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 (compounds7a‑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 meridianinC derivatives, with compound7a achieving the most prominent reduction. Compound7a 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 compound7a on MV4‑11 cells was unrelated to PIM kinase inhibition. Moreover, compound7a induced apoptosis, caspase‑9and‑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. Compound7a 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, compound7a 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 compound7a‑induced apoptosis, caspase‑9and‑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 compound7a on MV4‑11 cells through regulation of caspase‑9and‑3, Bcl‑2, Mcl‑1, XIAP, eIF‑2α and S6 molecules.