Effects of polyphenolic anthrone derivatives, resistomycin and hypercin, on apoptosis in human megakaryoblastic leukemia CMK-7 cell line.

Abstract

A tetrahydroxyanthrone derivative, resistomycin, was isolated from the culture broth of Streptomyces sulphureus and a similar polyphenolic dianthraquinone, hypericin, was isolated from an extract of Hypericum perforatum L. as modulators for apoptosis. Resistomycin inhibited apoptosis induced by actinomycin D (AD) with or without acceleration by colcemid (CL) in human megakaryoblastic leukemia CMK-7 cells, IC50 for inhibition against AD-induced apoptosis was about 0.5 microM and IC50 for inhibition against AD plus CL-induced apoptosis was about 1 microM. CL alone induced weak apoptosis in cells, which was enhanced by resistomycin. Hypericin did not inhibit AD-induced apoptosis and slightly enhanced CL-induced apoptosis. Emodin, corresponding to 1 of 2 anthraquinone units in hypericin, did not show any effect on this apoptotic system. AD-induced apoptosis was inhibited by the antioxidative flavonoid, luteolin (IC50 45 microM), and a protein kinase C (PKC) inhibitor, staurosporine (IC50 1.5 microM), but these compounds did not affect the CL-induced apoptosis. Hypericin and resistomycin scavenged superoxide anion radicals at the same rate as luteolin. PKC in CMK-7 cells was inhibited by hypericin and luteolin, but not significantly inhibited by resistomycin. This result suggests that the inhibition of AD-induced apoptosis by resistomycin is at least partly correlated with its antioxidative activity, and that the enhancement of CL-induced apoptosis by this compound depends upon the lack of PKC inhibitory activity. Though the mechanism is not clear, the enhancement of the CL-induced apoptosis might be hindered by PKC inhibition in the case of hypericin and luteolin.