Novel bile acid derivatives induce apoptosis via a p53-independent pathway in human breast carcinoma cells.
We have compared the anti-proliferative effects of ursodeoxycholic acid (UDCA), chenodeoxycholic acid (CDCA) and their derivatives, HS-1183, HS-1199 and HS-1200, on MCF-7 (wild-type p53) and MDA-MB-231 (mutant p53) cells. While UDCA and CDCA exhibited no significant effect, their novel derivatives inhibited the proliferation of both cell lines in a concentration-dependent manner, concomitant with apoptotic nuclear changes and the increase of a sub-G1 population and DNA fragmentation. Furthermore, we also observed an increase 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 MCF-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 cancer cells after treatment with novel bile acids. These findings suggest that these cytotoxic effects of novel bile acid derivatives on human breast carcinoma cells were mediated via apoptosis through a p53-independent pathway.
Im
E O
EO
Department of Pharmacy, Pusan Cancer Research Center, Pusan National University, Pusan 609-735, South Korea.
Choi
Y H
YH
Paik
K J
KJ
Suh
H
H
Jin
Y
Y
Kim
K W
KW
Yoo
Y H
YH
Kim
N D
ND
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002470:Cell Survival / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
C534696:CCND3 protein, human; C493956:CDKN1A protein, human; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D002635:Chenodeoxycholic Acid; D019938:Cyclin D1; D014580:Ursodeoxycholic Acid