Sunitinib Reduces Acute Myeloid Leukemia Clonogenic Cells in Vitro and Has Potent Inhibitory Effect on Sorted AML ALDH+ Cells  

作　　者：Asad M. Ilyas Youssri Ahmed Mamdooh Gari Mohammed H. Alqahtani Taha A. Kumosani Abdulrahman L. Al-Malki Khalid O. Abualnaja Saad H. S. Albohairi Adeel G. A. Chaudhary Farid Ahmed Asad M. Ilyas;Youssri Ahmed;Mamdooh Gari;Mohammed H. Alqahtani;Taha A. Kumosani;Abdulrahman L. Al-Malki;Khalid O. Abualnaja;Saad H. S. Albohairi;Adeel G. A. Chaudhary;Farid Ahmed(Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia;Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia;Production of Bioproducts for Industrial Applications Research Group, Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia;Microbial Biotechnology Department, National Research Center, Cairo, Egypt;Bioactive Natural Products Research Group, Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia;King Abdulaziz University Hospital, Jeddah, Saudi Arabia)

机构地区：[1]Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia [2]Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia [3]Production of Bioproducts for Industrial Applications Research Group, Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia [4]Microbial Biotechnology Department, National Research Center, Cairo, Egypt [5]Bioactive Natural Products Research Group, Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia [6]King Abdulaziz University Hospital, Jeddah, Saudi Arabia

出　　处：《Open Journal of Blood Diseases》2016年第1期9-16,共8页血液病期刊（英文）

摘　　要：Sunitinib is an orally administered, multi-target tyrosine kinase inhibitor that has been approved by the FDA for the treatment of renal cell carcinoma and imatinib resistant gastro-intestinal tumors. Anti-leukemic activity of sunitinib has been examined in early clinical trials with limited success. However, recent trials on acute myeloid leukemia (AML) patients carrying FLT3 mutations have shown promising results. Effects of sunitinib on leukemic clonogenic cells and potential leukemic stem cells have not been examined so far. We analyzed the anti-proliferative and apoptotic properties of sunitinib on AML-derived cell lines. We also tested the effect of sunitinib on AML patient derived clonogenic cells (AML-CFC), as well as flow-sorted potential leukemic progenitors. Peripheral blood or bone marrow samples were obtained from newly diagnosed AML patients and flow sorted for CD34+ CD133+ or ALDH+ cells. Umbilical cord blood derived CD34+ cells were used as normal controls. Sunitinib induced growth arrest and apoptosis in AML derived cell lines. In addition, 7 μM sunitinib induced 75% reduction of AML-CFC as compared to DMSO treated control (±6.79%;n = 4). In contrast, 7 μM sunitinib treatment of umbilical cord blood derived normal CD34+ cells showed 29% reduction in AML-CFC (±6.77%;n = 5). Treatment of ALDH+ cells sorted from 2 AML cases and CD34+ CD133+ cells from one patient showed reduction of AML-CFC on treatment with sunitinib. Our study highlighted a potent anti-proliferative and proapoptotic effect of sunitinib on AML cell lines, AML patient derived clonogenic cells and potential leukemic stem cells.Sunitinib is an orally administered, multi-target tyrosine kinase inhibitor that has been approved by the FDA for the treatment of renal cell carcinoma and imatinib resistant gastro-intestinal tumors. Anti-leukemic activity of sunitinib has been examined in early clinical trials with limited success. However, recent trials on acute myeloid leukemia (AML) patients carrying FLT3 mutations have shown promising results. Effects of sunitinib on leukemic clonogenic cells and potential leukemic stem cells have not been examined so far. We analyzed the anti-proliferative and apoptotic properties of sunitinib on AML-derived cell lines. We also tested the effect of sunitinib on AML patient derived clonogenic cells (AML-CFC), as well as flow-sorted potential leukemic progenitors. Peripheral blood or bone marrow samples were obtained from newly diagnosed AML patients and flow sorted for CD34+ CD133+ or ALDH+ cells. Umbilical cord blood derived CD34+ cells were used as normal controls. Sunitinib induced growth arrest and apoptosis in AML derived cell lines. In addition, 7 μM sunitinib induced 75% reduction of AML-CFC as compared to DMSO treated control (±6.79%;n = 4). In contrast, 7 μM sunitinib treatment of umbilical cord blood derived normal CD34+ cells showed 29% reduction in AML-CFC (±6.77%;n = 5). Treatment of ALDH+ cells sorted from 2 AML cases and CD34+ CD133+ cells from one patient showed reduction of AML-CFC on treatment with sunitinib. Our study highlighted a potent anti-proliferative and proapoptotic effect of sunitinib on AML cell lines, AML patient derived clonogenic cells and potential leukemic stem cells.

关 键 词：Acute Myeloid Leukemia SUNITINIB Tyrosine Kinase Inhibitor AML-CFC Leukemic Stem Cells 

分 类 号：R73[医药卫生—肿瘤]