Induction of mitochondria-dependent apoptosis through the inhibition of mevalonate pathway in human breast cancer cells by YM529, a new third generation bisphosphonate

YM529, a new third generation bisphosphonate, induced apoptosis of a human breast cancer cell line, MX-1. Cytotoxic activity of YM529 was more potent than that of incadronate. YM529 activated caspase-9, but not caspase-8, and induced the release of cytochrome c into cytosol. YM529 increased Bax expression and decreased Bcl-2 expression, while it did not induce caspase-8-dependent Bid truncation. Farnesyl pyrophosphate prevented YM529-mediated cytotoxicity. These results suggest that YM529 is a potent therapeutic agent for human breast cancers, activating the mitochondria-dependent apoptotic pathway through the inhibition of protein farnesylation.