| 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. |
| Authors | Heiko Konig, Tessa L Holyoake, Ravi Bhatia
(Affiliation: Department of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA.)
|
| Journal | Blood
(Blood)
Vol. 111
Issue 4
Pg. 2329-38
(Feb 15 2008)
ISSN: 0006-4971 United States |
| PMID | 18056843
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Aniline Compounds
- Antineoplastic Agents
- Nitriles
- Piperazines
- Protein Kinase Inhibitors
- Pyrimidines
- Quinolines
- SKI606
- imatinib
- Proto-Oncogene Proteins c-abl
- src-Family Kinases
|
| Topics |
- Aniline Compounds
(pharmacology)
- Antineoplastic Agents
(therapeutic use)
- Fetal Blood
(cytology, drug effects)
- Hematopoietic Stem Cells
(drug effects, pathology)
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
(drug therapy, pathology)
- Nitriles
(pharmacology)
- Piperazines
(therapeutic use)
- Protein Kinase Inhibitors
(pharmacology)
- Proto-Oncogene Proteins c-abl
(antagonists & inhibitors)
- Pyrimidines
(therapeutic use)
- Quinolines
(pharmacology)
- src-Family Kinases
(antagonists & inhibitors)
|
