Opydo-Chanek Małgorzata, Rak Agnieszka, Cierniak Agnieszka, Mazur Lidia
Department of Experimental Hematology, Institute of Zoology, Jagiellonian University, Gronostajowa 9, 30-387 Kraków, Poland.
Department of Physiology and Toxicology of Reproduction, Institute of Zoology, Jagiellonian University, Gronostajowa 9, 30-387 Kraków, Poland.
Toxicol In Vitro. 2017 Aug;42:38-46. doi: 10.1016/j.tiv.2017.03.013. Epub 2017 Mar 30.
ABT-737 belongs to a new class of anticancer agents named BH3 mimetics. ABT-737 competitively binds to surface hydrophobic grooves of anti-apoptotic proteins of Bcl-2 family, counteracting their protective effect. Resveratrol is a natural polyphenol that has been shown to inhibit the proliferation and/or induce apoptosis in a number of different types of cancer cells. The present study was designed to analyze the combined effects of ABT-737 and resveratrol on human acute lymphoblastic leukemia cells. The in vitro cytotoxic activity of these agents against MOLT-4 leukemia cells was determined using the Coulter electrical impedance method, comet assay, and flow cytometry, light microscopy and western blot techniques. The results are the first data showing that ABT-737 combined with resveratrol markedly decreased the cell viability, increased DNA damage, caused the cell cycle perturbation, and synergistically enhanced apoptosis in MOLT-4 cells, when compared to the data obtained after application of the single agent. Moreover, the simultaneous treatment of leukemia cells with ABT-737 and resveratrol resulted in a reduction in mitochondrial membrane potential, an increase of p53 protein level and up-regulation of the Bax/Bcl-2 ratio. The obtained data indicate that the combination of ABT-737 and resveratrol is a promising approach for acute lymphoblastic leukemia treatment that should be further explored.
ABT-737属于一类名为BH3模拟物的新型抗癌药物。ABT-737竞争性结合Bcl-2家族抗凋亡蛋白的表面疏水凹槽，抵消其保护作用。白藜芦醇是一种天然多酚，已被证明能抑制多种不同类型癌细胞的增殖和/或诱导其凋亡。本研究旨在分析ABT-737和白藜芦醇对人急性淋巴细胞白血病细胞的联合作用。使用库尔特电阻抗法、彗星试验、流式细胞术、光学显微镜和蛋白质免疫印迹技术测定了这些药物对MOLT-4白血病细胞的体外细胞毒性活性。结果首次表明，与单独使用药物后获得的数据相比，ABT-737与白藜芦醇联合使用可显著降低MOLT-4细胞的活力，增加DNA损伤，导致细胞周期紊乱，并协同增强细胞凋亡。此外，用ABT-737和白藜芦醇同时处理白血病细胞会导致线粒体膜电位降低、p53蛋白水平升高以及Bax/Bcl-2比值上调。所得数据表明，ABT-737和白藜芦醇联合使用是一种有前景的急性淋巴细胞白血病治疗方法，值得进一步探索。
