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

Nakajima, Hiroo; Magae, Junji; Tsuruga, Mie; Sakaguchi, Koichi; Fujiwara, Ikuya; Mizuta, Mitsuhiko; Sawai, Kiyoshi; Yamagishi, Hisakazu; Mizuta, Naruhiko

doi:10.1016/j.canlet.2007.01.008

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Volume 253, Issue 1 , Pages 89-96, 8 August 2007

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

Hiroo Nakajima
- Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kawaramachi, Hirokoji, Kamikyo-ku, Kyoto 602-0841, Japan
Junji Magae
- Department of Biotechnology, Institute of Research and Innovation, 1201 Takada, Kashiwa 277-0861, Japan
- Corresponding author. Tel.: +81 4 7144 9142; fax: +81 4 7144 9007.
Mie Tsuruga
- Department of Biotechnology, Institute of Research and Innovation, 1201 Takada, Kashiwa 277-0861, Japan
Koichi Sakaguchi
- Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kawaramachi, Hirokoji, Kamikyo-ku, Kyoto 602-0841, Japan
Ikuya Fujiwara
- Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kawaramachi, Hirokoji, Kamikyo-ku, Kyoto 602-0841, Japan
Mitsuhiko Mizuta
- Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kawaramachi, Hirokoji, Kamikyo-ku, Kyoto 602-0841, Japan
Kiyoshi Sawai
- Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kawaramachi, Hirokoji, Kamikyo-ku, Kyoto 602-0841, Japan
Hisakazu Yamagishi
- Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Kawaramachi, Hirokoji, Kamikyo-ku, Kyoto 602-0841, Japan
Naruhiko Mizuta
- Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kawaramachi, Hirokoji, Kamikyo-ku, Kyoto 602-0841, Japan

Received 15 November 2006; accepted 15 January 2007.

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.

Keywords: Apoptosis, Breast cancer, YM529, Bcl-2, Bax, Farnesylation