Synergism between arsenic trioxide and cyclopamine in the inhibition of PC3 cell survival via the Hedgehog signaling pathway

Abstract

Previous studies have shown that Hh signaling is overexpressed in the development and progression of prostate cancer (PCa), suggesting that Hh pathway inhibitors might be an effective strategy in the treatment of PCa. The combination of chemotherapeutic agents is one of the main approaches in cancer treatment, with the objective of improving efficacy. In the present study, we examined the effect of combing arsenic trioxide (ATO), a useful agent for Hedgehog-driven cancers, and cyclopamine (CYA), a classic Hh pathway inhibitor, on the suppression of PC3 cells (i.e., an androgen-independent PCa cell line). The combination of ATO and CYA more effectively inhibited the proliferation of PC3 cells than either single agent alone. In a xenograft mouse model, the combination of ATO and CYA significantly reduced tumor weight and volume in nude mice that were implanted with PC3 cells. The combination of ATO and CYA in PC3 cells resulted in a more distinct mode of Hh pathway inhibition and strengthened the S phase arrest. The present results indicate that a combination of ATO and CYA may be a rational strategy for treating PCa.