Repurposing Cationic Amphiphilic Drugs and Derivatives to Engage Lysosomal Cell Death in Cancer Treatment.
Repurposing Cationic Amphiphilic Drugs and Derivatives to Engage Lysosomal Cell Death in Cancer Treatment.
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DOI：
10.3389/fonc.2020.605361
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发表时间：
2020
影响因子：
4.7
通讯作者：
Carraway KL 3rd
中科院分区：
文献类型：
--
作者：
Hu M;Carraway KL 3rd
在成功的癌症治疗中，一个主要的令人困惑的问题是存在抵抗治疗药物和方案的肿瘤细胞群。虽然已经付出了巨大的努力来了解对每种传统和靶向治疗的耐药性背后的生化机制，但如果认识到现有的抗癌药物几乎完全通过细胞凋亡来诱导其细胞毒作用，那么可能会出现一个更广泛的方法来解决这个问题。考虑到癌细胞用来颠覆凋亡死亡的多种机制，一个有吸引力的替代方法是利用程序化的坏死机制来避开对凋亡诱导剂的治疗抵抗。溶酶体膜通透性(LMP)是溶酶体膜通透性降低所致的一种程序性坏死性细胞死亡机制。溶酶体组分在LMP作用下释放到胞浆中，触发生化级联反应，导致质膜破裂和坏死细胞死亡。有趣的是，细胞转化的过程似乎使肿瘤细胞的限制性溶酶体膜比未转化的细胞更脆弱，为药物开发提供了一个潜在的治疗窗口。在这里，我们概述了LMP和LCD的概念，并讨论了开发代理以参与这些过程的策略。重要的是，现有的阳离子两亲性药物，如抗抑郁药、抗生素、抗心律失常药和利尿剂，有可能被改变用途，以使LCD参与耐药肿瘤细胞群。
A major confounding issue in the successful treatment of cancer is the existence of tumor cell populations that resist therapeutic agents and regimens. While tremendous effort has gone into understanding the biochemical mechanisms underlying resistance to each traditional and targeted therapeutic, a broader approach to the problem may emerge from the recognition that existing anti-cancer agents elicit their cytotoxic effects almost exclusively through apoptosis. Considering the myriad mechanisms cancer cells employ to subvert apoptotic death, an attractive alternative approach would leverage programmed necrotic mechanisms to side-step therapeutic resistance to apoptosis-inducing agents. Lysosomal cell death (LCD) is a programmed necrotic cell death mechanism that is engaged upon the compromise of the limiting membrane of the lysosome, a process called lysosomal membrane permeabilization (LMP). The release of lysosomal components into the cytosol upon LMP triggers biochemical cascades that lead to plasma membrane rupture and necrotic cell death. Interestingly, the process of cellular transformation appears to render the limiting lysosomal membranes of tumor cells more fragile than non-transformed cells, offering a potential therapeutic window for drug development. Here we outline the concepts of LMP and LCD, and discuss strategies for the development of agents to engage these processes. Importantly, the potential exists for existing cationic amphiphilic drugs such as antidepressants, antibiotics, antiarrhythmics, and diuretics to be repurposed to engage LCD within therapy-resistant tumor cell populations.
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