spectrum antitumor agent that induces cell cycle arrest, apoptosis, endoplasmic reticulum stress and autophagy

Indinavir, a human immunodeficiency virus (HIV) protease inhibitor, inhibits the growth of tumor cells in vivo but does not show any cytotoxicity against cancer cells in vitro. To optimize the anticancer activity of indinavir, two novel analogs, CH05-0 and CH05-10, were synthesized. CH05-10 was much more cytotoxic than indinavir and had similar cytotoxicity to nelfinavir, the one with the best anticancer activities among all HIV protease inhibitors examined. For 14 cell lines representing 10 different types of human malignancies, the 50% inhibitory concentration (IC50) values of CH05-10 are in the range of 4.64‐38.87 lM. Further detailed studies using the lung cancer cell line A549 as the model system showed that the effect of CH05-10 on the A549 cell line is both time- and dose-dependent. The CH05-10 treatment not only induced cell cycle arrest at G1 and caused caspase-dependent apoptosis, but also resulted in caspase-independent death via the induction of endoplasmic reticulum stress and unfolded protein response. These findings demonstrate that CH05-10, a novel indinavir analog, is a potent anticancer agent with pleiotropic effects. (Cancer Sci 2010; 101: 2644‐2651)