[Isoharringtonine induces apoptosis in human leukemia HL-60 cell]

Harringtonine (HT), homoharringtonine (HHT) and isoharringtonine (IHT) are cephalotaxine alkaloids with anticancer activities which were isolated from Cephalotaxus hainanensis indigenous to China. Since the 1970s, HT and HHT have been developed as effective anticancer drugs in China and have been used widely in the treatment of acute nonlymphoid leukemia and chronic granulocyte leukemia. Although IHT has the advantage of low toxicity, it has not been developed as an anticancer drug because of its very low content in the plant. The cell apoptosis induced by isoharringtonine was investigated in human acute promyelocytic leukemia HL-60 cells by agarose gel electrophoresis of DNA, flow cytometry and transmission electron microscopy. In these experiments IHT showed significant and rapid apoptotic inductive effect on HL-60 cells in both concentration- and time-dependent fashion. The characteristic apoptosis-related features could be seen in IHT treated HL-60 cells. Transmission electron microscopy of IHT treated HL-60 cells displayed chromatin condensation and aggregation under the nuclear membrane, nuclear fragmentation and apoptosis body formation. Typical DNA ladder in agarose gel electrophoresis and pre-G1 peak in flow cytometric analysis were also observed in the cells exposed to IHT. The apoptotic rate could reach 43.8% in the HL-60 cells treated for 120 minutes with IHT 10(-7) mol.L-1. The cytotoxicity of IHT paralleled with cell apoptosis indicating that the anticancer activity of IHT results from the induction of apoptosis. These results are important impetus for further research and development of IHT as an anticancer agent.