Hematology & Oncology, Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan.
Leuk Res. 2010 Mar;34(3):352-7. doi: 10.1016/j.leukres.2009.09.003. Epub 2009 Sep 24.
Adult T-cell leukemia (ATL) is an aggressive malignancy of peripheral T cells infected with human T-cell leukemia virus type 1 (HTLV-1). The prognosis of aggressive ATL patients remains poor because of its resistance to conventional chemotherapy. We examined the effect of deguelin, a naturally occurring rotenoid, on HTLV-1-transformed T-cell lines, KUT-1 and MT-2 cells. We found that deguelin suppressed cell proliferation and induced cell death in these cells. Immunoblot analysis showed the inhibition of survivin expression and signal transducers, and activators of transcription (STAT) 3 phosphorylation of both cells. We also observed the cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP) in deguelin-treated cells, indicating that deguelin induces caspase-dependent apoptosis in these cells. Furthermore, proteasome inhibitor MG132 prevented the down-regulation of survivin expression and STAT3 dephosphorylation by deguelin, suggesting that the action mechanism of deguelin involves the degradation of survivin and phosphorylated STAT3 through the ubiquitin/proteasome pathway. Our data indicate that deguelin presents a potent anti-proliferative effect in part via the down-regulation of survivin expression and STAT3 phosphorylation in HTLV-1-transformed cells. Deguelin merits further investigation as a potential chemotherapeutic agent for ATL.
成人 T 细胞白血病（ATL）是一种由人类 T 细胞白血病病毒 1 型（HTLV-1）感染的外周 T 细胞的侵袭性恶性肿瘤。由于其对常规化疗的耐药性，侵袭性 ATL 患者的预后仍然很差。我们研究了天然罗替豆烷衍生物脱氢表雄酮（deguelin）对 HTLV-1 转化的 T 细胞系 KUT-1 和 MT-2 细胞的影响。我们发现 deguelin 抑制了这些细胞的增殖并诱导其死亡。免疫印迹分析显示，deguelin 抑制了这两种细胞中生存素表达和信号转导子和转录激活子 3（STAT3）磷酸化。我们还观察到 deguelin 处理的细胞中 caspase-3 和多聚（ADP-核糖）聚合酶（PARP）的裂解，表明 deguelin 在这些细胞中诱导了 caspase 依赖性细胞凋亡。此外，蛋白酶体抑制剂 MG132 阻止了 deguelin 下调生存素表达和 STAT3 去磷酸化，表明 deguelin 通过泛素/蛋白酶体途径降解生存素和磷酸化的 STAT3 发挥作用。我们的数据表明，deguelin 通过下调 HTLV-1 转化细胞中的生存素表达和 STAT3 磷酸化，表现出很强的抗增殖作用。脱氢表雄酮作为一种潜在的 ATL 化疗药物值得进一步研究。
