Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Pharmacol Ther. 2022 Feb;230:107943. doi: 10.1016/j.pharmthera.2021.107943. Epub 2021 Jun 25.
Cell death by apoptosis and permanent cell cycle arrest by senescence serve as barriers to the development of cancer. Chemotherapeutic agents not only induce apoptosis, they can also induce senescence known as therapy-induced senescence (TIS). There are, however, controversies whether TIS improves or worsens therapeutic outcome. Unlike apoptosis, which permanently removes cancer cells, senescent cells are metabolically active, and can contribute to tumor progression and relapse. If senescent cells are not cleared by the immune system or if cancer cells escape senescence, they may acquire resistance to apoptotic stimuli and become highly aggressive. Thus, there have been significant efforts in developing senolytics, drugs that target these pro-survival molecules to eliminate senescent cells. The anti-apoptotic Bcl-2 family proteins not only protect against cell death by apoptosis, but they also allow senescent cells to survive. While combining senolytics with chemotherapeutic drugs is an attractive approach, there are also limitations. Moreover, members of the Bcl-2 family have distinct effects on apoptosis and senescence. The purpose of this review article is to discuss recent literatures on how members of the Bcl-2 family orchestrate the interplay between apoptosis and senescence, and the challenges and progress in targeting these Bcl-2 family proteins for cancer therapy.
细胞凋亡和衰老导致的细胞周期永久停滞是癌症发展的障碍。化疗药物不仅能诱导细胞凋亡，还能诱导衰老，即治疗诱导的衰老（TIS）。然而，TIS 是否能改善或恶化治疗效果存在争议。与永久性去除癌细胞的细胞凋亡不同，衰老细胞代谢活跃，可能促进肿瘤进展和复发。如果衰老细胞不能被免疫系统清除，或者癌细胞逃避衰老，它们可能会对凋亡刺激产生抗性并变得高度侵袭性。因此，人们一直在努力开发衰老细胞清除剂，即靶向这些生存促进分子以清除衰老细胞的药物。抗凋亡 Bcl-2 家族蛋白不仅能防止细胞凋亡，还能使衰老细胞存活。虽然将衰老细胞清除剂与化疗药物联合使用是一种有吸引力的方法，但也存在局限性。此外，Bcl-2 家族成员对细胞凋亡和衰老有不同的影响。本文的目的是讨论最近关于 Bcl-2 家族成员如何协调细胞凋亡和衰老之间相互作用的文献，以及针对这些 Bcl-2 家族蛋白进行癌症治疗的挑战和进展。
