Apoptotic activity of novel bile acid derivatives in human leukemic T cells through the activation of caspases.
The therapeutic efficacies of bile acids, such as ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA), have been widely demonstrated in various liver diseases, suggesting that they might protect hepatocytes against common mechanisms of liver damage. Although they have been shown to prevent apoptotic cell death in certain cell lines, we have previously reported that a novel derivative (HS-1030) of UDCA significantly inhibited cell growth and induced apoptosis in cancer cells. To develop more effective agents, we synthesized several derivatives, named HS-1183, HS-1199 and HS-1200, based on the structure of UDCA and CDCA, and investigated them for anti-proliferative activity in Jurkat cells, a human leukemic T cell line. Whereas UDCA and CDCA had no significant effects on the growth of Jurkat cells in the concentration range tested, both HS-1199 and HS-1200 completely inhibited the cell proliferation, and HS-1183 showed only a weak inhibitory activity. Furthermore, chromatin condensation, DNA ladder formation and proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) were observed after treatment of novel bile acids, indicating the occurrence of apoptotic cell death, which was associated with down-regulation of caspase-3 and -8. The apoptotic manifestations such as PARP cleavage and DNA fragmentation were abolished in the presence of the tripeptide caspase inhibitor zVAD-fmk or the specific caspase-3 inhibitor DEVD-fmk. Our data thus demonstrate that novel bile acid derivatives-induced apoptosis of leukemic T cells is dependent on caspase activation.
Choi
Y H
YH
Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Pusan 614-052, Korea. choiyh@hyomin.dongeui.ac.kr
Im
E O
EO
Suh
H
H
Jin
Y
Y
Lee
W H
WH
Yoo
Y H
YH
Kim
K W
KW
Kim
N D
ND
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects; D007938:Leukemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000502:physiology*; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*
D061945:Caspase Inhibitors; D002756:Cholagogues and Choleretics; D004273:DNA, Neoplasm; D005765:Gastrointestinal Agents; D016159:Tumor Suppressor Protein p53; D002635:Chenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases