Shu-Min Xu, Lu Wang, Xing-Zi Liu, Wei-Hao Huang, Yu-Tao Hu, Shuo-Bin Chen, Zhi-Shu Huang, Shi-Liang Huang
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摘要

背景:热休克反应(HSR)是一种高度保守的机制,可在应对各种环境和生理压力时维持细胞内的平衡。热休克蛋白(HSPs),尤其是 HSP70,作为分子伴侣在这一过程中发挥着关键作用。尽管 HSP70 抑制剂已显示出抗癌活性,但其治疗潜力一直受到 HSP70 和热休克因子 1(HSF1)之间负反馈机制的限制。有人建议将 HSP70 抑制剂与 HSF1 抑制剂结合使用,以克服这一限制并增强抗癌效果:我们在 CRC 细胞中将 HSP70 抑制剂(VER-155008 和 YK-5)与 HSF1 抑制剂(DTHIB)联合使用,并评估了它们对细胞存活、凋亡和蛋白质平衡的影响:结果:在联合治疗中观察到了很强的协同效应(联合指数为 10),导致 CRC 细胞存活率下降,凋亡率上升。机制研究发现,HSP70抑制剂激活了HSF1的磷酸化,诱导了HSP70的表达,联合治疗导致了更明显的HSR抑制和蛋白稳态紊乱:结论:HSP70和HSF1抑制剂的联合疗法具有显著的协同抗肿瘤活性:综合意义:HSP70和HSF1抑制剂联合使用可能是一种很有前景的抗癌策略,为克服负反馈机制、增强抗癌效果提供了一种潜在的解决方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Synergistic anticancer activity of HSP70 and HSF1 inhibitors in colorectal cancer cells: A new strategy for combination therapy.

Background: The heat shock response (HSR) is a highly conserved mechanism that maintains intracellular homeostasis in response to various environmental and physiological stresses. Heat shock proteins (HSPs), particularly HSP70, play a pivotal role in this process as molecular chaperones. Although HSP70 inhibitors have demonstrated anti-cancer activity, their therapeutic potential has been limited by the negative feedback mechanism between HSP70 and heat shock factor 1 (HSF1). The combination of HSP70 inhibitors with HSF1 inhibitors has been proposed to overcome this limitation and enhance anti-cancer effects.

Methods: We combined HSP70 inhibitors (VER-155008 and YK-5) with an HSF1 inhibitor (DTHIB) in CRC cells and evaluated their effects on cell survival, apoptosis, and protein homeostasis.

Results: Strong synergistic effects were observed (combination index <0.5, ZIP score > 10) with the combination treatment, leading to decreased cell survival and increased apoptosis in CRC cells. Mechanistic studies revealed that HSP70 inhibitors activated the phosphorylation of HSF1, inducing HSP70 expression, and that the combination therapy resulted in more pronounced HSR inhibition and protein homeostasis disturbances.

Conclusion: The combination therapy of HSP 70 and HSF 1 inhibitors showed significant synergistic antitumor activity.

General significance: Combining HSP70 and HSF1 inhibitors may be a promising anti-cancer strategy, offering a potential solution to overcome the negative feedback mechanism and enhance anti-cancer effects.

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