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, Gerald M. Cohen

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)12668-12681
Number of pages14
JournalOncotarget
Volume6
Issue number14
DOIs
StatePublished - Jan 1 2015

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Apoptosis
Reactive Oxygen Species
Down-Regulation
Electron Transport Complex I
Caspase 9
Electron Transport Complex III
Neoplasms
Cell Death
marinopyrrole A
dinaciclib
Drug Therapy
Proteins
navitoclax

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Varadarajan, Shankar ; Poornima, Paramasivan ; Milani, Mateus ; Gowda, Krishne ; Amin, Shantu ; Wang, Hong-Gang ; Cohen, Gerald M. / Maritoclax and dinaciclib inhibit MCL-1 activity and induce apoptosis in both a MCL-1-dependent and -independent manner. In: Oncotarget. 2015 ; Vol. 6, No. 14. pp. 12668-12681.
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Maritoclax and dinaciclib inhibit MCL-1 activity and induce apoptosis in both a MCL-1-dependent and -independent manner. / Varadarajan, Shankar; Poornima, Paramasivan; Milani, Mateus; Gowda, Krishne; Amin, Shantu; Wang, Hong-Gang; Cohen, Gerald M.

In: Oncotarget, Vol. 6, No. 14, 01.01.2015, p. 12668-12681.

Research output: Contribution to journalArticle

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AU - Varadarajan, Shankar

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