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 (UDC A) and chenodeoxycholic acid (CDCA), have been widely demonstrated in vario us liver diseases, suggesting that they might protect hepatocytes against c ommon mechanisms of liver damage. Although they have been shown to prevent apoptotic cell death in certain cell lines, we have previously reported tha t 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-prolifer ative 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 co ncentration range tested, both HS-1199 and HS-1200 completely inhibited the cell proliferation, and HS-1183 showed only a weak inhibitory activity. Fu rthermore, chromatin condensation, DNA ladder formation and proteolytic cle avage of poly(ADP-ribose) polymerase (PARP) were observed after treatment o f novel bile acids, indicating the occurrence of apoptotic cell death, whic h was associated with down-regulation of caspase-3 and -8. The apoptotic ma nifestations such as PARP cleavage and DNA fragmentation were abolished in the presence of the tripeptide caspase inhibitor zVAD-fmk or the specific c aspase-3 inhibitor DEVD-fmk. Our data thus demonstrate that novel bile acid derivatives-induced apoptosis of leukemic T cells is dependent on caspase activation.