Apoptosis and modulation of cell cycle control by synthetic derivatives of ursodeoxycholic acid and chenodeoxycholic acid in human prostate cancer cells

The effects of synthetic derivatives of ursodeoxycholic acid (UDCA), HS-1183, and chenodeoxycholic acid (CDCA), HS-1199 and HS-1200, on the proliferation of human prostate carcinoma PC-3 cells were investigated. Whereas CDCA and UDCA had no effects on the growth of cells in a concentration range we have tested, HS-1199 and HS-1200 completely inhibited the cell proliferation, and HS-1183 showed a weak inhibitory activity. This proliferation-inhibitory effect of the synthetic bile acid derivatives was due to the induction of apoptosis, which was confirmed by observing DNA fragmentation, chromatin condensation and cleavage of PARP. Flow cytometric analysis also revealed that the synthetic bile acid derivatives arrested the cell cycle progression at the G1 phase, which effects were associated with inhibition of phosphorylation of pRB and enhanced binding of pRB and E2F-1. They also suppressed Cdk2 and cyclin E-dependent kinase activities without changes of their expressions. Furthermore, the synthetic bile acids increased the levels of Cdk inhibitor, p21(WAF1/CIP1), expression and activated the reporter construct of p21(WAF1/CIP1) promoter in p53-independent manner, and p21(WAF1/CIP1) proteins induced by the synthetic bile acid derivatives were associated with Cdk2 and proliferating cell nuclear antigen. These distinctive features suggest that it is possible to create the new drugs useful for cancer therapy from the synthetic bile acid derivatives as lead compounds. (C) 2003 Elsevier Ireland Ltd. All rights reserved.