Medical Research Council Group, Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, CF10 3AX, United Kingdom.
Drug Dev Res. 2017 Sep;78(6):313-318. doi: 10.1002/ddr.21405. Epub 2017 Aug 13.
Preclinical Research BH3 mimetics are anticancer agents that reproduce the spatial arrangement of the BH3 domain of Bcl-2 family proteins. Just like the BH3-only proteins, these compounds bind to the hydrophobic cleft of the pro-survival Bcl-2 members such as Bcl-2 or Bcl-xL, and disrupt their heterodimerization with pro-apoptotic Bax or Bak, sensitizing cells to chemotherapy. In recent years, it has become clear that Bcl-2 family proteins are engaged in regulation of intracellular Ca homeostasis, including Ca release from the intracellular stores as well as Ca fluxes across the plasma membrane. Given that BH3 mimetics shift the balance between the prosurvival and proapoptotic Bcl-2 members, they might indirectly exert effects on intracellular Ca signals. Indeed, it has been reported that some BH3 mimetics release Ca from the intracellular stores causing Ca overload in the cytosol. Therefore, the effects of any new BH3 mimetics on cellular Ca homeostasis should be tested before these compounds progress to clinical trials. Drug Dev Res 78 : 313-318, 2017. © 2017 Wiley Periodicals, Inc.
临床前研究 BH3 模拟物是抗癌药物，可复制 Bcl-2 家族蛋白 BH3 结构域的空间排列。与 BH3 仅有蛋白一样，这些化合物与生存 Bcl-2 成员（如 Bcl-2 或 Bcl-xL）的疏水区结合，并破坏它们与促凋亡 Bax 或 Bak 的异二聚化，使细胞对化疗敏感。近年来，人们已经清楚地认识到 Bcl-2 家族蛋白参与细胞内 Ca 稳态的调节，包括细胞内储存的 Ca 释放以及质膜的 Ca 流。鉴于 BH3 模拟物改变了生存和促凋亡 Bcl-2 成员之间的平衡，它们可能间接影响细胞内 Ca 信号。事实上，已经有报道称，一些 BH3 模拟物从细胞内储存库中释放 Ca，导致细胞质中的 Ca 超载。因此，在这些化合物进入临床试验之前，应该测试任何新的 BH3 模拟物对细胞内 Ca 稳态的影响。药物开发研究 78:313-318,2017. © 2017 年 Wiley 期刊出版公司
