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Raptinal bypasses BAX, BAK, and BOK for mitochondrial outer membrane permeabilization and intrinsic apoptosis.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-07-19 , DOI: 10.1038/s41419-019-1790-z
Sina Heimer 1 , Gertrud Knoll 2 , Klaus Schulze-Osthoff 3, 4 , Martin Ehrenschwender 2
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-07-19 , DOI: 10.1038/s41419-019-1790-z
Sina Heimer 1 , Gertrud Knoll 2 , Klaus Schulze-Osthoff 3, 4 , Martin Ehrenschwender 2
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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.
中文翻译：
Raptinal绕过BAX，BAK和BOK进行线粒体外膜通透性和固有凋亡。
大多数抗肿瘤化学疗法通过激活线粒体控制的固有凋亡途径来消除癌细胞。其中，BAX，BAK和/或BOK充当线粒体外膜通透性（MOMP）的基本成孔执行者。BAX和BAK的激活阈值还与诱导MOMP所需的细胞凋亡刺激强度成反比，从而有效地确定细胞是否准备好进行凋亡。因此，“守门人” BAX和BAK成为治疗目标，但功能或遗传损失使BAX / BAK靶向策略容易失败。在这里，我们表明小分子Raptinal通过触发BAX / BAK / BOK独立方式的细胞色素c释放克服了这一局限。Raptinal通过快速激活内在的凋亡途径并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可以用于难以治疗的，具有固有凋亡途径中缺陷的癌症实体。
更新日期：2019-07-19
中文翻译：
Raptinal绕过BAX，BAK和BOK进行线粒体外膜通透性和固有凋亡。
大多数抗肿瘤化学疗法通过激活线粒体控制的固有凋亡途径来消除癌细胞。其中，BAX，BAK和/或BOK充当线粒体外膜通透性（MOMP）的基本成孔执行者。BAX和BAK的激活阈值还与诱导MOMP所需的细胞凋亡刺激强度成反比，从而有效地确定细胞是否准备好进行凋亡。因此，“守门人” BAX和BAK成为治疗目标，但功能或遗传损失使BAX / BAK靶向策略容易失败。在这里，我们表明小分子Raptinal通过触发BAX / BAK / BOK独立方式的细胞色素c释放克服了这一局限。Raptinal通过快速激活内在的凋亡途径并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可以用于难以治疗的，具有固有凋亡途径中缺陷的癌症实体。
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