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Oncotarget. 2015 May 20;6(14):12668-81.

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

Author information

1
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
2
Department of Pharmacology, Pennsylvania State University College of Medicine, Pennsylvania, USA.
3
Department of Pediatrics, Pennsylvania State University College of Medicine, Pennsylvania, USA.

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.

KEYWORDS:

MCL-1; apoptosis; dinaciclib; maritoclax; mitochondria

PMID:
26059440
PMCID:
PMC4494965
DOI:
10.18632/oncotarget.3706
[Indexed for MEDLINE]
Free PMC Article

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