Anti-survival and pro-apoptotic effects of meridianin C derivatives on MV4-11 human acute myeloid leukemia cells

Abstract

Meridianin C is a marine natural product with anticancer activity. Several meridianin C derivatives (compounds 7a-j) were recently synthesized, and their inhibitory effects on pro-viral integration site for Moloney murine leukemia virus (PIM) kinases, as well as their antiproliferative effects on human leukemia cells, were reported. However, the anti-leukemic effects and mechanisms of action of meridianin C and its derivatives remain largely unknown. The aim of the present study was to investigate the effects of meridianin C and its derivatives on MV4-11 human acute myeloid leukemia cell growth. The parent compound meridianin C did not markedly affect the viability and survival of MV4-11 cells. By contrast, MV4-11 cell viability and survival were reduced by meridianin C derivatives, with compound 7a achieving the most prominent reduction. Compound 7a notably inhibited the expression and activity of PIM kinases, as evidenced by reduced B-cell lymphoma-2 (Bcl-2)-associated death promoter phosphorylation at Ser112. However, meridianin C also suppressed PIM kinase expression and activity, and the pan-PIM kinase inhibitor AZD1208 only slightly suppressed the survival of MV4-11 cells. Thus, the anti-survival effect of compound 7a on MV4-11 cells was unrelated to PIM kinase inhibition. Moreover, compound 7a induced apoptosis, caspase-9 and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage, but did not affect death receptor (DR)-4 or DR-5 expression in MV4-11 cells. Compound 7a also induced the generation of cleaved Bcl-2, and the downregulation of myeloid cell leukemia (Mcl)-1 and X-linked inhibitor of apoptosis (XIAP) in MV4-11 cells. Furthermore, compound 7a increased eukaryotic initiation factor (eIF)-2α phosphorylation and decreased S6 phosphorylation, whereas GRP-78 expression was unaffected. Importantly, treatment with a pan-caspase inhibitor (z-VAD-fmk) significantly attenuated compound 7a-induced apoptosis, caspase-9 and -3 activation, PARP cleavage, generation of cleaved Bcl-2 and downregulation of Mcl-1 and XIAP in MV4-11 cells. Collectively, these findings demonstrated the strong anti-survival and pro-apoptotic effects of compound 7a on MV4-11 cells through regulation of caspase-9 and -3, Bcl-2, Mcl-1, XIAP, eIF-2α and S6 molecules.