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Renal cell carcinoma (RCC) has been shown to be resistant to chemotherapyand 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 theinvolvement of the mevalonate pathway in antiproliferative effects, as well asthe effects of ZOL administration on mice inoculated with RCC. ACHN cells wereused and cell viability was measured via intra-cellular reductase activity. Chromatincondensation was detected by Hoechst 33342 staining. Proteins were detected bywestern blot analysis. Tumor volume was measured bidimensionally in mice inoculatedwith ACHN cells after vehicle or ZOL subcutaneous administration. ZOL exhibitedantiproliferative effects with an IC50 value of 2.29±0.53 µM in ACHN cells andchromatin condensation was observed when treated with ZOL. Farnesol (FOH) andgeranylgeraniol (GGOH), precursors of farnesyl pyrophosphate and geranylgeranylpyrophosphate, exhibited potency to rescue cells treated with ZOL. Additionally,Ras and RhoA proteins located in the membrane fraction decreased when treatedwith ZOL and recovered by FOH or GGOH treatment, suggesting that ZOL inhibitedthe mevalonate pathway, thereby suppressing the translocation of prenylated Rasand RhoA proteins to membrane fractions. An in vivo study showed the inhibitorypotential of ZOL on tumor growth in mice without changes in body weight. Our studyshowed 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 therapeuticagents against RCC.

Involvement of the mevalonate pathway in the antiproliferative effect of zoledronate on ACHN renal cell carcinoma cells