文章：

模拟BH3药物对肿瘤细胞凋亡的调控

The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs

原文发布日期：2021-10-18

DOI: 10.1038/s41568-021-00407-4

类型: Review Article

开放获取: 否

英文摘要：

Apoptosis is a form of programmed cell death that is regulated by the balance between prosurvival and proapoptotic BCL-2 protein family members. Evasion of apoptosis is a hallmark of cancer that arises when this balance is tipped in favour of survival. One form of anticancer therapeutic, termed ‘BH3-mimetic drugs’, has been developed to directly activate the apoptosis machinery in malignant cells. These drugs bind to and inhibit specific prosurvival BCL-2 family proteins, thereby mimicking their interaction with the BH3 domains of proapoptotic BCL-2 family proteins. The BCL-2-specific inhibitor venetoclax is approved by the US Food and Drug Administration and many regulatory authorities worldwide for the treatment of chronic lymphocytic leukaemia and acute myeloid leukaemia. BH3-mimetic drugs targeting other BCL-2 prosurvival proteins have been tested in preclinical models of cancer, and drugs targeting MCL-1 or BCL-XL have advanced into phase I clinical trials for certain cancers. As with all therapeutics, efficacy and tolerability need to be carefully balanced to achieve a therapeutic window whereby there is significant anticancer activity with an acceptable safety profile. In this Review, we outline the current state of BH3-mimetic drugs targeting various prosurvival BCL-2 family proteins and discuss emerging data regarding primary and acquired resistance to these agents and approaches that may overcome this. We highlight issues that need to be addressed to further advance the clinical application of BH3-mimetic drugs, both alone and in combination with additional anticancer agents (for example, standard chemotherapeutic drugs or inhibitors of oncogenic kinases), for improved responses in patients with cancer.

摘要翻译： 

细胞凋亡是一种由促存活与促凋亡BCL-2蛋白家族成员之间的平衡调控的程序性细胞死亡形式。凋亡逃逸是癌症的重要特征，当这种平衡倾向于存活时就会发生。一类被称为"BH3模拟药物"的抗癌疗法被开发出来，直接激活恶性细胞中的凋亡机制。这类药物通过结合并抑制特定促存活BCL-2家族蛋白，模拟其与促凋亡BCL-2家族蛋白BH3结构域的相互作用。BCL-2特异性抑制剂维奈托克已获得美国食品药品监督管理局及全球众多监管机构批准，用于治疗慢性淋巴细胞白血病和急性髓系白血病。针对其他BCL-2促存活蛋白的BH3模拟药物已在癌症临床前模型中完成测试，其中靶向MCL-1或BCL-XL的药物已针对某些癌症进入I期临床试验。与所有疗法一样，需要仔细平衡疗效与耐受性以获得治疗窗口，即在可接受的安全性前提下实现显著抗癌活性。本综述概述了针对不同促存活BCL-2家族蛋白的BH3模拟药物现状，探讨了关于原发性与获得性耐药的新数据及潜在应对策略。我们重点阐述了推进BH3模拟药物临床应用需解决的问题，包括单药治疗及与其它抗癌药物（如标准化疗药物或致癌激酶抑制剂）联合使用，以改善癌症患者的治疗反应。

原文链接：

The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs