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.

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

“…reports showing that MCL-1 expression was decreased by dinaciclib in various cancer cells (Chen, et al 2015, Fu, et al 2011, Gregory, et al 2015, Varadarajan, et al 2015. As shown in Figure 3F, we confirmed that dinaciclib inhibited both MCL-1 and BCL-xL in stimulated primary cells and MEC-1.…”

The selectivity of Marinopyrrole A to induce apoptosis in MCL1highBCL2low expressing myeloma cells is related to its ability to impair protein translation

“…Thus, while Marinopyrrole A sensitivity correlates with BCL2 family protein expression profile, it is clearly not a specific MCL1 inhibitor. Altogether, our results are in agreement with other reports showing that Marinopyrrole A fails to show strict selective cytotoxicity for MCL1‐dependent cell lines (Eichhorn et al , ; Varadarajan et al , ). Given that MCL1 level is known to be an important chemoresistance factor, particularly for BH3 mimetic drugs, such as Navitoclax and Venetoclax (Bodet et al , ), the ability of Marinopyrrole A to decrease MCL1 levels by multiple mechanisms suggests that it will be an interesting compound to enhance drug efficiency, as previously demonstrated in melanoma cells (Pandey et al , ).…”

Pathways and mechanisms of venetoclax resistance

“…[126] Maritoclax was reported to be a selective MCL-1 antagonist able to disrupt the BIM-MCL-1 interaction and promote proteasomal degradation of MCL-1 that markedly enhanced the efficacy of ABT-737 against multiple hematologic malignancies,[127] but subsequent studies have shown that the compound likely also acts through mechanisms independent of MCL-1. [128] Of the early putative MCL-1 inhibitors, TW-37 is one that induces apoptosis in a BAK-dependent manner in cells that require MCL-1 for survival, but apoptosis induced by TW-37 is also, in part, dependent on NOXA. [129] (-)BI97D6 is a pan-BCL-2 family inhibitor that was shown to disrupt Mcl-1/Bim and Bcl-2/Bax interactions and induce BAX/BAK-dependent apoptosis in AML cells, overcoming MCL-1-mediated resistance as well as extrinsic, microenvironmental resistance.…”