Zhang Chunlei, Li Baoqiang, Gaikwad Amos S, Haridas Valsala, Xu Zhixiang, Gutterman Jordan U, Duvic Madeleine
Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Invest Dermatol. 2008 Nov;128(11):2728-2735. doi: 10.1038/jid.2008.138. Epub 2008 May 22.
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.
阿魏菌素D是一种天然三萜皂苷，在体外可抑制转化肿瘤细胞系的细胞生长并诱导其凋亡，在体内可抑制小鼠皮肤癌发生模型。为研究阿魏菌素D在皮肤T细胞淋巴瘤（CTCL）中的抗肿瘤作用，我们将三种CTCL细胞系以及三名Sezary综合征（SS）患者的Sezary细胞与三名健康供体的正常CD4⁺和活化CD4⁺T细胞进行了比较。0.5 - 5μg/ml的阿魏菌素D在三种细胞系中均以时间和剂量依赖性方式诱导凋亡：在24小时和48小时时，MJ细胞系分别为（-0.2%至13%和0.6%至37%），Hut78细胞系分别为（2%至39%和3%至53%），HH细胞系分别为（13%至83%和44%至89%）。0.5 - 5μg/ml的阿魏菌素D作用48小时后，患者的Sezary细胞比健康供体的CD4⁺T细胞和活化CD4⁺T细胞发生更多凋亡。通用半胱天冬酶抑制剂Z - VAD - FMK和半胱天冬酶 - 3抑制剂Z - DEVD - FMK可减少阿魏菌素D诱导的CTCL细胞凋亡。阿魏菌素D处理后，半胱天冬酶 - 3被激活，聚（ADP - 核糖）聚合酶被切割。阿魏菌素D在所有三种细胞系以及两名患者的Sezary细胞中均未改变信号转导和转录激活因子 - 3（STAT - 3）的表达，但降低了磷酸化信号转导和转录激活因子 - 3（p - STAT - 3）的蛋白水平。阿魏菌素D还降低了这些CTCL细胞中凋亡抑制蛋白生存素、抗凋亡蛋白bcl - 2的表达，但未降低促凋亡蛋白bax的表达。总之，阿魏菌素D在CTCL细胞系和SS患者的Sezary细胞中选择性地诱导凋亡、抑制STAT - 3激活并降低凋亡抑制剂（bcl - 2和生存素）水平。我们的研究结果揭示了阿魏菌素D对SS患者的治疗潜力。
