A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment
| Autor: | Yi-Yu Ke, Ming-Chen Chou, Jiing-Jyh Jan, Trinh Kieu Dinh, Chien-Huang Wu, Chia-Jui Lee, Kai-Chia Yeh, Jing-Kai Huang, Yen-Nhi Ngoc Ta, Kuan-Wei Huang, Kak-Shan Shia, Jen-Shin Song, Yun-Chieh Sung, Chih-Chun Chang, Teng-Kuang Yeh, Ting-Yun Shiue, Yunching Chen |
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| Rok vydání: | 2021 |
| Předmět: |
Sorafenib
Male Receptors CXCR4 Carcinoma Hepatocellular Angiogenesis Antineoplastic Agents CXCR4 03 medical and health sciences Mice 0302 clinical medicine Liver Neoplasms Experimental Lymphocytes Tumor-Infiltrating Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Tumor-Associated Macrophages medicine Tumor Microenvironment Animals Humans Diethylnitrosamine CXC chemokine receptors 030304 developmental biology Pharmacology 0303 health sciences Tumor microenvironment Multidisciplinary CXCR4 antagonist business.industry Liver Neoplasms Drug Synergism hepatocellular carcinoma Biological Sciences medicine.disease Primary tumor Xenograft Model Antitumor Assays Rats Molecular Docking Simulation Tumor progression programmed cell death 1 030220 oncology & carcinogenesis Cancer research CXCR4 receptor business medicine.drug Signal Transduction T-Lymphocytes Cytotoxic |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance A highly selective, safe, and potent CXCR4 antagonist, BPRCX807, has been designed and experimentally validated in various hepatocellular carcinoma models. Through combination therapy, it can synergize with either a kinase (e.g., sorafenib) or checkpoint inhibitor (e.g. anti–PD-1) to augment effectiveness of current anticancer treatments. With its unique mode of action, a new anticancer strategy for preventing cell migration and metastasis is provided. The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti–PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly. |
| Databáze: | OpenAIRE |
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