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.
Nakajima
Hiroo
H
Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kawaramachi, Hirokoji, Kamikyo-ku, Kyoto 602-0841, Japan.
Magae
Junji
J
Tsuruga
Mie
M
Sakaguchi
Koichi
K
Fujiwara
Ikuya
I
Mizuta
Mitsuhiko
M
Sawai
Kiyoshi
K
Yamagishi
Hisakazu
H
Mizuta
Naruhiko
N
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D004164:Diphosphonates / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
D018906:Antineoplastic Agents, Alkylating; D004164:Diphosphonates; D007093:Imidazoles; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C087958:YM 529; C004808:farnesyl pyrophosphate; D008798:Mevalonic Acid