GL-V9 与奥沙利铂协同作用通过 HSP90 抑制介导的 Wee1 降解治疗结直肠癌。

GL-V9 synergizes with oxaliplatin of colorectal cancer via Wee1 degradation mediated by HSP90 inhibition.

机构信息

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China.

Department of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Institute of Hematology Southeast University, Nanjing 210009, People's Republic of China.

出版信息

J Pharm Pharmacol. 2024 Aug 2;76(8):1006-1017. doi: 10.1093/jpp/rgae060.

DOI:10.1093/jpp/rgae060

PMID:38767973

Abstract

OBJECTIVES

GL-V9 exhibited anti-tumour effects on various types of tumours. This study aimed to verify if GL-V9 synergized with oxaliplatin in suppressing colorectal cancer (CRC) and to explore the synergistic mechanism.

METHODS

The synergy effect was tested by MTT assays and the mechanism was examined by comet assay, western blotting and immunohistochemistry (IHC). Xenograft model was constructed to substantiated the synergy effect and its mechanism in vivo.

RESULTS

GL-V9 was verified to enhance the DNA damage effect of oxaliplatin, so as to synergistically suppress colon cancer cells in vitro and in vivo. In HCT-116 cells, GL-V9 accelerated the degradation of Wee1 and induced the abrogation of cell cycle arrest and mis-entry into mitosis, bypassing the DNA damage response caused by oxaliplatin. Our findings suggested that GL-V9 binding to HSP90 was responsible for the degradation of Wee1 and the vulnerability of colon cancer cells to oxaliplatin. Functionally, overexpression of either HSP90 or WEE1 annulled the synergistic effect of GL-V9 and oxaliplatin.

CONCLUSIONS

Collectively, our findings revealed that GL-V9 synergized with oxaliplatin to suppress CRC and displayed a promising strategy to improve the efficacy of oxaliplatin.

摘要

目的

GL-V9 对多种类型的肿瘤均具有抗肿瘤作用。本研究旨在验证 GL-V9 是否与奥沙利铂协同抑制结直肠癌（CRC），并探讨其协同作用机制。

方法

通过 MTT 检测评估协同作用，通过彗星试验、Western blot 和免疫组织化学（IHC）检测来探究其协同作用机制。构建异种移植模型以体内验证协同作用及其机制。

结果

GL-V9 被证实可增强奥沙利铂的 DNA 损伤作用，从而在体外和体内协同抑制结肠癌细胞。在 HCT-116 细胞中，GL-V9 加速了 Wee1 的降解，并导致细胞周期阻滞的解除和错误进入有丝分裂，从而绕过奥沙利铂引起的 DNA 损伤反应。我们的研究结果表明，GL-V9 与 HSP90 结合负责 Wee1 的降解和结肠癌细胞对奥沙利铂的敏感性。功能上，HSP90 或 WEE1 的过表达均可消除 GL-V9 和奥沙利铂的协同作用。