Hematologic Malignancies Research Center, Tehran University of Medical Sciences, Tehran, Iran; Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran.
Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran; Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
Eur J Pharmacol. 2018 Sep 5;834:65-76. doi: 10.1016/j.ejphar.2018.07.010. Epub 2018 Jul 19.
Reactive oxygen species (ROS) are essential mediators of crucial cellular processes including apoptosis, proliferation, survival and cell cycle. Their regulatory role in cancer progression has seen in different human malignancies such as acute myeloid leukemia (AML). AML patients suffer from high resistance of the tumors against routine therapeutics including ATO. ATO enhance reactive oxygen species levels and induce apoptosis and suppresses proliferation in AML cells. However, some pathways such as JAK2/STAT3 ease anti-tumor activity of ATO by reducing reactive oxygen species amount and protecting the cell from apoptosis. In the present study, we use ruxolitinib (potent JAK2 inhibitor) to increase the sensitivity of AML cells to ATO treatment. We test, the effect of this combination on metabolic activity, proliferation, colony formation, cell cycle distribution, apoptosis, oxidative stress and DNA damage. Our results showed that combination of ATO with ruxolitinib synergistically reduced metabolic activity, proliferation and survival of AML cell lines. This combination induced G1/S cell cycle arrest because of reactive oxygen species elevation and GSH reduction. Besides, enhancement of reactive oxygen species increased apoptosis rate in combination samples. We uncovered that the synergistic anti-tumor effect of ATO and ruxolitinib in AML cells mediates via reactive oxygen species elevation and DNA damage. Overall, our results show that the combinatorial therapy of AML cells is more effective than solo-targeted therapy.
活性氧（ROS）是包括细胞凋亡、增殖、存活和细胞周期在内的关键细胞过程的必需介质。它们在癌症进展中的调节作用在不同的人类恶性肿瘤中都有体现，如急性髓细胞白血病（AML）。AML 患者的肿瘤对常规治疗（包括ATO）具有很高的耐药性。ATO 会增加活性氧水平，诱导 AML 细胞凋亡并抑制增殖。然而，一些途径，如 JAK2/STAT3，通过减少活性氧的数量并保护细胞免受凋亡，减轻了 ATO 的抗肿瘤活性。在本研究中，我们使用鲁索替尼（一种强效的 JAK2 抑制剂）来提高 AML 细胞对 ATO 治疗的敏感性。我们测试了这种组合对代谢活性、增殖、集落形成、细胞周期分布、细胞凋亡、氧化应激和 DNA 损伤的影响。我们的结果表明，ATO 与鲁索替尼联合使用可协同降低 AML 细胞系的代谢活性、增殖和存活。这种组合通过增加活性氧和减少 GSH 来诱导 G1/S 细胞周期停滞。此外，活性氧的增加增加了组合样品中的细胞凋亡率。我们发现，ATO 和鲁索替尼在 AML 细胞中的协同抗肿瘤作用是通过活性氧的增加和 DNA 损伤介导的。总的来说，我们的结果表明，AML 细胞的联合治疗比单独靶向治疗更有效。
