Department of Pathology and Laboratory Medicine, New Jersey Medical School, University of Medicine and Dentistry New Jersey, Newark, USA.
Cell Cycle. 2010 Nov 15;9(22):4542-51. doi: 10.4161/cc.9.22.13790.
Acute myelogenous leukemia (AML) is a disease characterized by dysregulated cell proliferation associated with impaired cell differentiation, and current treatment regimens rarely save the patient. Thus, new mechanism-based approaches are needed to improve prognosis of this disease. We have investigated in preclinical studies the potential anti-leukemia use of the plant-derived polyphenol Silibinin (SIL) in combination with 1,25-dihydroxyvitamin D3 (1,25D). Although most of the leukemic blasts ex vivo responded by differentiation to treatment with this combination, the reasons for the absence of SIL-1,25D synergy in some cases were unclear. Here we report that failure of SIL to enhance the action of 1,25D is likely due to the SIL-induced increase in the activity of differentiation-antagonizing cell components, such as ERK5. This kinase is under the control of Cot1/Tlp2, and inhibition of Cot1 activity by a specific pharmacological inhibitor 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-yl-methylamino-3-cyano-[1-7]-naphthyridine, or by Cot1 siRNA, increases the differentiation by SIL/1,25D combinations. Conversely, over-expression of a Cot1 construct increases the cellular levels of P-ERK5, and SIL/1,25D-induced differentiation and cell cycle arrest are diminished. It appears that reduction in ERK5 activity by inhibition of Cot1 allows SIL to augment the expression of 1,25D-induced differentiation promoting factors and cell cycle regulators such as p27 (Kip1) , which leads to cell cycle arrest. This study shows that in some cell contexts SIL/1,25D can promote expression of both differentiation-promoting and differentiation-inhibiting genes, and that the latter can be neutralized by a highly specific pharmacological inhibitor, suggesting a potential for supplementing treatment of AML with this combination of agents.
急性髓系白血病 (AML) 是一种以细胞增殖失调为特征的疾病，与细胞分化受损有关，目前的治疗方案很少能挽救患者生命。因此，需要新的基于机制的方法来改善这种疾病的预后。我们在临床前研究中研究了植物源性多酚水飞蓟素 (SIL) 与 1,25-二羟基维生素 D3 (1,25D) 联合用于治疗白血病的潜力。尽管大多数白血病细胞在体外对这种联合治疗的反应是通过分化，但在某些情况下，SIL-1,25D 协同作用缺失的原因尚不清楚。在这里，我们报告说，SIL 未能增强 1,25D 的作用可能是由于 SIL 诱导的分化拮抗细胞成分（如 ERK5）活性增加所致。这种激酶受 Cot1/Tlp2 控制，用特异性药理学抑制剂 4-(3-氯-4-氟苯基氨基)-6-(吡啶-3-基-甲基氨基-3-氰基-[1-7]-萘啶，或 Cot1 siRNA 抑制 Cot1 活性，可增加 SIL/1,25D 组合的分化作用。相反，Cot1 构建体的过表达会增加细胞内 P-ERK5 的水平，并且 SIL/1,25D 诱导的分化和细胞周期停滞减少。似乎通过抑制 Cot1 降低 ERK5 活性可使 SIL 增强 1,25D 诱导的分化促进因子和细胞周期调节剂（如 p27（Kip1））的表达，从而导致细胞周期停滞。这项研究表明，在某些细胞环境中，SIL/1,25D 可以促进分化促进基因和分化抑制基因的表达，并且后者可以被一种高度特异性的药理学抑制剂中和，这表明该组合具有治疗 AML 的潜力。
