Abstract 3666: Delphinidin reduces cell proliferation and induces apoptosis of non-small cell lung cancer cellsin vitroandin vivo.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Lung cancer is a major health problem worldwide and accounts for approximately 28% of all cancer-related deaths in the USA. Like most cancers, lung cancer is a conglomeration of diseases of diverse etiology, broadly divided into small-cell lung cancer (SCLC, comprising 20% of lung cancers), and non-small-cell lung cancer (NSCLC, comprising 80% of lung cancers). 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 NSCLC in the USA. The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) have emerged as two clinically validated targets for NSCLC. The development of dietary agents which exhibit combined EGFR/VEGFR-2 inhibitory activities may be a step forward to improve antitumor efficacy and to broaden application possibilities. In our pursuit for the identification of non-toxic dietary ingredients for prevention and treatment of cancer, we found that delphinidin, an anthocyanidin, present in pigmented fruits and vegetables, is a potent inhibitor of both EGFR and VEGFR-2 in NSCLC cells. In the present study, we determined the effects of delphinidin on cell growth and apoptosis in vitro and on tumor growth and angiogenesis in vivo in NSCLC cells that overexpress EGFR/VEGFR-2. Delphinidin (5-60 μM) treatment of NSCLC cells inhibited the (i) activation of PI3K, and (ii) phosphorylation of AKT and MAPKs. We next determined whether inhibition of EGFR/VEGFR-2 signaling pathways by delphinidin exhibits a growth inhibitory effect. We observed that delphinidin treatment of NCI-H441, SK-MES-1 and A549 cells resulted in a dose-dependent inhibition of cell growth without having any substantial effects on normal human bronchial epithelial cells as assessed by 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 and Bak), and (v) decreased expression of PCNA and cyclin D1. In athymic nude mice implanted with human NSCLC cells (NCI-H441 or SK-MES-1), delphinidin (1-2 mg, i.p. thrice-weekly) treatment caused a significant inhibition of tumor growth. There was also a decrease in the expression of markers for cell proliferation (Ki-67 and PCNA) and angiogenesis (CD31 and VEGF) as well as an induction of apoptosis in tumor tissues treated with delphinidin, when compared with tumor tissues of control mice. Based on these observations, we suggest that delphinidin, alone or as an adjuvant to current therapies, could be useful for the management of NSCLCs, especially those that overexpress EGFR and VEGFR-2. Citation Format: Harish C. Pal, Samriti Sharma, Craig A. Elmets, Farrukh Afaq. Delphinidin reduces cell proliferation and induces apoptosis of non-small cell lung cancer cells in vitro and in vivo . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3666. doi:10.1158/1538-7445.AM2013-3666