title: 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.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Shankar
authors.initials: S
authors.lastname: Varadarajan
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Paramasivan
authors.initials: P
authors.lastname: Poornima
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Mateus
authors.initials: M
authors.lastname: Milani
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Pennsylvania, USA.
authors.forename: Krishne
authors.initials: K
authors.lastname: Gowda
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Pennsylvania, USA.
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Pennsylvania, USA.|Department of Pediatrics, Pennsylvania State University College of Medicine, Pennsylvania, USA.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Cohen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D007212:Indolizines; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011726:Pyridinium Compounds; D011758:Pyrroles; C528298:marinopyrrole A; C553669:dinaciclib
keywords: MCL-1; apoptosis; dinaciclib; maritoclax; mitochondria