Part2_Petromurin C induces protective autophagy and apoptosis in FLT3-ITD-positive AML: synergy with gilteritinib

Treatment of acute myeloid leukemia (AML) remains inefficient due to drug resistance and relapse, particularly in patients with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD). Marine-derived natural products have recently been used for drug development against AML. We show here that petromurin C, isolated from the culture extract of the marine-derived fungus Aspergillus candidus KUFA0062, which was isolated from the marine sponge Epipolasis sp., induces early autophagy followed by apoptotic cell death via activation of the intrinsic cell death pathway concomitant with mitochondrial stress and downregulation of Mcl-1 in FLT3-ITD mutated MV4-11 cells. Moreover, petromurin C synergized with the clinically-used FLT3 inhibitor gilteritinib at sub-toxic concentrations. Altogether our results suggest that petromurin C could act as an anti-leukemic agent alone or in combination with gilteritinib.