Oncotarget

Research Papers:

Drug repositioning of mevalonate pathway inhibitors as antitumor agents for ovarian cancer

Yusuke Kobayashi _, Hiroyasu Kashima, Yohan Suryo Rahmanto, Kouji Banno, Yu Yu, Yusuke Matoba, Keiko Watanabe, Moito Iijima, Takashi Takeda, Haruko Kunitomi, Miho Iida, Masataka Adachi, Kanako Nakamura, Kosuke Tsuji, Kenta Masuda, Hiroyuki Nomura, Eiichiro Tominaga and Daisuke Aoki

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Oncotarget. 2017; 8:72147-72156. https://doi.org/10.18632/oncotarget.20046

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Abstract

Yusuke Kobayashi1,2, Hiroyasu Kashima2,3, Yohan Suryo Rahmanto2, Kouji Banno1, Yu Yu2,4, Yusuke Matoba1, Keiko Watanabe1, Moito Iijima1, Takashi Takeda1, Haruko Kunitomi1, Miho Iida1, Masataka Adachi1, Kanako Nakamura1, Kosuke Tsuji1, Kenta Masuda1, Hiroyuki Nomura1, Eiichiro Tominaga1 and Daisuke Aoki1

1Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan

2Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America

3Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Nagano, Japan

4School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia

Correspondence to:

Yusuke Kobayashi, email: [email protected]

Keywords: ovarian cancer, drug repositioning, statin, bisphosphonate, mevalonate pathway

Received: July 03, 2017     Accepted: July 26, 2017     Published: August 07, 2017

ABSTRACT

Drug repositioning is an alternative strategy redirecting existing drugs for new disease. We have previously reported an antitumor effect of statins, antidyslipidemic drugs, on ovarian cancer in vitro and in vivo. In this study, we investigated the antitumor effects of other mevalonate pathway inhibitors and the mechanism of the antitumor effect from a metabolic perspective.

The effects of inhibitors of the mevalonate pathway on tumor cell growth were evaluated in vitro. Bisphosphonates that inhibit this pathway are commonly used as antiosteoporotic drugs, and antitumor effects of the bisphosphonate were examined in vitro and in vivo. Metabolites in SKOV3 ovarian cancer cells were analyzed before and after lovastatin treatment, using capillary electrophoresis-mass spectrometry.

All mevalonate pathway inhibitors showed concentration-dependent inhibitory effects on tumor cell growth. Particularly marked effects were obtained with inhibitors of farnesyltransferase and geranylgeranyltransferase. The bisphosphonate was also shown to have an antitumor effect in vivo. The expression of autophagy marker LC3A/3B was increased in cells after treatment. In metabolomics analysis, lovastatin treatment increased the metabolites involved in the tricarboxylic acid cycle while reducing the metabolites associated with glycolysis. Also it decreased glutathione and resulted to work with chemotherapeutic agents synergistically.

Inhibition at any point in the mevalonate pathway, and especially of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, suppresses growth of ovarian cancer cells. Inhibition of this pathway may induce autophagy, cause a shift to activation of the tricarboxylic acid cycle and enhance susceptibility to chemotherapy. Drug repositioning targeting mevalonate pathway for ovarian cancer deserves consideration for clinical application.


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