In addition, although capsacin has been shown to suppress human fibrosarcoma-induced angiogenesis in chick chorioallantoic membrane assay by inhibiting VEGF-induced proliferation, and capillary-like tube formation of primary cultured human endothelial cells, the effect of this phytochemical on the VEGF expression in NSCLC cell has not yet been explored in detail. Our results signify that while impediment of p53-SMAR1 loop induced VEGF expression in NLCSC cells thereby favoring endothelial cell migration and network formation in tumor environment, reframing of these pro-angiogenic signals by capsaicin blocked VEGF production even under hypoxic condition, thereby restraining NSCLC-induced net work formation by the endothelial cells. Such development in understanding may offer the panorama of exclusively targeting pro-angiogenic factors and pathways to achieve more efficient and cogent lung cancer therapy. Highly resistant non-small cell lung cancer is one of the major causes of cancer death across the world and angiogenesis has emerged as an integral process in promoting the growth and metastasis of NSCLCs. Inhibition of VEGF, one of the key mediators of angiogenesis, by molecular-targeting agent may, therefore, be an important approach towards development of potential anticancer therapy for regressing NSCLC. However, in spite of modest positive outcome with the use of anti-angiogenic drugs based on some clinical trials, no long-term survival benefits have been documented as yet for different cancers. In addition, toxicity of most of these drugs towards normal cells as well as development of drug-resistance in tumor cells necessitated investigations into alternative compounds to improve current therapeutic management. Recently capsaicin has been recognized for its pharmacological and toxicological properties and for selectively suppressing the growth of various human tumor cell lines. However, although there is considerable clinical interest in regressing NSCLC by halting tumor-angiogenesis, there is no scientific evaluation of the molecular mechanisms underneath the effect of capsaicin in the management of NSCLCinduced angiogenesis. The present study portrayed detailed molecular mechanisms underlying the anti-angiogenic effect of capsaicin, the major pungent ingredient from red chili pepper. According to Patel et al., capsaicin treatment inhibited NFkB activation and cell proliferation, but enhanced VEGF production by enhancing HIF-1a expression and binding to hypoxia response element in human malignant melanoma cells. These findings support the hypothesis that inhibition of growth-signaling pathways by capsaicin might trigger tumor cells to produce paracrine factors such as VEGF, critical for neovascularization, allowing tumors to survive and progress. Contradicting this hypothesis, Min et al. demonstrated suppression of human fibrocarcoma-induced angiogenesis in chick chorioallantoic membrane assay by capsaicin.