Abstract 1747: Biochanin A overcomes gemcitabine resistance in pancreatic cancer cells

Abstract

Abstract Drug resistance is one of the major reasons for failure of chemotherapy and high mortality rate in pancreatic cancer. Gemcitabine (GEM) and 5-fluorouracil are two drugs which have shown to improve the survival of pancreatic cancer patients but intrinsic or acquired characteristics make this cancer resistant to these drugs. Previously, we have observed that biochanin A (bioA) effectively reduces the survival, signaling and progression of pancreatic cancer cells. In this study, we aim at determining the effect of bioA on drug resistant pancreatic cancer cells. To test our hypothesis, first we compared three pancreatic cancer cells line: Panc1, MiaPaCa2 and AsPC1 for their sensitivity to gemcitabine and protein expressions. We found that Panc1 cells are highly resistant to GEM with IC50 of 75µM while the same for MiaPaCa2 and AsPC1 cells was 0.04µM. Our western blot data show that the levels of NFkappaB, EGFR and CD133 were higher in Panc1 cells compared to other two cell lines suggesting the role of these factors in imparting drug resistant characteristics to pancreatic cancer cells. Our cell survival studies show that bioA is more effective in reducing the survival of Panc1 cells compared to the other two cell lines. Next, we selected GEM resistant cells (AsPC/G) by continuously exposing AsPC1 cells with increasing concentration of GEM. We generated a GEM resistant cell line that was 20-fold resistant to GEM compared to the parent cell line. AsPC/G cells had higher colony formation ability and in vivo tumorigenicity compared to the parent cells. Also, the expression of p-EGFR, NFκB, p-Akt and EMT markers were upregulated in AsPC/G cell compared to AsPC1 cells. We found that bioA was more cytotoxic to AsPC/G cells compared to AsPC1 cells suggesting that bioA affects the molecular mechanisms which impart drug resistant characteristics. To further understand this phenomenon, we analyzed the molecular mechanisms affected by bioA. We observed that bioA reduces the levels of p-EGFR, p-Akt and NFκB in AsPC1 cells. Upregulation of these proteins is known to impart drug resistant characteristics to pancreatic cancer cells; therefore, by inhibiting them, bioA reduces the survival of GEM resistant pancreatic cancer cells. Our study concludes that bioA reduces the survival of GEM resistant pancreatic cancer cells and a treatment regimen with bioA may improve the outcome of chemotherapy in pancreatic cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1747. doi:10.1158/1538-7445.AM2011-1747