Gene interactions and pathways from curated databases and text-mining
Blood 2008, PMID: 18056843

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

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.

Diseases/Pathways annotated by Medline MESH: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Document information provided by NCBI PubMed

Text Mining Data

Bcr-Abl ⊣ SKI-606: " 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 "

Src ⊣ SKI-606: " 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 "

Bcr-Abl ⊣ SKI-606: " 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 "

Bcr-Abl ⊣ SKI-606: " SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34 ( + ) cells and inhibited Src phosphorylation more potently than imatinib "

Bcr-Abl ⊣ Src: " SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34 ( + ) cells and inhibited Src phosphorylation more potently than imatinib "

Src ⊣ SKI-606: " SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34 ( + ) cells and inhibited Src phosphorylation more potently than imatinib "

Src ⊣ Bcr-Abl: " SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34 ( + ) cells and inhibited Src phosphorylation more potently than imatinib "

Bcr-Abl ⊣ SKI-606: " SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34 ( + ) cells and inhibited Src phosphorylation more potently than imatinib "

Bcr-Abl ⊣ SKI-606: " SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors "

Src ⊣ SKI-606: " SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors "

Bcr-Abl ⊣ SKI-606: " SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors "

Manually curated Databases

No curated data.