Abstract |
Src family kinase activity is elevated in many human tumors, including breast cancer, and is often associated with aggressive disease. We examined the effects of SKI-606 ( bosutinib), a selective Src family kinase inhibitor, on human cancer cells derived from breast cancer patients to assess its potential for breast cancer treatment. Our results show that SKI-606 caused a decrease in cell motility and invasion of breast cancer cell lines with an IC50 of approximately 250 nmol/L, which was also the IC50 for inhibition of cellular Src kinase activity in intact tumor cells. These changes were accompanied by an increase in cell-to-cell adhesion and membrane localization of beta-catenin. By contrast, cell proliferation and survival were unaffected by SKI-606 at concentrations sufficient to block cell migration and invasion. Analysis of downstream effectors of Src revealed that SKI-606 inhibits the phosphorylation of focal adhesion kinase (FAK), proline-rich tyrosine kinase 2 (Pyk2), and Crk-associated substrate (p130Cas), with an IC50 similar to inhibition of cellular Src kinase. Our findings indicate that SKI-606 inhibits signaling pathways involved in controlling tumor cell motility and invasion, suggesting that SKI-606 is a promising therapeutic for breast cancer.
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Authors | Adina Vultur, Ralf Buettner, Claudia Kowolik, Wei Liang, David Smith, Frank Boschelli, Richard Jove |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 7
Issue 5
Pg. 1185-94
(May 2008)
ISSN: 1535-7163 [Print] United States |
PMID | 18483306
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Aniline Compounds
- Antineoplastic Agents
- Crk-Associated Substrate Protein
- Nitriles
- Protein Kinase Inhibitors
- Quinolines
- beta Catenin
- bosutinib
- Focal Adhesion Kinase 1
- PTK2 protein, human
- src-Family Kinases
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Topics |
- Aniline Compounds
(pharmacology)
- Antineoplastic Agents
(pharmacology)
- Breast Neoplasms
(enzymology, metabolism, pathology)
- Cell Adhesion
- Cell Line, Tumor
- Cell Movement
(drug effects)
- Cell Proliferation
- Crk-Associated Substrate Protein
(antagonists & inhibitors, metabolism)
- Female
- Focal Adhesion Kinase 1
(antagonists & inhibitors, metabolism)
- Humans
- Models, Biological
- Nitriles
(pharmacology)
- Phosphorylation
- Protein Kinase Inhibitors
(pharmacology)
- Quinolines
(pharmacology)
- Signal Transduction
- beta Catenin
(metabolism)
- src-Family Kinases
(antagonists & inhibitors, metabolism)
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