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

Varadarajan, Shankar ORCID: 0000-0002-8827-6567, Poornima, Paramasivan, Milani, Mateus, Gowda, Krishne, Amin, Shantu, Wang, Hong-Gang and Cohen, Gerry (2015) Maritoclax and Dinaciclib inhibit MCL-1 activity and induce apoptosis in both a MCL-1-dependent and -independent manner. Oncotarget, 6 (14). pp. 12668-12681.

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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.

Item Type:	Article
Uncontrolled Keywords:	dinaciclib, maritoclax, MCL-1, apoptosis, mitochondria
Depositing User:	Symplectic Admin
Date Deposited:	28 Jul 2015 12:03
Last Modified:	15 Dec 2022 12:19
DOI:	10.18632/oncotarget.3706
Publisher's Statement :	This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,distribution, and reproduction in any medium, provided the original author and source are credited.
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/2018084