Comparison of antitumor effects of multitargeted tyrosine kinase inhibitors in acute myelogenous leukemia

Shuiying Hu, Hongmei Niu, Patton Minkin, Shelley Orwick, Akira Shimada, Hiroto Inaba, Gary V H Dahl, Jeffrey Rubnitz, Sharyn D. Baker

Research output: Contribution to journalArticle

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Abstract

We compared the antitumor activities of the multitargeted tyrosine kinase inhibitors imatinib, sorafenib, and sunitinib to determine which inhibitor is best suited to be used for the treatment of acute myelogenous leukemia (AML). In nine human AML cell lines, sorafenib and sunitinib were more potent inhibitors of cellular proliferation than imatinib (IC50, 0.27 to >40, 0.002-9.1, and 0.007-13 μmol/L for imatinib, sorafenib, and sunitinib, respectively). Sorafenib and sunitinib were potent inhibitors of cells with fms-like tyrosine kinase 3 internal tandem duplication (IC50, 2 and 7 nmol/L) and c-KIT N822K mutations (IC50, 23 and 40 nmol/L). In four cell lines (MV4-11, Kasumi-1, KG-1, and U937) that spanned a range of drug sensitivities, sorafenib and sunitinib had similar activity in apoptosis and cell cycle assays, except that sunitinib did not promote apoptosis in U937 cells. Both drugs inhibited mitogen-activated protein kinase signaling but had no effect on AKT signaling in most of the cell lines tested. Sorafenib was substantially more bound than sunitinib in human plasma (unbound fraction, 0.59% versus 8.4%) and cell culture medium (unbound fraction, 1.3% versus 39%), indicating that sorafenib was more potent than sunitinib and that unbound sorafenib concentrations with activity against most AML cell lines are achievable in vivo. There was more intracellular accumulation of sorafenib than of sunitinib and imatinib in AML cells. Between 1 and 10 μmol/L, sorafenib inhibited the proliferation of six of nine primary AML blast samples by ≥50%. Our results highlight the pharmacologic features of sorafenib that may provide it an advantage in the treatment of AML.

Original languageEnglish
Pages (from-to)1110-1120
Number of pages11
JournalMolecular Cancer Therapeutics
Volume7
Issue number5
DOIs
Publication statusPublished - 2008
Externally publishedYes

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Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Inhibitory Concentration 50
Cell Line
fms-Like Tyrosine Kinase 3
sorafenib
Apoptosis
sunitinib
U937 Cells
Mitogen-Activated Protein Kinases
Pharmaceutical Preparations
Culture Media
Cell Cycle
Cell Culture Techniques
Cell Proliferation
Mutation
Imatinib Mesylate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

Cite this

Comparison of antitumor effects of multitargeted tyrosine kinase inhibitors in acute myelogenous leukemia. / Hu, Shuiying; Niu, Hongmei; Minkin, Patton; Orwick, Shelley; Shimada, Akira; Inaba, Hiroto; Dahl, Gary V H; Rubnitz, Jeffrey; Baker, Sharyn D.

In: Molecular Cancer Therapeutics, Vol. 7, No. 5, 2008, p. 1110-1120.

Research output: Contribution to journalArticle

Hu, Shuiying ; Niu, Hongmei ; Minkin, Patton ; Orwick, Shelley ; Shimada, Akira ; Inaba, Hiroto ; Dahl, Gary V H ; Rubnitz, Jeffrey ; Baker, Sharyn D. / Comparison of antitumor effects of multitargeted tyrosine kinase inhibitors in acute myelogenous leukemia. In: Molecular Cancer Therapeutics. 2008 ; Vol. 7, No. 5. pp. 1110-1120.
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