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

// Yusuke Kobayashi 1, 2 , Hiroyasu Kashima 2, 3 , Yohan Suryo Rahmanto 2 , Kouji Banno 1 , Yu Yu 2, 4 , Yusuke Matoba 1 , Keiko Watanabe 1 , Moito Iijima 1 , Takashi Takeda 1 , Haruko Kunitomi 1 , Miho Iida 1 , Masataka Adachi 1 , Kanako Nakamura 1 , Kosuke Tsuji 1 , Kenta Masuda 1 , Hiroyuki Nomura 1 , Eiichiro Tominaga 1 and Daisuke Aoki 1 1 Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan 2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America 3 Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Nagano, Japan 4 School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia Correspondence to: Yusuke Kobayashi, email: kobax@a2.keio.jp 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.