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

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.

• Authors: Shankar Varadarajan, Paramasivan Poornima, Mateus Milani, Krishne Gowda, Shantu Amin, Hong-Gang Wang, Gerald M Cohen
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 14 Pg. 12668-81 (May 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26059440 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Cyclic N-Oxides
• Indolizines
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Pyridinium Compounds
• Pyrroles
• marinopyrrole A
• dinaciclib

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Cyclic N-Oxides
• Flow Cytometry
• Gene Knockdown Techniques
• Humans
• Indolizines
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors)
• Pyridinium Compounds (pharmacology)
• Pyrroles (pharmacology)