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

IF 2.8 4区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of Pharmacy and Pharmacology Pub Date : 2024-08-02 DOI:10.1093/jpp/rgae060

Hongyu Chen, Fan Yang, Qianying Zhao, Hongzheng Wang, Mengyuan Zhu, Hui Li, Zheng Ge, Shuai Zhang, Qinglong Guo, Hui Hui

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引用次数: 0

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.

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通过抑制 HSP90 使 Wee1 降解，GL-V9 可与奥沙利铂协同治疗结直肠癌。

研究目的GL-V9对多种肿瘤具有抗肿瘤作用。本研究旨在验证 GL-V9 是否能与奥沙利铂协同抑制结直肠癌（CRC），并探讨其协同机制：方法：GL-V9与奥沙利铂能否协同抑制结直肠癌（CRC），并探讨其协同作用机制。建立异种移植模型以证实体内的协同作用及其机制：结果：研究证实，GL-V9能增强奥沙利铂的DNA损伤效应，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能加速Wee1的降解，诱导细胞周期停滞和误入有丝分裂，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的结合是导致Wee1降解和结肠癌细胞易受奥沙利铂影响的原因。从功能上讲，过表达 HSP90 或 WEE1 会使 GL-V9 和奥沙利铂的协同作用失效：总之，我们的研究结果表明，GL-V9与奥沙利铂协同抑制CRC，是提高奥沙利铂疗效的一种有前途的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Pharmacy and Pharmacology 医学-药学

CiteScore

6.60

自引率

0.00%

发文量

审稿时长

3 months

期刊介绍： JPP keeps pace with new research on how drug action may be optimized by new technologies, and attention is given to understanding and improving drug interactions in the body. At the same time, the journal maintains its established and well-respected core strengths in areas such as pharmaceutics and drug delivery, experimental and clinical pharmacology, biopharmaceutics and drug disposition, and drugs from natural sources. JPP publishes at least one special issue on a topical theme each year.