Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
Apoptosis. 2023 Feb;28(1-2):20-38. doi: 10.1007/s10495-022-01780-7. Epub 2022 Nov 7.
Acquired resistance to cell death is a hallmark of cancer. The BCL-2 protein family members play important roles in controlling apoptotic cell death. Abnormal over-expression of pro-survival BCL-2 family members or abnormal reduction of pro-apoptotic BCL-2 family proteins, both resulting in the inhibition of apoptosis, are frequently detected in diverse malignancies. The critical role of the pro-survival and pro-apoptotic BCL-2 family proteins in the regulation of apoptosis makes them attractive targets for the development of agents for the treatment of cancer. This review describes the roles of the various pro-survival and pro-apoptotic members of the BCL-2 protein family in normal development and organismal function and how defects in the control of apoptosis promote the development and therapy resistance of cancer. Finally, we discuss the development of inhibitors of pro-survival BCL-2 proteins, termed BH3-mimetic drugs, as novel agents for cancer therapy.
获得性细胞死亡抵抗是癌症的一个标志。BCL-2 蛋白家族成员在控制细胞凋亡中起着重要作用。在各种恶性肿瘤中，经常检测到抗凋亡的生存促进 BCL-2 家族成员的异常过表达或促凋亡 BCL-2 家族蛋白的异常减少，这两者均导致细胞凋亡的抑制。生存促进和促凋亡 BCL-2 家族蛋白在凋亡调控中的关键作用使它们成为开发抗癌药物的有吸引力的靶标。这篇综述描述了 BCL-2 蛋白家族的各种生存促进和促凋亡成员在正常发育和机体功能中的作用，以及凋亡控制缺陷如何促进癌症的发展和治疗耐药性。最后，我们讨论了生存促进 BCL-2 蛋白抑制剂的开发，称为 BH3 模拟药物，作为癌症治疗的新型药物。
