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Delphinidin: A Novel Agent for Inhibition of Breast Tumor Kinase Signaling by Targeting EGFR
Final rept. 1 Aug 2005-31 Jul 2007
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Epidermal growth factor receptor EGFR is expressed at high levels in at least 25 of breast cancers and is associated with poor prognosis. Upon epidermal growth factor EGF-stimulation breast tumor kinase Brk is recruited to the EGFR and this event activates the catalytic activity of Brk which in turn phosphorylates paxillin a binding partner and substrate for Brk. The phosphorylation of paxillin promotes the activation of RacI thereby stimulating cell migration and invasion in response to EGF. Many synthetic inhibitors of EGFR are known but their use is limited because of their unacceptable cytotoxic effects on normal cells. Therefdre identification of a natural nontoxic agents as an inhibitor of EGFR is of utmost importance. Delphinidin a major anthocyanin known to be present in pigmented fruits and vegetables inhibits constitutive and EGF-induced phosphorylation of EGFR activation of Pl3K phosphorylation of AKT and MAPK. We also found that delphinidin treatment inhibits constitutive and EGF-induced activation of Brk signaling mediated through EGFR. Furthermore treatment of breast cancer cells with delphindin inhibited cell growth and invasion and induced apoptosis. Taken together the composite result suggest that delphinidin is an effective inhibitor of EGFR signaling at least in breast cancer cells that act through novel Brk signaling pathway and holds great promise for its treatment.
APPROVED FOR PUBLIC RELEASE