leucinostatin-a and Prostatic-Neoplasms

Modulation of prostate stromal cells (PrSCs) within tumor tissues is gaining attention for the treatment of solid tumors. Using our original in vitro coculture system, we previously reported that leucinostatin (LCS)-A, a peptide mycotoxin, inhibited prostate cancer DU-145 cell growth through reduction of insulin-like growth factor 1 (IGF-I) expression in PrSCs. To further obtain additional bioactive compounds from LCS-A, we designed and synthesized a series of LCS-A derivatives as compounds that target PrSCs. Among the synthesized LCS-A derivatives, LCS-7 reduced IGF-I expression in PrSCs with lower toxicity to PrSCs and mice than LCS-A. As LCS-A has been suggested to interact with mitochondrial adenosine triphosphate (ATP) synthase, a docking study was performed to elucidate the mechanism of reduced IGF-I expression in the PrSCs. As expected, LCS-A and LCS-7 directly interacted with mitochondrial ATP synthase, and like LCS-A and LCS-7, other mitochondrial ATP synthase inhibitors also reduced the expression of IGF-I by PrSCs. Furthermore, LCS-A and LCS-7 significantly decreased the growth of mouse xenograft tumors. Based on these data, we propose that the mitochondrial ATP synthases-IGF-I axis of PrSCs plays a critical role on cancer cell growth and inhibition could be a potential anticancer target for prostate cancer.

Topics: Animals; Antimicrobial Cationic Peptides; Cell Line, Tumor; Coculture Techniques; Female; Humans; Insulin-Like Growth Factor I; Male; Mice; Mitochondria; Mitochondrial Proton-Translocating ATPases; Molecular Docking Simulation; Prostate; Prostatic Neoplasms; Stromal Cells; Xenograft Model Antitumor Assays

Targeting stroma in tumor tissues is an attractive new strategy for cancer treatment. We developed in vitro coculture 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 molecules in vitro and in 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 A in vivo was 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-rho(0) 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-rho(0) PrSC and reduced IGF-I expression in pseudo-rho(0) PrSC. Taken together, our results suggested that leucinostatin A inhibited prostate cancer cell growth through reduction of IGF-I expression in PrSC.

Topics: Animals; Antimicrobial Cationic Peptides; Antineoplastic Agents; Cell Division; Cell Line, Tumor; Coculture Techniques; DNA Primers; Humans; Male; Mice; Mice, Nude; Mitochondria; Mycotoxins; Peptides; Prostatic Neoplasms; Pyridones; Reverse Transcriptase Polymerase Chain Reaction; Stromal Cells