Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China.
Department of Emergency, Ankang People's Hospital, 725000, Ankang, Shaanxi, China.
Biochem Biophys Res Commun. 2021 Apr 9;548:60-66. doi: 10.1016/j.bbrc.2021.02.043. Epub 2021 Feb 22.
Repeated and long-term oxaliplatin therapy leads to drug resistance and severe adverse events, which limit its clinical use. These difficulties highlight the importance of identifying potent and specific drug combinations to enhance the antitumor effects of oxaliplatin. The farnesoid X receptor (FXR) deficiency in colorectal cancer (CRC) suggests that restoring FXR function might be a promising strategy for CRC treatment. A drug combination study showed that the GW4064 acted synergistically with oxaliplatin in colon cancer cells. The combination of oxaliplatin plus GW4064 inhibited cell growth and colony formation, induced apoptosis and pyroptosis in vitro, and slowed tumor growth in vivo. Mechanistically, GW4064 enhanced the chemosensitivity of cells to oxaliplatin by inducing BAX/caspase-3/GSDME-mediated pyroptosis. Furthermore, the combination of oxaliplatin and GW4064 synergistically inhibited STAT3 signaling by restoring SHP expression. Our study revealed that GW4064 could enhance the antitumor effects of oxaliplatin against CRC, which provides a novel therapeutic strategy based on a combinational approach for CRC treatment.
重复和长期的奥沙利铂治疗会导致耐药性和严重的不良反应，从而限制了其临床应用。这些困难突显了确定有效和特异的药物组合以增强奥沙利铂抗肿瘤作用的重要性。结直肠癌（CRC）中的法尼醇 X 受体（FXR）缺失表明，恢复 FXR 功能可能是 CRC 治疗的一种有前途的策略。一项药物联合研究表明，GW4064 与奥沙利铂在结肠癌细胞中具有协同作用。奥沙利铂加 GW4064 的联合用药抑制了细胞生长和集落形成，体外诱导细胞凋亡和细胞焦亡，并在体内减缓肿瘤生长。在机制上，GW4064 通过诱导 BAX/caspase-3/GSDME 介导的细胞焦亡来增强细胞对奥沙利铂的化疗敏感性。此外，奥沙利铂和 GW4064 的联合用药通过恢复 SHP 表达协同抑制了 STAT3 信号通路。我们的研究表明，GW4064 可以增强奥沙利铂对 CRC 的抗肿瘤作用，为 CRC 治疗提供了一种基于联合治疗的新的治疗策略。
