TITLE:
Sunitinib Reduces Acute Myeloid Leukemia Clonogenic Cells in Vitro and Has Potent Inhibitory Effect on Sorted AML ALDH+ Cells
AUTHORS:
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
KEYWORDS:
Acute Myeloid Leukemia, Sunitinib, Tyrosine Kinase Inhibitor, AML-CFC, Leukemic Stem Cells
JOURNAL NAME:
Open Journal of Blood Diseases,
Vol.6 No.1,
March
31,
2016
ABSTRACT: 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.