Hafezi Shirin, Rahmani Mohamed
Research Institute of Medical & Health Sciences, University of Sharjah, P.O. Box 27272 Sharjah, United Arab Emirates.
Department of Basic Medical Sciences, College of Medicine, University of Sharjah, P.O. Box 27272 Sharjah, United Arab Emirates.
Cancers (Basel). 2021 Mar 14;13(6):1292. doi: 10.3390/cancers13061292.
The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advances, challenges focusing on drug resistance, and future perspectives for effective targeting the Bcl-2 family of proteins in cancer.
正常细胞和恶性细胞中主要的细胞死亡形式是细胞凋亡，这是一个由BCL-2蛋白家族高度调控的程序性过程。这包括抗凋亡蛋白（BCL-2、BCL-XL、MCL-1、BCLW和BFL-1）和促凋亡蛋白，促凋亡蛋白可分为两组：效应蛋白（BAX、BAK和BOK）和仅含BH3结构域的蛋白（BIM、BAD、NOXA、PUMA、BID、BIK、HRK）。值得注意的是，BCL-2抗凋亡蛋白在恶性细胞中常过度表达。虽然这为恶性细胞提供了生存优势并增强了它们的耐药能力，但它也为选择性杀死此类细胞的新型靶向治疗提供了机会。本综述全面概述了针对BCL-2蛋白的广泛临床前和临床研究，这些研究使用了各种BCL-2蛋白抑制剂，重点介绍了维奈克拉作为单一药物以及与其他治疗药物联合使用的情况。本综述还讨论了近期进展、聚焦耐药性的挑战以及在癌症中有效靶向Bcl-2蛋白家族的未来前景。
