Abstract 2565: Delphinidin: A dual tyrosine kinase inhibitor of EGFR and VEGFR-2 reduces cell proliferation and induces apoptosis of non-small-cell lung cancer cells

Lung cancer has proven difficult to control with conventional therapeutic and surgical approaches, and the prognosis is poor with an overall 5-year survival rate of only 15% for non-small-cell lung cancer (NSCLC) in the USA. Over the last decade, the notions of targeting tyrosine kinase receptors for prevention and treatment of cancers have gained considerable attention. The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) have emerged as two clinically validated targets for NSCLC. Dual specific tyrosine kinase receptor inhibitors, which target two different classes of growth factor receptors, represent an elegant way to avoid multiple treatment modalities when used alone and in combination with various anti-signaling agents. The development of dietary agents with combined EGFR/VEGFR-2 inhibitory activities in the same molecule may be a step forward to improve antitumor efficacy and to broaden application possibilities. In our pursuit for identification of non-toxic dietary ingredients for prevention and treatment of cancer, we found that delphinidin, an anthocyanidin, present in pigmented fruits (such as pomegranate, berries, and dark grapes) and vegetables (such as egg plant, tomato, carrot and red onion), is a potent inhibitor of EGFR and VEGFR-2 in NSCLC cells. Employing EGFR and VEGFR-2 over expressing NSCLC cells (NCI-H441 and SK-MES-1); we evaluated the effect of delphinidin on EGFR/VEGFR-2 downstream signaling pathways. Delphinidin (5-60 μM) treatment of both NCI-H441 and SK-MES-1 cells inhibited the (i) activation of PI3K, and (ii) phosphorylation of AKT and mitogen activated protein kinases (such as ERK1/2, JNK1/2 and p38). We next determined whether inhibition of EGFR/VEGFR-2 signaling pathways by delphinidin exhibits growth inhibitory effect. We observed that delphinidin treatment of NCI-H441, SK-MES-1 and A-549 cells resulted in a dose-dependent inhibition of cell growth without having any substantial effect on normal human bronchial epithelial cells as assessed by an MTT assay. Treatment of NCI-H441 and SK-MES-1 cells with delphindin (5-60 μM) resulted in (i) cleavage of PARP protein, (ii) activation of caspase-3 and-9, (iii) downregulation of anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1), (iv) upregulation of pro-apoptotic proteins (Bax, Bid and Bak), and (v) decrease expression of PCNA and cyclin D1. In addition, we found that delphinidin was effective in reducing the invasive potential of NSCLC cells. This study identifies an abundant fruits and vegetables based anthocyanidin delphinidin as an effective blocker of EGFR and VEGFR-2 in lung cancer cells. Based on these observations, we suggest that delphinidin, alone or as an adjuvant to current therapies, could be useful for the management of NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2565. doi:1538-7445.AM2012-2565