Avicin D selectively induces apoptosis and downregulates p-STAT-3, bcl-2, and survivin in cutaneous T-cell lymphoma cells

Avicin D, a natural triterpenoid saponin, inhibits cell growth and induces Apoptosis in transformed tumor cell lines in vitro and mouse skin carcinogenesis models in vivo. To investigate the anti-tumor effects of avicin D in cutaneous T-cell lymphomas (CTCL), we compared three CTCL cell lines and Sézary cells from three Sézary syndrome (SS) patients with normal CD4+ and activated CD4+ T cells from three healthy donors. Avicin D at 0.5-5 mug ml(-1) induced Apoptosis in a time- and dose-dependent manner in three cell lines: MJ (-0.2 to 13% and 0.6-37%), Hut78 (2-39% and 3-53%), and HH (13-83% and 44-89%) at 24 and 48 hours, respectively. Avicin D at 0.5-5 microg ml(-1) for 48 hours caused more Apoptosis in patients' Sézary cells than in healthy donors' CD4+ T cells and activated CD4+ T cells. The general Caspase Inhibitor Z-VAD-FMK and Caspase-3 inhibitor Z-DEVD-FMK decreased avicin D-induced Apoptosis in CTCL cells. Caspase-3 was activated and poly (ADP-ribose) polymerase was cleaved after avicin D treatment. Avicin D did not change the expression of signal transducer and activator of transcription-3 (STAT-3) but decreased phospho-signal transducer and activator of transcription-3 (p-STAT-3) protein levels in all three cell lines and two patients' Sézary cells. Avicin D also decreased expression of the inhibitor of Apoptosis protein Survivin, the anti-apoptotic protein Bcl-2, but not the pro-apoptotic protein Bax in these CTCL cells. In summary, avicin D selectively induced Apoptosis, inhibited STAT-3 activation, and decreased Apoptosis inhibitors (Bcl-2 and Survivin) in CTCL cell lines and SS patients' Sézary cells. Our findings underlie the therapeutic potential of avicin D in patients with SS.