Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606

Heiko Konig, Tessa L. Holyoake, Ravi Bhatia

Research output: Contribution to journalArticle

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Abstract

Imatinib mesylate (imatinib) is highly effective in the treatment of chronic myeloid leukemia (CML) but is less effective in eliminating CML stem cells. We investigated whether SKI-606, a potent Bcr-Abl and Src kinase inhibitor without anti-PDGF or c-Kit activity, could effectively target primitive CML progenitors. CML and normal progenitors were cultured with SKI-606 or imatinib. SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34+ cells and inhibited Src phosphorylation more potently than imatinib. However, SKI-606 and imatinib resulted in similar suppression of CML primitive and committed progenitor proliferation and growth in CFC and LTC-IC assays. Exposure to either agent alone or in combination resulted in only modest increase in apoptosis. Evaluation of downstream signaling pathways indicated that Akt and STAT5 activity was not changed, but a delayed increase in MAPK activity was seen at high concentrations of SKI-606. SKI-606 inhibited normal progenitor proliferation to a lesser extent than imatinib. SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors. However, SKI-606 does not demonstrate increased ability to eliminate primitive CML progenitors by apoptosis compared with imatinib, emphasizing the need for additional strategies besides Bcr-Abl kinase inhibition for curative therapy of CML.

Original languageEnglish (US)
Pages (from-to)2329-2338
Number of pages10
JournalBlood
Volume111
Issue number4
DOIs
StatePublished - Feb 15 2008
Externally publishedYes

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src-Family Kinases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Phosphotransferases
Apoptosis
Chlorofluorocarbons
Phosphorylation
Myeloid Progenitor Cells
bosutinib
Imatinib Mesylate
Stem cells
Growth
Assays

ASJC Scopus subject areas

  • Hematology

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Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606. / Konig, Heiko; Holyoake, Tessa L.; Bhatia, Ravi.

In: Blood, Vol. 111, No. 4, 15.02.2008, p. 2329-2338.

Research output: Contribution to journalArticle

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