Novel bile acid derivatives induce apoptosis via a p53-independent pathwayin human breast carcinoma cells

We have compared the anti-proliferative effects of ursodeoxycholic acid (UD CA), chenodeoxycholic acid (CDCA) and their derivatives, HS-1183, HS-1199 a nd HS-1200, on MCF-7 (wild-type p53) and MDA-MB-231 (mutant p53) cells. Whi le UDCA and CDCA exhibited no significant effect, their novel derivatives i nhibited the proliferation of both cell lines in a concentration-dependent manner, concomitant with apoptotic nuclear changes and the increase of a su b-G1 population and DNA fragmentation. Furthermore, rye also observed an in crease in the ratio of pro-apoptotic protein Bax to anti-apoptotic protein Bcl-2 and cleavages of lamin B and poly(ADP-ribose) polymerase (PARP) in MC F-7 and MDA-MB-231 cells. Cell cycle related proteins, cyclin D1 and D3, as well as retinoblastoma protein (pRb) were down-regulated, while the level of cyclin-dependent kinase inhibitor p21(WAF1/CIP1) was increased in both c ancer cells after treatment with novel bile acids. These findings suggest t hat these cytotoxic effects of novel bile acid derivatives on human breast carcinoma cells were mediated via apoptosis through a p53-independent pathw ay. (C) 2001 Elsevier Science ireland Ltd. All rights reserved.