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

• Published in: Cancer letters Vol. 253; no. 1; pp. 89 - 96
• Main Authors: Nakajima, Hiroo, Magae, Junji, Tsuruga, Mie, Sakaguchi, Koichi, Fujiwara, Ikuya, Mizuta, Mitsuhiko, Sawai, Kiyoshi, Yamagishi, Hisakazu, Mizuta, Naruhiko
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 08.08.2007; Elsevier Limited
• Subjects: Antineoplastic Agents, Alkylating - pharmacology; Apoptosis; Apoptosis - drug effects; Bax; Bcl-2; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer therapies; Cell culture; Deoxyribonucleic acid; Diphosphonates - pharmacology; DNA; Drug Screening Assays, Antitumor; Enzymes; Farnesylation; Hematology, Oncology and Palliative Medicine; Humans; Imidazoles - pharmacology; Lipids; Mevalonic Acid - metabolism; Mitochondria; Mitochondria - metabolism; Mortality; Nitrogen; Permeability; Polyisoprenyl Phosphates - pharmacology; Proteins; Sesquiterpenes - pharmacology; Signal Transduction - drug effects; YM529; Bcl-2; Bax; YM529; Breast cancer; Farnesylation; Apoptosis
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2007.01.008

Abstract 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.