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Targeting stroma in tumor tissues is an attractive new strategy for cancer treatment. We developedin vitrococulture system, in which the growth of human prostate cancer DU-145 cells is stimulated by prostate stromal cells (PrSC) through insulin-like growth factor I (IGF-I). Using this system, we have been searching for small molecules that inhibit tumor growth through modulation of tumor-stromal cell interactions. As a result, we have found that leucinostatins and atpenins, natural antifungal antibiotics, inhibit the growth of DU-145 cells cocultured with PrSC more strongly than that of DU-145 cells alone. In this study we examined the antitumor effects of these small moleculesin vitroandin vivo. When DU-145 cells were coinoculated with PrSC subcutaneously in nude mice, leucinostatin A was found to significantly suppress the tumor growth more than atpenin B. The antitumor effect of leucinostatin Ain vivowas not obtained against the tumors of DU-145 cells alone. RT-PCR experiments revealed that leucinostatin A specifically inhibited IGF-I expression in PrSC without effect on expressions of other IGF axis molecules. Leucinostatins and atpenins are known to abrogate mitochondrial functions. However, when we used mitochondrial DNA-depleted, pseudo-ρ0 cells, we found that one of leucinostain A actions certainly depended on mitochondrial function, but it actually inhibited the growth of DU-145 cells more strongly in coculture with pseudo-ρ0 PrSC and reduced IGF-I expression in pseudo-ρ0 PrSC. Taken together, our results suggested that leucinostatin A inhibited prostate cancer cell growth through reduction of IGF-I expression in PrSC.