AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death.

ABSTRACT: BH3 mimetics, including the BCL2/BCLX_L/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLX_L inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors. Cell fractionation and phosphoproteomic analyses suggest that sensitization

SUBMITTER: Jia J 

PROVIDER: S-EPMC11043078 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature