Schonthal Axel H
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Front Biosci (Schol Ed). 2012 Jan 1;4(2):412-31. doi: 10.2741/s276.
The endoplasmic reticulum (ER) stress response, in combination with autophagy, represents an adaptive mechanism to support cellular survival in response to a great variety of detrimental conditions, such as low nutrient levels, hypoxia, calcium imbalance, or accumulation of misfolded proteins. However, when stress conditions become too severe and excessive, this cellular stress response system turns on its pro-apoptotic module, which then gains dominance and triggers cell death. In tumor cells, the cell-protective features of the ER stress response appear to be chronically activated and thus provide support for continuous proliferation and survival even under adverse microenvironmental conditions, which may include chemotherapy. However, persistent activity of these pro-survival pathways primarily in tumor cells may provide a window of opportunity for therapeutic intervention that is principally aimed at these tumor-specific conditions. Appropriate therapeutic regimens would seek to further aggravate this already engaged system in tumor cells in order to exhaust its protective features and instead trigger its pro-apoptotic module. There is accumulating evidence that this can indeed be accomplished, and that tumor-specific ER stress can be exploited by treatment with select pharmacological agents. The principles of this promising new approach to cancer therapy, as well as representative ER stress-aggravating compounds, will be presented in this review.
内质网（ER）应激反应与自噬相结合，是一种适应性机制，可支持细胞在应对各种有害条件（如低营养水平、缺氧、钙失衡或错误折叠蛋白的积累）时存活。然而，当应激条件变得过于严重和过度时，这种细胞应激反应系统会开启其促凋亡模块，该模块随后占据主导地位并触发细胞死亡。在肿瘤细胞中，内质网应激反应的细胞保护特性似乎被长期激活，因此即使在包括化疗在内的不利微环境条件下，也能为持续增殖和存活提供支持。然而，这些促生存途径主要在肿瘤细胞中的持续活性可能为主要针对这些肿瘤特异性条件的治疗干预提供一个机会窗口。合适的治疗方案将试图进一步加剧肿瘤细胞中这个已经启动的系统，以耗尽其保护特性，转而触发其促凋亡模块。越来越多的证据表明，这确实可以实现，并且可以通过使用特定的药物制剂来利用肿瘤特异性内质网应激。本综述将介绍这种有前景的癌症治疗新方法的原理以及代表性的内质网应激加剧化合物。
