Sabutoclax (BI97C1) and BI112D1, Putative Inhibitors of MCL-1, Induce Mitochondrial Fragmentation Either Upstream of or Independent of Apoptosis

• Published in: Neoplasia (New York, N.Y.) Vol. 15; no. 5; pp. 568 - IN22
• Main Authors: Varadarajan, Shankar, Butterworth, Michael, Wei, Jun, Pellecchia, Maurizio, Dinsdale, David, Cohen, Gerald M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2013; Elsevier
• Subjects: Adenosine Triphosphate - metabolism; Aniline Compounds - pharmacology; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line; Dynamins; Gossypol - analogs & derivatives; Gossypol - pharmacology; GTP Phosphohydrolases - metabolism; Humans; Membrane Potential, Mitochondrial - drug effects; Mice; Microtubule-Associated Proteins - metabolism; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Dynamics - drug effects; Mitochondrial Proteins - metabolism; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Oncology; Reactive Oxygen Species - metabolism; Sulfonamides - pharmacology; DKO; double knockout; ROS; reactive oxygen species
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.13230

Abstract 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.