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.
Highlights
Acute myeloid leukemia (AML) is a clonal proliferative disorder of the myeloid progenitors that results in an accumulation of immature myeloid cells in the bone marrow and peripheral blood
We have evaluated the activity of sunitinib on AML cell lines and clonogenic cells from primary AML samples and potential AML stem cells subpopulation
Anti-Proliferative Effect of Sunitinib in Different Leukemia Cell Lines In order to explore the antiproliferative effects of sunitinib (Figure 1(a)), on AML cells, human HL60, K562 and NB4 cell lines were cultured with increasing concentrations of sunitinib
Summary
Acute myeloid leukemia (AML) is a clonal proliferative disorder of the myeloid progenitors that results in an accumulation of immature myeloid cells in the bone marrow and peripheral blood. Treatment of elderly AML patients, patients carrying mutations in FLT3 and those with complex cytogenetic abnormalities and monosomies still remain challenging. In this regard, development of novel targeted therapeutic approaches is crucial for improving the clinical outcome of AML subsets [2]. Combination of sunitinib with AraC or Daunorubicin demonstrated synergistic inhibition of FLT3-ITD positive AML cells [7]. A 25 mg/day dose of sunitinib was well tolerated and complete remission was achieved in 59% AML patients irrespective of the type of FLT3 mutation [8]. We have evaluated the activity of sunitinib on AML cell lines and clonogenic cells from primary AML samples and potential AML stem cells subpopulation
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