Abstract 3678: Enhanced activity of chemotherapeutic drugs by blueberry anthocyanidins and withaferin A against human lung cancer cells.

Lung cancer is the leading cause of all cancer deaths in the U.S., Europe and the World. With only an expected 16% relative 5-year survival rate in the U.S., treatment of this aggressive and progressive disease continues to remain a fundamental problem. Moreover, resistance to chemotherapy is a major problem in cancer treatment. In an attempt to overcome drug resistance and improve treatment efficacy, new molecular targeted drugs are being developed and tested in clinical studies. Over the recent years various epidemiological studies have provided compelling evidence for the chemopreventive/therapeutic efficacies of various functional foods and natural products. We hypothesize that non-toxic natural compounds such as a native mixture of blueberry anthocyanidins (BB anthos) and withaferin A (WFA), alone and in combination with a suboptimal dose of the chemo drug paclitaxel (PAC) will have therapeutic response and also chemosensitize the lung cancer cells. We evaluated whether BB anthos could enhance the sensitivity of H1299 cells to PAC and reduce its effective dose to inhibit cell proliferation. Data show significantly enhanced cell death by PAC at a suboptimal concentration (1 nM) (IC50 ≈ 40 nM) when combined with 5 μM (25% vs. 5% inhibition) and 10 μM (49% vs. 5% inhibition) BB anthos (1:1 mixture of Dp, Cy, Mv, Pe and Pt). The significant inhibition of H1299 lung cancer xenografts in nude mice was also evident from the same combination, while no significant growth inhibition was observed with the individual entities. Since BB is a known antioxidant, we determined if BB anthos would attenuate oxidative stress-induced by PAC in H1299 lung cancer cells by measuring intracellular ROS production. Our data showed that addition of BB anthos (10 μM each) did not affect the ROS levels produced by PAC (10 nM), as determined by cell permeable fluorescence probe DCFH-DA. Similarly, we also determined the antiproliferative potential of WFA alone and in combination with chemo drugs, PAC and docetaxel (DOC) against non-small-carcinoma lung cancer cells. WFA demonstrated high antiproliferative activity against the growth of both H1299 and A549 cells as determined by MTT assay. When suboptimal concentrations of WFA were tested in combination with suboptimal concentration of DOC and PAC, significantly enhanced antiproliferative activities were observed against H1299 and A549 compared with individual entities. The combination effect was found to be synergistic as analyzed using the CalcuSyn software. Together, our results suggest that both BB anthos and WFA enhanced therapeutic response of chemo drugs against lung cancer and reduce their required dose thus minimizing their toxicity. (Supported from Duggan endowment fund.) Citation Format: Farrukh Aqil, Radha Munagala, Hina Kausar, Jeyaprakash Jeyabalan, Ramesh Gupta. Enhanced activity of chemotherapeutic drugs by blueberry anthocyanidins and withaferin A against human lung cancer cells. [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 3678. doi:10.1158/1538-7445.AM2013-3678