Inhibition of XPO1 enhances cell death induced by ABT-199 in acute myeloid leukaemia via Mcl-1.

ABSTRACT: The antiapoptotic Bcl-2 family proteins play critical roles in resistance to chemotherapy in acute myeloid leukaemia (AML). The Bcl-2-selective inhibitor ABT-199 (Venetoclax) shows promising antileukaemic activity against AML, though Mcl-1 limits its antileukaemic activity. XPO1 is a nuclear exporter overexpressed in AML cells and its inhibition decreases Mcl-1 levels in cancer cells. Thus, we hypothesized that the XPO1-selective inhibitor KPT-330 (Selinexor) can synergize with ABT-199 to induce apoptosis in AML cells through down-regulation of Mcl-1. The combination of KPT-330 and ABT-199 was found to synergistically induce apoptosis in AML cell lines and primary patient samples and cooperatively inhibit colony formation capacity of primary AML cells. KPT-330 treatment decreased Mcl-1 pro

SUBMITTER: Luedtke DA 

PROVIDER: S-EPMC6237582 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature