A new therapeutic strategy for castration-resistant prostate cancer by off-target effects of naftopidil

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In the tumor microenvironment, carcinoma-associated fibroblasts (CAFs) are considered to play a critical role in the promotion of tumorigenesis. Recently, we have reported that the antiproliferative effect of naftopidil is not related to androgen sensitivity of the cells or the ? 1-adrenoceptor subtype expression in prostate cancer cells, suggesting that naftopidil has an off-target effect for various types of cells. To identify the cellular signal targets of naftopidil in CAFs, we used the SCADS inhibitor kits including more than 320 chemicals. Our results demonstrated that inhibitors against GSK-3 and CDK showed the similar effects with naftopidil in PCaSC-8. In addition, western blot analysis showed that the decreases of GSK-3 phosphorylation and CDK2 abundance were observed in naftopidil-treated cells. Finally, we suggest that GSK-3 and CDK2 might be important targets for induction of G1 cell cycle arrest by naftopidil treatment.