[HTML][HTML] Maritoclax and dinaciclib inhibit MCL-1 activity and induce apoptosis in both a MCL-1-dependent and-independent manner

S Varadarajan, P Poornima, M Milani, K Gowda… - Oncotarget, 2015 - ncbi.nlm.nih.gov
S Varadarajan, P Poornima, M Milani, K Gowda, S Amin, HG Wang, GM Cohen
Oncotarget, 2015ncbi.nlm.nih.gov
The anti-apoptotic BCL-2 family proteins are important targets for cancer chemotherapy.
Specific and potent inhibitors of the BCL-2 family, such as ABT-263 (navitoclax) and ABT-
199, are only effective against some members of the BCL-2 family but do not target MCL-1,
which is commonly amplified in tumors and associated with chemoresistance. In this report,
the selectivity and potency of two putative MCL-1 inhibitors, dinaciclib and maritoclax, were
assessed. Although both compounds induced Bax/Bak-and caspase-9-dependent …
Abstract
The anti-apoptotic BCL-2 family proteins are important targets for cancer chemotherapy. Specific and potent inhibitors of the BCL-2 family, such as ABT-263 (navitoclax) and ABT-199, are only effective against some members of the BCL-2 family but do not target MCL-1, which is commonly amplified in tumors and associated with chemoresistance. In this report, the selectivity and potency of two putative MCL-1 inhibitors, dinaciclib and maritoclax, were assessed. Although both compounds induced Bax/Bak-and caspase-9-dependent apoptosis, dinaciclib was more potent than maritoclax in downregulating MCL-1 and also in inducing apoptosis. However, the compounds induced apoptosis, even in cells lacking MCL-1, suggesting multiple mechanisms of cell death. Furthermore, maritoclax induced extensive mitochondrial fragmentation, and a Bax/Bak-but MCL-1-independent accumulation of mitochondrial reactive oxygen species (ROS), with an accompanying loss of complexes I and III of the electron transport chain. ROS scavengers, such as MitoQ, could not salvage maritoclax-mediated effects on mitochondrial structure and function. Taken together, our data demonstrate that neither dinaciclib nor maritoclax exclusively target MCL-1. Although dinaciclib is clearly not a specific MCL-1 inhibitor, its ability to rapidly downregulate MCL-1 may be beneficial in many clinical settings, where it may reverse chemoresistance or sensitize to other chemotherapeutic agents.
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