Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
Cell Death Dis. 2019 Jul 19;10(8):556. doi: 10.1038/s41419-019-1790-z.
Most antineoplastic chemotherapies eliminate cancer cells through activation of the mitochondria-controlled intrinsic apoptotic pathway. Therein, BAX, BAK, and/or BOK function as the essential pore-forming executioners of mitochondrial outer membrane permeabilization (MOMP). The activation threshold of BAX and BAK also correlates inversely with the required strength of an apoptotic stimulus to induce MOMP and thereby effectively determines a cell's readiness to undergo apoptosis. Consequently, the 'gatekeepers' BAX and BAK emerged as therapeutic targets, but functional or genetic loss renders BAX/BAK-targeting strategies prone to fail. Here, we show that the small molecule Raptinal overcomes this limitation by triggering cytochrome c release in a BAX/BAK/BOK-independent manner. Raptinal exerts a dual cytotoxic effect on cancer cells by rapid activation of the intrinsic apoptotic pathway and simultaneous shutdown of mitochondrial function. Together with its efficacy to eliminate cancer cells in vivo, Raptinal could be useful in difficult-to-treat cancer entities harboring defects in the intrinsic apoptosis pathway.
大多数抗肿瘤化学疗法通过激活线粒体控制的内在凋亡途径来消除癌细胞。在此过程中，BAX、BAK 和/或 BOK 作为线粒体外膜通透性（MOMP）的必需孔形成执行者发挥作用。BAX 和 BAK 的激活阈值也与诱导 MOMP 所需的凋亡刺激强度呈反比，从而有效地决定了细胞发生凋亡的准备程度。因此，“守门员”BAX 和 BAK 成为治疗靶点，但功能或遗传缺失使 BAX/BAK 靶向策略容易失败。在这里，我们表明，小分子 Raptinal 通过以 BAX/BAK/BO 独立的方式触发细胞色素 c 释放来克服这一限制。Raptinal 通过快速激活内在凋亡途径和同时关闭线粒体功能对癌细胞产生双重细胞毒性作用。结合其在体内消除癌细胞的功效，Raptinal 可用于治疗内在凋亡途径存在缺陷的难治性癌症实体。
