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.
Zhang
Chunlei
C
Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address: czhang@mdanderson.org.
Li
Baoqiang
B
Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Gaikwad
Amos S
AS
Department of Pediatric Hematology-Oncology, Texas Children Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
Haridas
Valsala
V
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Xu
Zhixiang
Z
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Gutterman
Jordan U
JU
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Duvic
Madeleine
M
Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D016410:Lymphoma, T-Cell, Cutaneous / Q000378:metabolism* / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012503:Saponins / Q000494:pharmacology*; D012751:Sezary Syndrome / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D000077022:Survivin; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D012503:Saponins; D000077022:Survivin; D051028:bcl-2-Associated X Protein; C478445:avicin D; D053148:Caspase 3