Involvement of the mevalonate pathway in the antiproliferative effect             of zoledronate on ACHN renal cell carcinoma cells.
Renal cell carcinoma (RCC) has been shown to be resistant to chemotherapy             and radiotherapy. In order to examine the potential of zoledronate (ZOL), a bisphosphonate,             as an anticancer agent, we investigated the effects of ZOL on RCC cells and the             involvement of the mevalonate pathway in antiproliferative effects, as well as             the effects of ZOL administration on mice inoculated with RCC. ACHN cells were             used and cell viability was measured via intra-cellular reductase activity. Chromatin             condensation was detected by Hoechst 33342 staining. Proteins were detected by             western blot analysis. Tumor volume was measured bidimensionally in mice inoculated             with ACHN cells after vehicle or ZOL subcutaneous administration. ZOL exhibited             antiproliferative effects with an IC50 value of 2.29±0.53 µM in ACHN cells and             chromatin condensation was observed when treated with ZOL. Farnesol (FOH) and             geranylgeraniol (GGOH), precursors of farnesyl pyrophosphate and geranylgeranyl             pyrophosphate, exhibited potency to rescue cells treated with ZOL. Additionally,             Ras and RhoA proteins located in the membrane fraction decreased when treated             with ZOL and recovered by FOH or GGOH treatment, suggesting that ZOL inhibited             the mevalonate pathway, thereby suppressing the translocation of prenylated Ras             and RhoA proteins to membrane fractions. An in vivo study showed the inhibitory             potential of ZOL on tumor growth in mice without changes in body weight. Our study             showed that ZOL could be useful as an anticancer agent for the treatment of RCC,             and the mevalonate pathway could be an efficient target for novel therapeutic             agents against RCC.
Department of Clinical Pharmacy, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyogo 663-8179, Japan.
Megumi
M
Fujita
Makiko
M
Tohi
Kyoko
K
Sawada
Yasuhiro
Y
Yamamoto
Tsutomu
T
Nakamura
Tatsurou
T
Yagami
Motohiro
M
Yamamori
Noboru
N
Okamura
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D008798:Mevalonic Acid