Confounding off-target effects of BH3 mimetics at commonly used concentrations: MIM1, UMI-77, and A-1210477 View Full Text


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Article Info

DATE

2019-03

AUTHORS

David J. Mallick, Ryan S. Soderquist, Darcy Bates, Alan Eastman

ABSTRACT

Targeting anti-apoptotic BCL2 family proteins has become an attractive therapeutic strategy for many cancers, and the BCL2-selective inhibitor ABT-199 (venetoclax) has obtained clinical success. However, MCL1 can promote drug resistance and overall cancer cell survival. Thus, there is a critical need to develop an effective drug that antagonizes MCL1. However, most putative MCL1 inhibitors have been misclassified as they fail to directly inhibit MCL1 in cells, but rather induce the pro-apoptotic protein NOXA. We have investigated three putative MCL1 inhibitors: MIM1, UMI-77, and A-1210477. All three compounds were developed in cell-free assays and then found to be cytotoxic, and hence assumed to directly target MCL1 in cells. Here, we investigated whether these compounds directly inhibit MCL1 or inhibit MCL1 indirectly through the induction of NOXA. Both MIM1- and UMI-77-induced NOXA through the unfolded protein response pathway, and sensitized leukemia cells to ABT-199; this cytotoxicity was dependent on NOXA suggesting that these compounds do not directly target MCL1. A-1210477 was the only compound that did not induce NOXA, but it still sensitized cells to ABT-199. A-1210477 induced accumulation of MCL1 protein consistent with it binding and preventing MCL1 degradation. However, at concentrations used in several prior studies, A-1210477 also induced cytochrome c release, caspase activation, and apoptosis in a BAX/BAK-independent manner. Furthermore, the release of cytochrome c occurred without loss of mitochondrial membrane potential. This apoptosis was extremely rapid, sometimes occurring within 0.5-1 h. Hence, we have identified a novel mechanism of apoptosis that circumvents the known mechanisms of cytochrome c release. It remains to be determined whether these unexpected mechanisms of action of putative BH3 mimetics will have therapeutic potential. More... »

PAGES

185

References to SciGraph publications

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  • 2017-04-07. Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells in SIGNAL TRANSDUCTION AND TARGETED THERAPY
  • 2015-02. The Bcl-2 family: structures, interactions and targets for drug discovery in APOPTOSIS
  • 2017-01. Functional disparities among BCL-2 members in tonsillar and leukemic B-cell subsets assessed by BH3-mimetic profiling in CELL DEATH & DIFFERENTIATION
  • 2016-06. Venetoclax: First Global Approval in DRUGS
  • 2014-01. The putative BH3 mimetic S1 sensitizes leukemia to ABT-737 by increasing reactive oxygen species, inducing endoplasmic reticulum stress, and upregulating the BH3-only protein NOXA in APOPTOSIS
  • 2012-11. JC-1: alternative excitation wavelengths facilitate mitochondrial membrane potential cytometry in CELL DEATH & DISEASE
  • 2015-01. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax) in CELL DEATH & DISEASE
  • 2003-06. Mitochondrial membrane potential regulates matrix configuration and cytochrome c release during apoptosis in CELL DEATH & DIFFERENTIATION
  • 2013-11. Evaluation and critical assessment of putative MCL-1 inhibitors in CELL DEATH & DIFFERENTIATION
  • 1998-12. Simultaneous release of adenylate kinase and cytochrome c in cell death in CELL DEATH & DIFFERENTIATION
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    http://scigraph.springernature.com/pub.10.1038/s41419-019-1426-3

    DOI

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    DIMENSIONS

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    PUBMED

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