Resveratrol blocks interleukin-1β-induced activation of the nuclear transcription factor NF-κB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells
Resveratrol blocks interleukin-1β-induced activation of the nuclear transcription factor NF-κB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells
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DOI：
10.1182/blood-2002-11-3550
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发表时间：
2003-08-01
期刊：
影响因子：
20.3
通讯作者：
Aggarwal, BB
中科院分区：
文献类型：
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作者：
Estrov, Z;Shishodia, S;Aggarwal, BB
白藜芦醇是一种可食用的多酚二苯乙烯，据报道在不同的白血病细胞系中具有显着的抗白血病活性。我们研究了白藜芦醇是否对新鲜的急性髓系白血病 (AML) 细胞具有活性及其作用机制。由于白细胞介素 1β (IL-1β) 在 AML 细胞增殖中发挥关键作用，我们首先测试了白藜芦醇对 AML 细胞系 OCIM2 和 OCI/AML3 的影响，这两种细胞均产生 IL-1β 并对其做出反应而增殖。白藜芦醇通过将细胞阻滞在 S 期，以剂量依赖性方式 (5-75 muM) 抑制两种细胞系的增殖，从而阻止它们在细胞周期中的进展； IL-1β部分逆转了这种抑制作用。白藜芦醇显着减少 OCIM2 细胞中 IL-1β 的产生。它还抑制 IL-1β 诱导的转录因子核因子 kappaB (NF-kappaB) 激活，该因子调节一系列控制细胞存活、增殖和细胞因子产生的信号。事实上，OCIM2 细胞与白藜芦醇一起孵育会导致细胞凋亡。由于Caspase抑制剂Ac-DEVD-CHO或z-DEVD-FMK部分逆转了白藜芦醇的抗增殖作用，我们测试了其对Caspase途径的影响，发现白藜芦醇诱导半胱氨酸蛋白酶Caspase 3的激活以及随后DNA修复酶聚（腺苷二磷酸[ADP]-核糖）的裂解 聚合酶。最后，白藜芦醇以剂量依赖性方式抑制 5 名新诊断 AML 患者的新鲜 AML 骨髓细胞的集落形成细胞增殖。总而言之，我们的数据显示白藜芦醇是 AML 细胞的有效体外抑制剂，表明该化合物可能在未来的 AML 治疗中发挥作用。
Resveratrol, an edible polyphenolic stilbene, has been reported to possess substantial antileukemic activities in different leukemia cell lines. We investigated whether resveratrol is active against fresh acute myeloid leukemia (AML) cells and its mechanism of action. Because interleukin 1beta (IL-1beta) plays a key role in proliferation of AML cells, we first tested the effect of resveratrol on the AML cell lines OCIM2 and OCI/AML3, both of which produce IL-1beta and proliferate in response to it. Resveratrol inhibited proliferation of both cell lines in a dose-dependent fashion (5-75 muM) by arresting the cells at S phase, thus preventing their progression through the cell cycle; IL-1beta partially reversed this inhibitory effect. Resveratrol significantly reduced production of IL-1beta in OCIM2 cells. It also suppressed the IL-1beta-induced activation of transcription factor nuclear factor kappaB (NF-kappaB), which modulates an array of signals controlling cellular survival, proliferation, and cytokine production. Indeed, incubation of OCIM2 cells with resveratrol resulted in apoptotic cell death. Because caspase inhibitors Ac-DEVD-CHO or z-DEVD-FMK partially reversed the anti proliferative effect of resveratrol, we tested its effect on the caspase pathway and found that resveratrol induced the activation of the cysteine protease caspase 3 and subsequent cleavage of the DNA repair enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase. Finally, resveratrol suppressed colony-forming cell proliferation of fresh AML marrow cells from 5 patients with newly diagnosed AML in a dose-dependent fashion. Taken together, our data showing that resveratrol is an effective in vitro inhibitor of AML cells suggest that this compound may have a role in future therapies for AML.