Abstract 1884: Synergistic anti-cancer activities of berry anthocyanidins on human lung cancer cells (2010)

Abstract Emerging evidence suggest that cancer develops due to defects in multiple genes, therefore, a combination of naturally occurring compounds targeting multiple signal transduction pathways would be ideal for the prevention/treatment of cancer. Berries are emerging as one of the most effective fruits because of their potent antioxidant, antiproliferative and anti-inflammatory activities. The various biological activities of berries have been attributed to abundance of diverse phenolic constituents, particularly anthocyanins (anthocyanidins glycosides) that cause intense coloration. Several studies with individual anthocyanidins have been shown to inhibit malignant cell survival and confound many oncogenic signaling events. In this study we tested individual anthocyanidins (cyanidin, malvidin, peonidin, petunidin and delphinidin) and their mixture isolated from bilberry or black current for their abilities to inhibit the growth of two non small cell lung cancer (NSCLC) cells in culture and in vivo. The MTT cell proliferation assay demonstrated that all the five commercial anthocyanidins resulted in a dose- and time-dependent inhibition of H1299 and A549 cell growth, with delphinidin being the most potent. Interestingly, however, a 1:1 mixture of all these five anthocyanidins elicited significantly higher, dose-dependent, antiproliferative activity, indicating a synergistic effect. Selected glycosides of these anthocyanidins were found to be significantly less active. Assuming that the growth inhibition occurred due to induction of apoptosis mediated by cell-cycle arrest, we investigated the effect of individual anthocyanidins and their mixture on cell-cycle distribution and apoptosis. Flow-cytometric analysis of apoptosis with propidium iodide staining revealed that the induction of apoptosis was significantly greater with the mixture than either agent alone. The superior apoptotic effects of the combinatorial treatment were, in part, attributed to the enhanced cleavage of PARP, decreased expression of cyclin D1, cyclin B1 and pERK proteins in H1299 cells. Anti-tumor activity of delphinidin and the anthocyanidin mixture, isolated from black currant and bilberry, respectively was determined using nude mouse lung cancer xenograft model. We found that both delphinidin and the mixture of anthocyanidins reduced the H1299 tumor xenograft growth by 50% compared to the vehicle treatment. The effective dose of anthocyanidin mixture (0.5 mg/dose) was 3-times lower than delphinidin (1.5 mg/dose) when given i.p. on alternate days, indicating synergistic anti-tumor activity of anthocyanidins, consistent with our cell culture data. Together, our results suggest that increased consumption of bilberry, blueberry, or Indian blackberry or ‘jamun’ which are rich in this mixture of anthocyanidins would be useful for the prevention/treatment of NSCLC (Supported from KLCRP grant &amp; Duggan Endowment). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1884.