Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.
Department of Pathology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan.
Int J Oncol. 2017 Aug;51(2):633-643. doi: 10.3892/ijo.2017.4026. Epub 2017 Jun 2.
Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) but there is no effective treatment for HTLV-1-associated diseases. Herein, we determined the effect of butein, a bioactive plant polyphenol, on cell growth, apoptosis and signaling pathways in HTLV-1-infected T-cell lines and on tumor growth in SCID mice. Treatment with butein caused a decrease in viability of HTLV-1-infected T-cell lines. T cells cultured with butein showed obvious apoptosis morphology, and cleavage of poly(ADP-ribose) polymerase with activation of caspase-3, -8 and -9. Pretreatment of cells with caspase inhibitor partially blocked butein-induced inhibition of cell viability. Butein also resulted in cell cycle arrest at G1 phase. Butein markedly downregulated the protein expression levels of CDK4, CDK6, cyclin D1, cyclin D2, cyclin E, survivin, XIAP, c-IAP2 and phospho-pRb. Butein also inhibited i) total and phospho-protein levels of IκB kinase (IKK)α and IKKβ, ii) degradation and phosphorylation of IκBα, iii) JunB and JunD, iv) total and phospho-protein levels of Akt, v) phosphorylation of RelA, vi) heat shock protein 90, and vii) DNA-binding activity of NF-κB and AP-1. In mice harboring ATLL xenograft tumors, butein caused a significant inhibition of tumor growth and reduced serum levels of soluble interleukin-2 receptor α chain and soluble cluster of differentiation 30. Considered together, the results indicated that butein has antiproliferative and proapoptotic properties through the suppression of NF-κB, AP-1 and Akt signaling in HTLV-1-infected T cells, both in vitro and in vivo, suggesting its therapeutic potential against HTLV-1-associated diseases including ATLL.
人 T 细胞白血病病毒 1（HTLV-1）是成人 T 细胞白血病/淋巴瘤（ATLL）的致病因子，但目前尚无针对 HTLV-1 相关疾病的有效治疗方法。在此，我们研究了一种生物活性植物多酚白藜芦醇对 HTLV-1 感染的 T 细胞系细胞生长、凋亡和信号通路的影响，以及对 SCID 小鼠肿瘤生长的影响。白藜芦醇处理导致 HTLV-1 感染的 T 细胞系活力下降。用白藜芦醇培养的 T 细胞表现出明显的凋亡形态，同时激活 caspase-3、-8 和 -9 导致多聚（ADP-核糖）聚合酶的裂解。细胞用 caspase 抑制剂预处理可部分阻断白藜芦醇诱导的细胞活力抑制。白藜芦醇还导致细胞周期停滞在 G1 期。白藜芦醇显著下调 CDK4、CDK6、cyclin D1、cyclin D2、cyclin E、survivin、XIAP、c-IAP2 和磷酸化 pRb 的蛋白表达水平。白藜芦醇还抑制了 i）IKKα 和 IKKβ 的总蛋白和磷酸化蛋白水平，ii）IκBα 的降解和磷酸化，iii）JunB 和 JunD，iv）Akt 的总蛋白和磷酸化蛋白水平，v）RelA 的磷酸化，vi）热休克蛋白 90，以及 vii）NF-κB 和 AP-1 的 DNA 结合活性。在携带 ATLL 异种移植肿瘤的小鼠中，白藜芦醇显著抑制肿瘤生长，并降低血清可溶性白细胞介素 2 受体 α 链和可溶性分化簇 30 的水平。综上所述，结果表明白藜芦醇通过抑制 NF-κB、AP-1 和 Akt 信号通路在 HTLV-1 感染的 T 细胞中具有抗增殖和促凋亡作用，无论是在体外还是在体内，都提示其在治疗 HTLV-1 相关疾病包括 ATLL 方面具有潜在的治疗价值。
