Sabutoclax (BI97C1) and BI112D1, putative inhibitors of MCL-1, induce mitochondrial fragmentation either upstream of or independent of apoptosis.
Sabutoclax (BI97C1) and BI112D1, putative inhibitors of MCL-1, induce mitochondrial fragmentation either upstream of or independent of apoptosis.
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DOI：
10.1593/neo.13230
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发表时间：
2013-05
期刊：
影响因子：
4.8
通讯作者：
S. Varadarajan;M. Butterworth;Jun Wei;M. Pellecchia;D. Dinsdale;G. Cohen
中科院分区：
文献类型：
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作者：
S. Varadarajan;M. Butterworth;Jun Wei;M. Pellecchia;D. Dinsdale;G. Cohen
由于在几种癌症中观察到高水平的抗凋亡B细胞淋巴瘤2（BCL-2）家族成员，因此一直在努力开发BCL 2家族的抑制剂作为化疗剂。在BCL-2家族的不同成员中，髓样细胞白血病序列1（MCL-1）通常在人类肿瘤中扩增，并且与其复发和化学抗性相关。因此，正在设计MCL-1的特异性抑制剂来治疗耐药肿瘤。然而，越来越多的证据表明BCL-2家族的其他非凋亡作用，从离子稳态和自噬到亚细胞器（包括内质网和线粒体）中的分裂融合动力学调节。在这项研究中，我们表征了两种新的推定的MCL-1抑制剂，BI 97 C1（Sabutoclax）和BI 112 D1，在诱导凋亡的BAX/BAK依赖的方式和MCL-1依赖的系统中的特异性。除了它们是促凋亡的，这些抑制剂还引起增强的线粒体片段化，伴随视神经萎缩1（OPA 1）的时间依赖性丧失，表明线粒体融合的损害。这种线粒体片段化独立于动力蛋白相关蛋白1（DRP 1）介导的分裂活性发生，并且与大多数凋亡刺激不同，其发生在BAX、BAK和其他仅BH 3蛋白的上游和/或独立于BAX、BAK和其他仅BH 3蛋白。此外，这种线粒体片段化发生迅速，并先于其他凋亡标志，包括线粒体膜电位的丧失和细胞色素c的释放。虽然这样的线粒体碎片并没有耗尽总细胞三磷酸腺苷（ATP）或改变其他线粒体复合物，有显着积累的活性氧。
Owing to the high levels of antiapoptotic B-cell lymphoma 2 (BCL-2) family members observed in several cancers, there has been a major effort to develop inhibitors of the BCL2-family as chemotherapeutic agents. Of the different members in the BCL-2 family, myeloid cell leukemia sequence 1 (MCL-1) is commonly amplified in human tumors and is associated with their relapse and chemoresistance. As a result, specific inhibitors of MCL-1 are being designed to treat resistant tumors. However, there is increasing evidence for other nonapoptotic roles of the BCL-2 family, ranging from ionic homeostasis and autophagy to the regulation of fission-fusion dynamics in subcellular organelles, including the endoplasmic reticulum and mitochondria. In this study, we characterize the specificity of two novel putative MCL-1 inhibitors, BI97C1 (Sabutoclax) and BI112D1, in inducing apoptosis in a BAX/BAK-dependent manner and in an MCL-1-dependent system. In addition to their being proapoptotic, these inhibitors also cause enhanced mitochondrial fragmentation that accompanies a time-dependent loss of optic atrophy 1 (OPA1), suggesting an impairment of mitochondrial fusion. This mitochondrial fragmentation occurs independently of dynamin-related protein 1 (DRP1)-mediated fission activity and, unlike most apoptotic stimuli, occurs upstream of and/or independent of BAX, BAK, and other BH3-only proteins. Furthermore, this mitochondrial fragmentation occurred rapidly and preceded other hallmarks of apoptosis, including the loss in mitochondrial membrane potential and the release of cytochrome c. Although such mitochondrial fragmentation did not deplete total cellular adenosine triphosphate (ATP) or alter other mitochondrial complexes, there was significant accumulation of reactive oxygen species.