Molecular radiobiologyDasatinib, a multi-kinase inhibitor increased radiation sensitivity by interfering with nuclear localization of epidermal growth factor receptor and by blocking DNA repair pathways
Section snippets
Materials
Dasatinib was obtained from Bristol-Myers Squibb (New York, NY). Primary antibodies, EGFR, Her-2, PARP and tubulin were from Santa Cruz Biotechnology Inc. (Santa Cruz, CA). All other primary antibodies were from Cell Signaling Technology (Beverly, MA). Secondary antibodies conjugated with horse-radish peroxidase and ECL-plus were from GE Healthcare (Piscataway, NJ). Fluorescent probes, DAPI was from Sigma Chemical Company (St. Louis, MO), YO-PRO1 was from Invitrogen Life Technologies (Carlsbad,
Basal levels of c-Src and EGFR in HNSCCs
Whole cell lysates were processed for Western blot analysis and expression levels of c-Src and EGFR were quantified. Fig. 1A shows that all HNSCCs constitutively expressed c-Src protein. However, EGFR expression levels were higher in HN-5 and MDA-183 than the other four cell lines. Assessment of cell viability by MTT assay showed that dasatinib (5–200 nM, 72 h) exerted differential effect on the six lines tested. The IC50 values for four cell lines (HN-5, UMSCC-1, MDA-183 and UMSCC-22A) ranged
Discussion
The present study demonstrated that dasatinib has the potential to increase tumor cell response to radiotherapy in some tumors but not in others. Our study suggests three ways in which c-Src and its inhibition may differentially regulate cellular viability and radiation sensitivity.
First, HNSCCs may possess alternative pathways for survival. Dasatinib suppressed phosphorylation of its target molecule, c-Src and FAK, a protein that is associated with c-Src activity in HN-5 and FaDu cell lines
Conflict of Interest Statement
Dr. K.K. Ang served on Advisory Board of Bristol-Myers Squibb Company. All other authors have no conflict of interest.
Acknowledgments
This study was supported by a sponsored agreement with Bristol-Myers Squibb Company (U.R.), Multidisciplinary Research Program at University of Texas M.D. Anderson Cancer Center (B.G.), DAMD17-01-1-0689 05, DOD US Army (B.G.), NIH PO-1 Grant CA-06294 (K.K.A.), Gilbert H. Fletcher Memorial Distinguished Chair (K.K.A.) and a UICC ACSBI fellowship supplemented by University of Zurich (O.R.).
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Current address: Department of Radiation Oncology, University Hospital Zurich, Ramistrasse 100, 8091 Zurich, Switzerland.