期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 834, 期 -, 页码 65-76出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2018.07.010
关键词
Acute myeloid leukemia; Arsenic trioxide; JAK2/STAT3; Reactive oxygen species; DNA damage
资金
- Elite Researcher Grant Committee under National Institute for Medical Research Development (NIMAD), Tehran, Iran [963627]
- Hematology, Oncology and Stem Cell Transplantation Research Center under Tehran University of Medical Sciences, Tehran, Iran [97-01-36-37612]
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 antitumor 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 solotargeted therapy.
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