Translational Therapeutics
British Journal of Cancer (2009) 101, 38–47. doi:10.1038/sj.bjc.6605101 www.bjcancer.com
Published online 9 June 2009
Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells
C S Pichot1, S M Hartig2, L Xia3, C Arvanitis4, D Monisvais4, F Y Lee5, J A Frost1 and S J Corey4
- 1Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas, USA
- 2Department of Cell Biology, Baylor College of Medicine, Houston, Texas, USA
- 3Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- 4Departments of Pediatrics and Cellular and Molecular Biology, Children's Memorial Hospital and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA
- 5Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, USA
Correspondence: Dr SJ Corey, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Lurie 5-107, 303 East Superior Street, Chicago, Illinois 60611, USA; E-mail: s-corey@northwestern.edu
Revised 22 April 2009; Accepted 27 April 2009; Published online 9 June 2009.
Abstract
Background:
Src family kinases control multiple cancer cell properties including cell cycle progression, survival, and metastasis. Recent studies suggest that the Src inhibitor dasatinib blocks these critical cancer cell functions.
Methods:
Because the molecular mechanism of action of dasatinib in breast cancers has not been investigated, we evaluated the effects of dasatinib as a single agent and in combination with the commonly used chemotherapeutic doxorubicin, on the proliferation, viability, and invasive capacity of breast cancer cells lines earlier categorised as dasatinib-sensitive (MDA-MB-231) and moderately resistant (MCF7 and T47D). We also tested the effects of these drugs on the actin cytoskeleton and associated signalling pathways.
Results:
The cell lines tested varied widely in sensitivity to growth inhibition (IC50=0.16–12.3 
M), despite comparable Src kinase inhibition by dasatinib (IC50=17–37 nM). In the most sensitive cell line, MDA-MB-231, dasatinib treatment induced significant G1 accumulation with little apoptosis, disrupted cellular morphology, blocked migration, inhibited invasion through Matrigel (P<0.01), and blocked the formation of invadopodia (P<0.001). Importantly, combination treatment with doxorubicin resulted in synergistic growth inhibition in all cell lines and blocked the migration and invasion of the highly metastatic, triple-negative MDA-MB-231 cell line.
Conclusion:
The observed synergy between dasatinib and doxorubicin warrants the re-evaluation of dasatinib as an effective agent in multi-drug regimens for the treatment of invasive breast cancers.
Keywords:
dasatinib, Src, invasion, invadopodia, breast cancer
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