancer Research UK Centre of Excellence Queen Mary University of London, John Vane Science Building Charterhouse Square, London, EC1M 6BQ, UK.
| | - Isabel Fabregat
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain; Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Spain.
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Cao J, Kong FH, Liu X, Wang XB. Immunotherapy with dendritic cells and cytokine-induced killer cells for hepatocellular carcinoma: A meta-analysis. World J Gastroenterol 2019; 25:3649-3663. [PMID: 31367163 PMCID: PMC6658393 DOI: 10.3748/wjg.v25.i27.3649] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/18/2019] [Accepted: 06/07/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) has been revealed as the second most common cause of cancer-related deaths worldwide. The introduction of cell-based immunotherapy, including dendritic cells (DCs) and cytokine-induced killer cells (CIKs), has brought HCC patients an effective benefit. However, the efficacy and necessity of cellular immunotherapy after different interventional therapy remains to be further explored. AIM To investigate the efficacy of cellular immunotherapy, involving DCs and CIKs, combined with different conventional treatments of HCC. METHODS We performed a literature search on PubMed and Web of Science up to February 15, 2019. Long-term efficacy (overall survival and recurrence) and short-term adverse effects were investigated to assess the effectiveness of immunotherapy with DCs and/or CIKs. Review Manager 5.3 was used to perform the analysis. RESULTS A total of 22 studies involving 3756 patients selected by eligibility inclusion criteria were forwarded for meta-analysis. Combined with the conventional clinical treatment, immunotherapy with DCs and/or CIKs was demonstrated to significantly improve overall survival at 6 mo [risk ratio (RR) = 1.07; 95% confidence interval (CI): 1.01-1.13, P = 0.02], 1 year (RR = 1.12; 95%CI: 1.07-1.17, P < 0.00001), 3 years (RR = 1.23; 95%CI: 1.15-1.31, P < 0.00001) and 5 years (RR = 1.26; 95%CI: 1.15-1.37, P < 0.00001). Recurrence rate was significantly reduced by cellular immunotherapy at 6 mo (RR = 0.50; 95%CI: 0.36-0.69, P < 0.0001) and 1 year (RR = 0.82; 95%CI: 0.75-0.89, P < 0.00001). Adverse effect assessment addressed that immunotherapy with DCs and/or CIKs was accepted as a safe, feasible treatment. CONCLUSION Combination immunotherapy with DCs, CIKs and DC/CIK with various routine treatments for HCC was evidently suggested to improve patients' prognosis by increasing overall survival and reducing cancer recurrence.
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Affiliation(s)
- Jing Cao
- Department of Surgery, Technical University of Munich, Munich 80333, Germany
| | - Fan-Hua Kong
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Xi Liu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Xiao-Bo Wang
- Department of Surgery, Technical University of Munich, Munich 80333, Germany
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28
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Li JJ, Yang Z, Huang ZS. Progress in basic and clinical research on molecular targeted therapy for primary hepatic carcinoma. Shijie Huaren Xiaohua Zazhi 2019; 27:643-650. [DOI: 10.11569/wcjd.v27.i10.643] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
As the second most common cancer in the world, primary liver cancer has become one of the most common causes of cancer-related death in China, causing great pain and financial burden to patients and their families. Traditional treatment methods have not achieved satisfactory results so far, and people are gradually turning their attention to targeted drug therapy, which has many advantages, such as accuracy and little adverse reactions. Previous studies have shown that the introduction of targeted drug sorafenib can improve the survival of patients with primary liver cancer and open a new era of tumor targeted therapy. In recent years, molecular targeted therapy for liver cancer has become a research hotspot. A variety of new molecular targeted drugs have been found to be able to improve the prognosis of patients with advanced liver cancer. The purpose of this article is to review the progress in basic and clinical research on molecular targeted therapy for primary hepatic carcinoma.
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Affiliation(s)
- Jian-Ji Li
- Graduate College, Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Zhe Yang
- Graduate College, Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Zan-Song Huang
- Department of Gastroenterology, the Affiliated Hospital of Youjiang Medical College for Nationalities, Guangxi Clinical Medical Research Center for Hepatobiliary Diseases Baise 533000, Guangxi Zhuang Autonomous Region, China
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Systemic Management for Advanced Hepatocellular Carcinoma: A Review of the Molecular Pathways of Carcinogenesis, Current and Emerging Therapies, and Novel Treatment Strategies. Dig Dis Sci 2019; 64:1016-1029. [PMID: 30887150 DOI: 10.1007/s10620-019-05582-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) arises from a number of cirrhosis-related and non-cirrhosis-related exposures and is one of the leading causes of cancer-related deaths worldwide. Achieving a durable cure currently relies on either resection or transplantation, but since most patients will be diagnosed with inoperable disease, there is great interest in achieving more effective systemic therapies. At a molecular level, HCC is heterogeneous, but initial treatment strategies, including the use of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, have been fairly homogenous, depending on general host factors and overall tumor burden rather than specific molecular signatures. Over the past 2 decades, however, there has been significant success in identifying key molecular targets, including driver mutations involving the telomerase reverse transcriptase, p53, and beta-catenin genes, and significant work is now being devoted to translating these discoveries into the development of robust and well-tolerated targeted therapies. Furthermore, multi-modal therapies have also begun to emerge, harnessing possible synergism amongst a variety of different treatment classes. As the findings of these landmark trials become available over the next several years, the landscape of the systemic management of advanced HCC will change significantly.
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30
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Huang SZ, Wei MN, Huang JR, Zhang ZJ, Zhang WJ, Jiang QW, Yang Y, Wang HY, Jin HL, Wang K, Xing ZH, Yuan ML, Li Y, He XS, Shi Z, Zhou Q. Targeting TF-AKT/ERK-EGFR Pathway Suppresses the Growth of Hepatocellular Carcinoma. Front Oncol 2019; 9:150. [PMID: 30931258 PMCID: PMC6428933 DOI: 10.3389/fonc.2019.00150] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 02/22/2019] [Indexed: 01/20/2023] Open
Abstract
Tissue factor (TF) is a transmembrane glycoprotein to initiate blood coagulation and frequently overexpressed in a variety of tumors. Our previous study has showed that the expression of TF is upregulated and correlated with prognosis in hepatocellular carcinoma (HCC). However, the role and molecular mechanism of TF in the growth of HCC are still unclear. In vitro and in vivo functional experiments were performed to determine the effect of TF on the growth of HCC cells. A panel of biochemical assays was used to elucidate the underlying mechanisms. TF could promote the growth of HCC in vitro and in vivo by activating both ERK and AKT signaling pathways. TF induced EGFR upregualtion, and inhibition of EGFR suppressed TF-mediated HCC growth. In addition, TF protein expression was correlated with EGFR in HCC tissues. TF promotes HCC growth by upregulation of EGFR, and TF as well as EGFR may be potential therapeutic targets of HCC.
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Affiliation(s)
- Shan-Zhou Huang
- Department of Hepatic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Meng-Ning Wei
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Jia-Rong Huang
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Zi-Jian Zhang
- Department of Hepatobiliary Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Wen-Ji Zhang
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Qi-Wei Jiang
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yang Yang
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Huan-Yu Wang
- Department of Thyroid and Breast Surgery, Nanshan District People's Hospital, Shenzhen, China
| | - Hui-Lin Jin
- Department of Hepatic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kun Wang
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Zi-Hao Xing
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Meng-Ling Yuan
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yao Li
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Xiao-Shun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi Shi
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qi Zhou
- Department of Hepatic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of General Surgery, Hui Ya Hospital of The First Affiliated Hospital, Sun Yat-sen University, Huizhou, China
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You RI, Wu WS, Cheng CC, Wu JR, Pan SM, Chen CW, Hu CT. Involvement of N-glycan in Multiple Receptor Tyrosine Kinases Targeted by Ling-Zhi-8 for Suppressing HCC413 Tumor Progression. Cancers (Basel) 2018; 11:cancers11010009. [PMID: 30577605 PMCID: PMC6356446 DOI: 10.3390/cancers11010009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 12/14/2018] [Accepted: 12/18/2018] [Indexed: 12/21/2022] Open
Abstract
The poor prognosis of hepatocellular carcinoma (HCC) is resulted from tumor metastasis. Signaling pathways triggered by deregulated receptor tyrosine kinases (RTKs) were the promising therapeutic targets for prevention of HCC progression. However, RTK-based target therapy using conventional kinase-based inhibitors was often hampered by resistances due to compensatory RTKs signaling. Herein, we report that Ling-Zhi-8 (LZ-8), a medicinal peptide from Ganoderma lucidium, was effective in suppressing cell migration of HCC413, by decreasing the amount and activity of various RTKs. These led to the suppression of downstream signaling including phosphorylated JNK, ERK involved in HCC progression. The capability of LZ-8 in targeting multiple RTKs was ascribed to its simultaneous binding to these RTKs. LZ-8 may bind on the N-linked glycan motif of RTKs that is required for their maturation and function. Notably, pretreatment of the N-glycan trimming enzyme PNGase or inhibitors of the mannosidase (N-glycosylation processing enzyme), kifunensine (KIF) and swainsonine (SWN), prevented LZ-8 binding on the aforementioned RTKs and rescued the downstream signaling and cell migration suppressed by LZ-8. Moreover, pretreatment of KIF prevented LZ-8 triggered suppression of tumor growth of HCC413. Our study suggested that a specific type of N-glycan is the potential target for LZ-8 to bind on multiple RTKs for suppressing HCC progression.
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Affiliation(s)
- Ren-In You
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan.
| | - Wen-Sheng Wu
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan.
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan.
| | - Chuan-Chu Cheng
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan.
| | - Jia-Ru Wu
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan.
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan.
| | - Siou-Mei Pan
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan.
| | - Chi-Wen Chen
- School of Chinese medicine, China Medical University, Taichung 40402, Taiwan.
| | - Chi-Tan Hu
- Division of Gastroenterology, Department of Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien 97004, Taiwan.
- Research Centre for Hepatology, Buddhist Tzu Chi General Hospital, Hualien 97004, Taiwan.
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The EGFR Inhibitor Gefitinib Enhanced the Response of Human Oral Squamous Cell Carcinoma to Cisplatin In Vitro. Drugs R D 2018; 17:545-555. [PMID: 28828595 PMCID: PMC5694417 DOI: 10.1007/s40268-017-0204-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Introduction The epidermal growth factor receptor (EGFR) is highly expressed in a variety of solid tumors including oral cavity squamous cell carcinoma (OSCC) and has been implicated in the resistance of these tumors to cisplatin. This study was performed to determine if the EGFR tyrosine kinase inhibitor gefitinib could enhance the cytotoxic effect of cisplatin on OSCC cells in vitro. Methods The expression of EGFR and the phosphorylation of its downstream signaling to ERK, and AKT pathway were detected by Western blotting. Cell proliferation and survival were determined by AlamarBlue and colony formation assay respectively. Cells apoptosis were determined by Western blotting for cleaved PARP protein and by flowcytometry of cells stained with Annexin V and PI. Results Cal27, OSC19, and SCC25 cells treated with gefitinib 1 μM demonstrated reduced phosphorylation of EGFR, AKT, and ERK proteins with very limited inhibition of proliferation. Cisplatin inhibited proliferation of the same cell lines in a dose-dependent manner. The concentration producing 50% inhibition (IC50) for cisplatin decreased in the presence of gefitinib 1 μM, and a combination of cisplatin 5 µM and gefitinib 1 µM caused synergistic growth inhibition and synergistic reduction in cell survival. The growth inhibitory effect of the combination was associated with reduced ERK and AKT activation, increased poly ADP ribose polymerase (PARP) cleavage, and increased apoptosis. Conclusion Thus, in OSCC cells in vitro, inhibition of EGFR activity with gefitinib enhances the apoptotic effect of cisplatin. This has potential implications for enhancement of cisplatin effectiveness in tumors that over-express the EGFR.
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NKG2D Immunoligand rG7S-MICA Enhances NK Cell-mediated Immunosurveillance in Colorectal Carcinoma. J Immunother 2018. [DOI: 10.1097/cji.0000000000000215] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Ray EM, Sanoff HK. Optimal therapy for patients with hepatocellular carcinoma and resistance or intolerance to sorafenib: challenges and solutions. J Hepatocell Carcinoma 2017; 4:131-138. [PMID: 29184856 PMCID: PMC5687453 DOI: 10.2147/jhc.s124366] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The only US Food and Drug Administration (FDA)-approved first-line systemic therapy for hepatocellular carcinoma (HCC) is sorafenib; however, resistance or intolerance to sorafenib is unfortunately common. In this review, we briefly describe systemic therapies that can be considered for patients with HCC who show resistance or intolerance to sorafenib. For all patients with HCC who need systemic therapy, we strongly advocate for participation in clinical trials. Cytotoxic chemotherapy plays a minor role in the treatment of advanced HCC, with some data supporting the use of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) and GEMOX (gemcitabine-oxaliplatin). Multi-target kinase inhibitors such as lenvantinib and regorafenib have recently met their primary endpoints as first- and second-line therapy, respectively, with regorafenib now representing the only FDA-approved drug for second-line treatment of HCC. Other targeted therapies remain under investigation, but results so far have not significantly changed clinical practice. Immunotherapy is an interesting area of research in the treatment of HCC with preclinical and early clinical data demonstrating exciting results; thus numerous investigational studies are currently focusing on immunotherapy in the treatment of HCC. While systemic treatment options in HCC remain a challenge for providers, in this review, we summarize the current literature and highlight areas of progress with respect to the treatment of patients with HCC and resistance or intolerance to sorafenib.
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Affiliation(s)
- Emily M Ray
- Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, USA
| | - Hanna K Sanoff
- Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, USA
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Niu L, Liu L, Yang S, Ren J, Lai PBS, Chen GG. New insights into sorafenib resistance in hepatocellular carcinoma: Responsible mechanisms and promising strategies. Biochim Biophys Acta Rev Cancer 2017; 1868:564-570. [PMID: 29054475 DOI: 10.1016/j.bbcan.2017.10.002] [Citation(s) in RCA: 141] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 10/04/2017] [Accepted: 10/15/2017] [Indexed: 02/06/2023]
Abstract
It is disappointing that only a few patients with hepatocellular carcinoma (HCC) obtain a significant survival benefit from the sorafenib treatment, which is currently regarded as a first-line chemotherapeutic therapy in patients with advanced HCC. Most patients are highly refractory to this therapy. Therefore, it is necessary to identify resistant factors and explore potential protocols that can be used to overcome the resistance or substitute sorafenib once the resistance is formed. In fact, a growing body of studies has been focusing on the resistance mechanisms or the method to overcome it. The limitation of sorafenib efficacy has been partially but not fully elucidated. Moreover, some protocols have shown encouraging outcomes but still need to be further verified in clinical trials. In this review, we summarize the recent findings on the potential mechanisms that contribute to sorafenib resistance and discuss strategies that can be used to improve the treatment outcome.
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Affiliation(s)
- Leilei Niu
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China; Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Liping Liu
- Department of Hepatobiliary and Pancreas Surgery, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong Province, China
| | - Shengli Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jianwei Ren
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Paul B S Lai
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China.
| | - George G Chen
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
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Ma Z, He H, Sun F, Xu Y, Huang X, Ma Y, Zhao H, Wang Y, Wang M, Zhang J. Selective targeted delivery of doxorubicin via conjugating to anti-CD24 antibody results in enhanced antitumor potency for hepatocellular carcinoma both in vitro and in vivo. J Cancer Res Clin Oncol 2017; 143:1929-1940. [PMID: 28536738 DOI: 10.1007/s00432-017-2436-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 05/08/2017] [Indexed: 12/21/2022]
Abstract
PURPOSE Antibody-drug conjugates (ADCs) represent a promising therapeutic approach for clinical application. Cluster of differentiation 24 (CD24) is over-expressed in several human malignancies, especially in hepatocellular carcinoma (HCC). We aimed to develop a new class of CD24-targeted ADCs for HCC. METHODS DOX was conjugated with G7mAb by a heterobifunctional cross-linker GMBS (N-[gamma-maleimido butyryloxy] succinimide ester) and further analyzed using HPLC. The targeting specificity and endocytosis of the newly generated ADC, G7mAb-DOX, were characterized using flow cytometry assay, near-infrared fluorescence imaging and laser scanning confocal microscope. The antitumor effects were evaluated in nude mice bearing HCC xenografts. RESULTS G7mAb-DOX with average two drug molecules per antibody was selectively captured and endocytosed by CD24 (+) tumor cells in vitro. In vivo, the ADC was proved to target tumor tissues, suppress tumor growth and prolong the survival of HCC-bearing nude mice with improved efficacy and less systemic toxicity compared with either G7mAb or DOX single-agent treatment. CONCLUSION These studies provide proof of concept for development of DOX-based ADCs which provide a novel approach for HCC-targeted immune therapy in clinical application.
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Affiliation(s)
- Zhaoxiong Ma
- Antibody Engineering Laboratory, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 154#, Tong Jia Xiang 24, Nanjing, 210009, People's Republic of China
| | - Hua He
- Antibody Engineering Laboratory, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 154#, Tong Jia Xiang 24, Nanjing, 210009, People's Republic of China
| | - Fumou Sun
- Antibody Engineering Laboratory, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 154#, Tong Jia Xiang 24, Nanjing, 210009, People's Republic of China
| | - Yao Xu
- Antibody Engineering Laboratory, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 154#, Tong Jia Xiang 24, Nanjing, 210009, People's Republic of China
| | - Xuequn Huang
- Antibody Engineering Laboratory, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 154#, Tong Jia Xiang 24, Nanjing, 210009, People's Republic of China
| | - Yuexing Ma
- Antibody Engineering Laboratory, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 154#, Tong Jia Xiang 24, Nanjing, 210009, People's Republic of China
| | - Hong Zhao
- First Affiliate Hospital of Zhejiang Chinese Medicine University, Hangzhou, 310006, China
| | - Yang Wang
- Antibody Engineering Laboratory, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 154#, Tong Jia Xiang 24, Nanjing, 210009, People's Republic of China
| | - Min Wang
- Antibody Engineering Laboratory, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 154#, Tong Jia Xiang 24, Nanjing, 210009, People's Republic of China.
| | - Juan Zhang
- Antibody Engineering Laboratory, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 154#, Tong Jia Xiang 24, Nanjing, 210009, People's Republic of China.
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Song P, Yang J, Li X, Huang H, Guo X, Zhou G, Xu X, Cai Y, Zhu M, Wang P, Zhao S, Zhang D. Hepatocellular carcinoma treated with anti-epidermal growth factor receptor antibody nimotuzumab: A case report. Medicine (Baltimore) 2017; 96:e8122. [PMID: 28953642 PMCID: PMC5626285 DOI: 10.1097/md.0000000000008122] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
RATIONALE Molecular targeted therapy provides new ideas and hope for the treatment of hepatocellular cancer. Epidermal growth factor receptor (EGFR) is closely related to tumor cell proliferation, apoptosis, invasion, and metastasis. PATIENT CONCERNS Several reports indicate that the EGFR is expressed frequently in hepatocellular carcinoma (HCC), thus targeting EGFR research has become a hot topic to explore the treatment of HCC patient. DIAGNOSES Anti-EGFR might serve as a potential therapeutic agent, especially for patients with HCC who are unable to tolerate chemotherapy and surgery. INTERVENTIONS Although phase II open-label study of cetuximab in unresectable HCC was negative, the clinical relevance of this report by Song et al which is based on a single patient is questionable. OUTCOMES We for the first time report that nimotuzumab (an anti-EGFR mAb) resulted in a complete remission (CR) in an 87-year-old patient with HCC. The patient was in B stage according to Barcelona center staging criteria and his liver function was Child-Pugh B grade. LESSONS Our case suggested that anti-EGFR mAbs might be potential therapeutic options for HCC.
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Affiliation(s)
| | | | | | | | | | | | - Xian Xu
- Department of Geriatric Radiology, The General Hospital of Chinese People's liberation Army, Beijing, China
| | - Yi Cai
- Department of Geriatric Oncology
| | - Min Zhu
- Department of Geriatric Oncology
| | | | - Shu Zhao
- Department of Geriatric Oncology
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Chen Z, Wang T, Tu X, Xie W, He H, Wang M, Zhang J. Antibody-based targeting of CD24 enhances antitumor effect of cetuximab via attenuating phosphorylation of Src/STAT3. Biomed Pharmacother 2017; 90:427-436. [PMID: 28391164 DOI: 10.1016/j.biopha.2017.03.094] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 03/27/2017] [Accepted: 03/27/2017] [Indexed: 01/29/2023] Open
Abstract
Epidermal growth factor receptor (EGFR) is a cell-surface receptor for some extracellular protein ligands relating to cancers and has been recognized as a key target for tumor therapy. Cetuximab, a chimerical monoclonal EGFR IgG1 antibody, is used for the treatment of various malignancies. However, recent clinical trials reported that the anti-tumor effect of cetuximab is still controversial. Cluster of differentiation 24 (CD24) is a tumor-associated antigen correlating with poor prognosis and regulating the activity of Src/STAT3 in multiple cancers. G7mAb was an anti-CD24 antibody derived by hybridoma technology in our previous study. To further evaluate the relationship between cetuximab and G7mAb in cancer therapy, this combination treatment was performed in vitro (A549, HT-29 and Huh-7 cells) and in vivo (xenograft mouse models). We showed that G7mAb suppressed the invasion and enhanced the anti-proliferation effect of cetuximab in A549, HT-29 and Huh-7 cells. Combination of cetuximab with G7mAb had enhanced effects on blocking the activation of signal transducer and activator of transcription 3 (STAT3) signal pathway. Furthermore, combination therapy of cetuximab with G7mAb significantly suppressed tumor developments and improved the survival rates in xenografted mice. In conclusion, G7mAb enhanced the antitumor effect of cetuximab by attenuating phosphorylation of Src/STAT3 both in vitro and in vivo. Combination of antibodies targeting EGFR or CD24 provided a potential strategy for cancer therapy.
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Affiliation(s)
- Zhiguo Chen
- State Key Laboratory of Natural Medicines, Life Science & Technology, China Pharmaceutical University, PR China
| | - Tong Wang
- State Key Laboratory of Natural Medicines, Life Science & Technology, China Pharmaceutical University, PR China
| | - Xiaojie Tu
- State Key Laboratory of Natural Medicines, Life Science & Technology, China Pharmaceutical University, PR China
| | - Wei Xie
- State Key Laboratory of Natural Medicines, Life Science & Technology, China Pharmaceutical University, PR China
| | - Hua He
- State Key Laboratory of Natural Medicines, Life Science & Technology, China Pharmaceutical University, PR China
| | - Min Wang
- State Key Laboratory of Natural Medicines, Life Science & Technology, China Pharmaceutical University, PR China.
| | - Juan Zhang
- State Key Laboratory of Natural Medicines, Life Science & Technology, China Pharmaceutical University, PR China.
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Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy. Int J Mol Sci 2017. [PMID: 28216578 DOI: 10.3390/ijms18020405.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most lethal and prevalent cancers in the human population. Different etiological factors such as hepatitis B and C virus, alcohol and diabetes cause liver injury followed by inflammation, necrosis and hepatocytes proliferation. Continuous cycles of this destructive-regenerative process culminates in liver cirrhosis which is characterized by regenerating nodules that progress to dysplastic nodules and ultimately HCC. Despite its significance, there is only an elemental understanding of the pathogenetic mechanisms, and there are only limited therapeutic options. Therefore, the study of the involved molecular mechanisms can open a new insight to define more effective treatment strategies. A variety of alterations have been reported in HCC patients, particularly the cancer-associated microenvironment components including immune cells, fibroblast cells, endothelial cells and extracellular matrix can support the neoplastic cells to proliferate, growth and invade. This review summarizes the current state of knowledge and highlights the principal challenges that are relevant to controlling this milieu.
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Tahmasebi Birgani M, Carloni V. Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy. Int J Mol Sci 2017; 18:ijms18020405. [PMID: 28216578 PMCID: PMC5343939 DOI: 10.3390/ijms18020405] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 02/02/2017] [Accepted: 02/08/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most lethal and prevalent cancers in the human population. Different etiological factors such as hepatitis B and C virus, alcohol and diabetes cause liver injury followed by inflammation, necrosis and hepatocytes proliferation. Continuous cycles of this destructive–regenerative process culminates in liver cirrhosis which is characterized by regenerating nodules that progress to dysplastic nodules and ultimately HCC. Despite its significance, there is only an elemental understanding of the pathogenetic mechanisms, and there are only limited therapeutic options. Therefore, the study of the involved molecular mechanisms can open a new insight to define more effective treatment strategies. A variety of alterations have been reported in HCC patients, particularly the cancer-associated microenvironment components including immune cells, fibroblast cells, endothelial cells and extracellular matrix can support the neoplastic cells to proliferate, growth and invade. This review summarizes the current state of knowledge and highlights the principal challenges that are relevant to controlling this milieu.
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Affiliation(s)
- Maryam Tahmasebi Birgani
- Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 63461, Iran.
| | - Vinicio Carloni
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, Florence 50134, Italy.
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Xue F, Liu Y, Zhang H, Wen Y, Yan L, Tang Q, Xiao E, Zhang D. Let-7a enhances the sensitivity of hepatocellular carcinoma cells to cetuximab by regulating STAT3 expression. Onco Targets Ther 2016; 9:7253-7261. [PMID: 27932893 PMCID: PMC5135407 DOI: 10.2147/ott.s116127] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Let-7 miRNAs are reported to play an inhibitory role in carcinogenesis, tumor progression, recurrence, and pluripotency of cancer. However, few studies have reported the relationship between let-7 and drug sensitivity, especially for let-7a (a subtype of let-7). This study aimed to investigate the function of let-7a in regulating the sensitivity of hepatocellular carcinoma (HCC) cell lines to cetuximab. Methods The cytotoxicity of cetuximab on HCC cell lines (Huh7, Hep3B, HepG2, SNU449, and SNU387) was evaluated using a cell viability assay (the Cell Counting Kit-8 assay) and a cell proliferation assay (the Click-iT EdU Imaging Kit) in the presence of a control, a let-7a mimic, and a let-7a inhibitor. Small interfering RNA to knockdown the expression of signal transducer and activator of transcription 3 (STAT3) were employed. Protein and mRNA expression levels were determined using quantitative polymerase chain reaction and Western blot analysis. Results It was found that let-7a enhances the sensitivity of HCC cells with an epithelial phenotype (Huh7, Hep3B, and HepG2) to cetuximab, but has no effect on cells with the mesenchymal phenotype (SNU449 and SNU387). It was determined that STAT3 was a target mRNA of let-7a using TargetScan. Expression of STAT3 and let-7a mRNA were negatively correlated in HCC cell lines. Moreover, let-7a altered the protein and mRNA expression of STAT3. Furthermore, STAT3 knockdown enhanced the function of cetuximab on HCC cell lines with epithelial phenotypes, but not on HCC cell lines with mesenchymal phenotypes. Finally, a rescue experiment confirmed that let-7a affected the sensitivity of HCC cell lines to cetuximab by interacting with STAT3. Conclusions There is a functional link between let-7a and STAT3 in enhancing the sensitivity of HCC cells with an epithelial phenotype to cetuximab. Our results provide novel insight into new methodologies for combating HCC drug resistance.
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Affiliation(s)
- Fei Xue
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, People's Republic of China
| | - Yanhui Liu
- Department of Hematology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, People's Republic of China
| | - Hongwei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, People's Republic of China
| | - Yu Wen
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, People's Republic of China
| | - Lei Yan
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, People's Republic of China
| | - Qiang Tang
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, People's Republic of China
| | - Erhui Xiao
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, People's Republic of China
| | - Dongyi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, People's Republic of China
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Ungerleider N, Han C, Zhang J, Yao L, Wu T. TGFβ signaling confers sorafenib resistance via induction of multiple RTKs in hepatocellular carcinoma cells. Mol Carcinog 2016; 56:1302-1311. [PMID: 27862334 DOI: 10.1002/mc.22592] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 10/28/2016] [Accepted: 11/11/2016] [Indexed: 12/15/2022]
Abstract
Transforming growth factor β (TGFβ) is a multifunctional cytokine which is importantly implicated in hepatocarcinogenesis. The current study provides novel evidence that TGFβ upregulates the expression of multiple receptor tyrosine kinases (RTKs), including IGF1R, EGFR, PDGFβR, and FGFR1 in human hepatocellular carcinoma (HCC) cells. This, in turn, sensitized HCC cells to individual cognate RTK ligands, leading to cell survival. Our data showed that the TGFβ-mediated increase in growth factor sensitivity led to evasion of apoptosis induced by the mutikinase inhibitor, sorafenib. Conversely, we observed that inhibition of the TGFβ signaling pathway by LY2157299, a TGFβRI kinase inhibitor, enhanced sorafenib-induced apoptosis, in vitro. Our findings disclose an important interplay between TGFβ and RTK signaling pathways, which is critical for hepatocellular cancer cell survival and resistance to therapy. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Nathan Ungerleider
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Chang Han
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Jinqiang Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Lu Yao
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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Yegin EG, Oymaci E, Karatay E, Coker A. Progress in surgical and nonsurgical approaches for hepatocellular carcinoma treatment. Hepatobiliary Pancreat Dis Int 2016; 15:234-56. [PMID: 27298100 DOI: 10.1016/s1499-3872(16)60097-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a complex and heterogeneous malignancy, frequently occurs in the setting of a chronically diseased organ, with multiple confounding factors making its management challenging. HCC represents one of the leading causes of cancer-related mortality globally with a rising trend of incidence in some of the developed countries, which indicates the need for better surgical and nonsurgical management strategies. DATA SOURCES PubMed database was searched for relevant articles in English on the issue of HCC management. RESULTS Surgical resection represents a potentially curative option for appropriate candidates with tumors detected at earlier stages and with well-preserved liver function. The long-term outcome of surgery is impaired by a high rate of recurrence. Surgical approaches are being challenged by local ablative therapies such as radiofrequency ablation and microwave ablation in selected patients. Liver transplantation offers potential cure for HCC and also correction of underlying liver disease, and minimizes the risk of recurrence, but is reserved for patients within a set of criteria proposed for a prudent allocation in the shortage of donor organs. Transcatheter locoregional therapies have become the palliative standard allowing local control for intermediate stage patients with noninvasive multinodular or large HCC who are beyond the potentially curative options. The significant survival benefit with the multikinase inhibitor sorafenib for advanced HCC has shifted the direction of research regarding systemic treatment toward molecular therapies targeting the disregulated pathways of hepatocarcinogenesis. Potential benefit is suggested from simultaneous or sequential multimodal therapies, and optimal combinations are being investigated. Despite the striking progress in preclinical studies of HCC immunotherapy and gene therapy, extensive clinical trials are required to achieve successful clinical applications of these innovative approaches. CONCLUSION Treatment decisions have become increasingly complex for HCC with the availability of multiple surgical and nonsurgical therapeutic options and require a comprehensive, multidisciplinary approach.
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Affiliation(s)
- Ender Gunes Yegin
- Department of Gastroenterology, Bozyaka Training and Research Hospital, Izmir 35170, Turkey.
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Wang T, Sun F, Xie W, Tang M, He H, Jia X, Tian X, Wang M, Zhang J. A bispecific protein rG7S-MICA recruits natural killer cells and enhances NKG2D-mediated immunosurveillance against hepatocellular carcinoma. Cancer Lett 2016; 372:166-78. [PMID: 26791237 DOI: 10.1016/j.canlet.2016.01.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 12/11/2015] [Accepted: 01/04/2016] [Indexed: 12/12/2022]
Abstract
MHC class I-related chain A (MICA) is a principal immunoligand of the natural killer (NK) cell receptor NK group 2, member D (NKG2D) and plays a key role in NK cell-mediated immune recognition. Shedding of MICA from tumor cells leads to immunosuppression. To reconstitute the immunosurveilance function of NK cells, we constructed a fusion protein rG7S-MICA and explored its potential anti-tumor activity against hepatocellular carcinoma (HCC). rG7S-MICA consists of human MICA and a single-chain antibody fragment (scFv) targeting the tumor-associated antigen cluster of differentiation 24 (CD24). In vitro, rG7S-MICA engaged both NK cells and CD24(+) human HCC cells, and triggered NK cell-mediated cytolysis. Furthermore, in CD24(+) HCC-bearing nude mice, rG7S-MICA specifically targeted to the tumor tissue, where it effectively recruited NK cells and induced the release of cytokines, and showed superior anti-tumor activity. In conclusion, rG7S-MICA provides a new approach for HCC-targeting immunotherapy and has attracting potentials for clinical applications.
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Affiliation(s)
- Tong Wang
- State Key Laboratory of Natural Medicines, School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Fumou Sun
- State Key Laboratory of Natural Medicines, School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Wei Xie
- State Key Laboratory of Natural Medicines, School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Mingying Tang
- State Key Laboratory of Natural Medicines, School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Hua He
- State Key Laboratory of Natural Medicines, School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Xuelian Jia
- State Key Laboratory of Natural Medicines, School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Xuemei Tian
- State Key Laboratory of Natural Medicines, School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Min Wang
- State Key Laboratory of Natural Medicines, School of Life Science & Technology, China Pharmaceutical University, Nanjing, China.
| | - Juan Zhang
- State Key Laboratory of Natural Medicines, School of Life Science & Technology, China Pharmaceutical University, Nanjing, China.
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Komposch K, Sibilia M. EGFR Signaling in Liver Diseases. Int J Mol Sci 2015; 17:E30. [PMID: 26729094 PMCID: PMC4730276 DOI: 10.3390/ijms17010030] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Revised: 12/17/2015] [Accepted: 12/21/2015] [Indexed: 02/07/2023] Open
Abstract
The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that is activated by several ligands leading to the activation of diverse signaling pathways controlling mainly proliferation, differentiation, and survival. The EGFR signaling axis has been shown to play a key role during liver regeneration following acute and chronic liver damage, as well as in cirrhosis and hepatocellular carcinoma (HCC) highlighting the importance of the EGFR in the development of liver diseases. Despite the frequent overexpression of EGFR in human HCC, clinical studies with EGFR inhibitors have so far shown only modest results. Interestingly, a recent study has shown that in human HCC and in mouse HCC models the EGFR is upregulated in liver macrophages where it plays a tumor-promoting function. Thus, the role of EGFR in liver diseases appears to be more complex than what anticipated. Further studies are needed to improve the molecular understanding of the cell-specific signaling pathways that control disease development and progression to be able to develop better therapies targeting major components of the EGFR signaling network in selected cell types. In this review, we compiled the current knowledge of EGFR signaling in different models of liver damage and diseases, mainly derived from the analysis of HCC cell lines and genetically engineered mouse models (GEMMs).
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Affiliation(s)
- Karin Komposch
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
| | - Maria Sibilia
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
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Nguyen K, Jack K, Sun W. Hepatocellular Carcinoma: Past and Future of Molecular Target Therapy. Diseases 2015; 4:E1. [PMID: 28933381 PMCID: PMC5456309 DOI: 10.3390/diseases4010001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 12/03/2015] [Accepted: 12/16/2015] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer related mortality worldwide. The incidence of HCC has been increasing annually. Viral infection, alcohol usage, and other causes of cirrhosis have been identified as major risk factors for HCC development. The underlying pathogenesis has not been as well defined. There have been multiple hypotheses to the specific mechanisms of hepatocarcinogenesis and they share the common theme of chronic inflammation, increase oxidative stress, and genomic alteration. Therapeutic options of HCC have been primarily local and/or regional including transplantation, resection, and radial frequency ablation, chemoembolization or radio-embolization. For unresectable or metastatic disease, the options are limited. Conventional chemotherapeutic options have been noted to have limited benefit. Sorafenib has been the one and only systemic therapy which has demonstrated modest overall survival benefit. This has led to more extensive research with focus on targeted therapy. Numerous pre-clinical and early phase clinical studies have been noted but failed to show efficacy in later phase clinical trials. In an effort to identify new potential therapeutic options, new understanding of underlying pathways to hepatocarcinogenesis should be one of the main focuses. This leads to development of more molecularly targeted agents to specific pathways, and immunotherapy. This article provides a review of major studies of molecular targeted agents which attempts to target these specific pathways in HCC.
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Affiliation(s)
- Khanh Nguyen
- University of Pittsburgh Medical Center, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150 Center Ave. 5th floor, Pittsburgh, PA 15232, USA.
| | - Kerri Jack
- University of Pittsburgh Medical Center, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150 Center Ave. 5th floor, Pittsburgh, PA 15232, USA.
| | - Weijing Sun
- University of Pittsburgh Medical Center, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150 Center Ave. 5th floor, Pittsburgh, PA 15232, USA.
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Qin S, Gong X. Progression of systemic chemotherapy with oxaliplatin-containing regimens for advanced hepatocellular carcinoma in China. Hepat Oncol 2015; 3:71-81. [PMID: 30191027 DOI: 10.2217/hep.15.42] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 07/29/2015] [Indexed: 12/29/2022] Open
Abstract
Hepatocellular carcinoma (HCC) characterized by insidious onset is a highly invasive malignance and has a rapid progress. The majority of patients, especially in Asian countries, present with locally advanced or distant metastatic disease at diagnosis and are not eligible for local treatment. Before the publication of the EACH study results showing the survival benefits of the FOLFOX 4 regimen in Chinese patients with advanced HCC, no chemotherapeutical drug or regimen was considered as systemic chemotherapy standard for this group of patients due to the lack of evidence-based recommendations. Oxaliplatin-containing regimens have shown clinical activity against advanced HCC with an acceptable safety profile. The aim of this article is to present a review of the scientific evidence mainly originating from China that supports the recommendation of oxaliplatin-based regimens for the treatment of Chinese patients with advanced HCC.
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Affiliation(s)
- Shukui Qin
- Chinese People's Liberation Army Cancer Center, Bayi Hospital, Nanjing, 210002, China
| | - Xinlei Gong
- Chinese People's Liberation Army Cancer Center, Bayi Hospital, Nanjing, 210002, China
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Turhal NS, Savaş B, Çoşkun Ö, Baş E, Karabulut B, Nart D, Korkmaz T, Yavuzer D, Demir G, Doğusoy G, Artaç M. Prevalence of K-Ras mutations in hepatocellular carcinoma: A Turkish Oncology Group pilot study. Mol Clin Oncol 2015; 3:1275-1279. [PMID: 26807232 DOI: 10.3892/mco.2015.633] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 08/17/2015] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common male-predominant type of cancer worldwide. There is no effective treatment regimen available for advanced-stage disease and chemotherapy is generally ineffective in these patients. The number of studies on the prevalence of K-Ras mutations in HCC patients is currently limited. A total of 58 patients from 6 comprehensive cancer centers in 4 metropolitan cities of Turkey were enrolled in this study. Each center committed to enroll approximately 10 random patients whose formalin-fixed paraffin-embedded tumor tissues were available for K-Ras, exon 2 genotyping. Two methods were applied based on the availability of adequate amounts of tumor DNA. In the first method, the samples were processed using TheraScreen. The genomic DNA was further used to detect the 7 most frequent somatic mutations (35G>A; 35G>C; 35G>T; 34G>A; 34G>C; 34G>T and 38G>A) in codons 12 and 13 in exon 2 of the K-Ras oncogene by quantitative polymerase chain reaction (PCR). In the second method, the genomic DNA was amplified by PCR using primers specific for K-Ras exon 2 with the GML SeqFinder Sequencing System's KRAS kit. The identified DNA sequence alterations were confirmed by sequencing both DNA strands in two independent experiments with forward and reverse primers. A total of 40 samples had adequate tumor tissue for the mutation analysis. A total of 33 (82.5%) of the investigated samples harbored no mutations in exon 2. All the mutations were identified via a direct sequencing technique, whereas none were identified by TheraScreen. In conclusion, in our patients, HCC exhibited a remarkably low (<20%) K-Ras mutation rate. Patients harboring K-Ras wild-type tumors may be good candidates for treatment with epidermal growth factor inhibitors, such as cetuximab.
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Affiliation(s)
- Nazim Serdar Turhal
- Department of Medical Oncology, Marmara University, Faculty of Medicine, 34722 Istanbul, Turkey
| | - Berna Savaş
- Department of Pathology, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey
| | - Öznur Çoşkun
- Department of Pathology, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey
| | - Emine Baş
- Department of Pathology, Marmara University, Faculty of Medicine, 34899 Istanbul, Turkey
| | - Bülent Karabulut
- Department of Medical Oncology, Ege University, Faculty of Medicine, 35100 Izmir, Turkey
| | - Deniz Nart
- Department of Pathology, Ege University, Faculty of Medicine, 35100 Izmir, Turkey
| | - Taner Korkmaz
- Department of Medical Oncology, Acibadem University, Faculty of Medicine, Maslak Hospital, 34662 Istanbul, Turkey
| | - Dilek Yavuzer
- Department of Pathology, Kartal Training and Research Hospital, 34890 Istanbul, Turkey
| | - Gökhan Demir
- Department of Medical Oncology, Bilim University, Faculty of Medicine, 34340 Istanbul, Turkey
| | - Gülen Doğusoy
- Department of Pathology, Bilim University, Faculty of Medicine, 34340 Istanbul, Turkey
| | - Mehmet Artaç
- Department of Medical Oncology, Necmettin Erbakan University, Meram Faculty of Medicine, 42080 Konya, Turkey
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Kuang Y, El-Khoueiry A, Taverna P, Ljungman M, Neamati N. Guadecitabine (SGI-110) priming sensitizes hepatocellular carcinoma cells to oxaliplatin. Mol Oncol 2015; 9:1799-814. [PMID: 26160429 DOI: 10.1016/j.molonc.2015.06.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Revised: 05/10/2015] [Accepted: 06/05/2015] [Indexed: 12/14/2022] Open
Abstract
Promoter DNA hypermethylation is an important biomarker of hepatocellular carcinoma (HCC), supporting the potential utility of demethylating agents in this disease. Guadecitabine (SGI-110) is a second-generation hypomethylating agent formulated as a dinucleotide of decitabine and deoxyguanosine that yields longer half-life and more extended decitabine exposure than decitabine IV infusion. Here we performed preclinical evaluation of SGI-110 in HCC models to guide the design of a phase I/II clinical trial. HCC cell lines and xenograft models were used to determine the antitumor activity of SGI-110 as a single agent and in combination with oxaliplatin. Pretreatment with low doses of SGI-110 significantly synergized with oxaliplatin yielding enhanced cytotoxicity. The combination of SGI-110 and oxaliplatin was well tolerated and significantly delayed tumor growth in mice compared to oxaliplatin alone. Bromouridine-labeled RNA sequencing (Bru-seq) was employed to elucidate the effects of SGI-110 and/or oxaliplatin on genome-wide transcription. SGI-110 and the combination treatment inhibited the expression of genes involved in WNT/EGF/IGF signaling. DNMT1 and survivin were identified as novel PD markers to monitor the efficacy of the combination treatment. In conclusion, SGI-110 priming sensitizes HCC cells to oxaliplatin by inhibiting distinct signaling pathways. We expect that this combination treatment will show low toxicity and high efficacy in patients. Our study supports the use of the combination of low doses of SGI-110 and oxaliplatin in HCC patients.
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Affiliation(s)
- Yuting Kuang
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA; Department of Medicinal Chemistry, College of Pharmacy, Translational Oncology Program, University of Michigan, Ann Arbor, MI, USA
| | - Anthony El-Khoueiry
- Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | | | - Mats Ljungman
- Department of Radiation Oncology, Translational Oncology Program, University of Michigan, Ann Arbor, MI, USA
| | - Nouri Neamati
- Department of Medicinal Chemistry, College of Pharmacy, Translational Oncology Program, University of Michigan, Ann Arbor, MI, USA.
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