Oncotarget

Research Papers:

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

Shankar Varadarajan _, Paramasivan Poornima, Mateus Milani, Krishne Gowda, Shantu Amin, Hong-Gang Wang and Gerald M. Cohen

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Oncotarget. 2015; 6:12668-12681. https://doi.org/10.18632/oncotarget.3706

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Abstract

Shankar Varadarajan1, Paramasivan Poornima1, Mateus Milani1, Krishne Gowda2, Shantu Amin2, Hong-Gang Wang2,3 and Gerald M. Cohen1

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

Correspondence to:

Shankar Varadarajan, email:

Keywords: dinaciclib, maritoclax, MCL-1, apoptosis, mitochondria

Received: January 14, 2015 Accepted: March 05, 2015 Published: March 30, 2015

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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