Autophagy promotes apoptosis induction through repressed nitric oxide generation in the treatment of human breast cancer MCF-7 cells with L-A03, a dihydroartemisinin derivative

Abstract

The scaffold of 4-quinolylhydrazone was attached to dihydroartemisinin by the combination and bioisosterism principles to get a dihydroartemisinin derivative called L-A03. The previous study demonstrated that L-A03 inhibited cysteine protease falcipain-2 of Plasmodium falciparum. Our preliminary assay showed that this compound exhibited significant antitumor activity in some cancer cell lines. Besides, cytotoxicity was low against human peripheral blood mononuclear cells. These suggest that L-A03 could be used as a potent antitumor drug. This study indicated that L-A03 induced both apoptosis and autophagy in human breast cancer MCF-7 cells. L-A03 caused autophagy prior to the onset of apoptotic cell death. In the presence of chloroquine, an autophagic inhibitor, L-A03-induced apoptosis was attenuated, indicating that autophagy was indispensable for apoptosis induction. Nitric oxide generation blocked apoptotic cell death, but did not affect autophagy, suggesting that autophagy may take place in the upstream of nitric oxide generation. Moreover, autophagy decreased the generation of nitric oxide. This study provided a new insight on the mechanism of anti-tumor effect of L-A03.