Abstract
Abstract Pancreatic carcinoma (PC) is a deadly form of cancer with poor overall survival. Currently, chemotherapeutic such as gemcitabine and 5-fluorouracil (5-FU) are the most popular medication that can slightly improve survival, but rapid drug-resistance makes it urgent to search for more effective drugs. In hunting for natural components that cure PC, we found that arenobufagin, a cardiac glycosides-like compound, showed significant effects on the gemcitabine-resistant cell line Panc-1, the gemcitabine-sensitive cell line ASPC-1 and K-Ras activating HPNE cells at nanomolar concentrations. We used MTT and clonogenic survival assays to examine survival and proliferation and western blotting to assess changes of K-Ras downstream and apoptosis related proteins. We also detected the cell cycle and migration by flow cytometry and wound healing assay. Arenobufagin inhibited cellular survival and proliferation, decreased the phosphorylation of key proteins of K-Ras downstream such as Akt, Erk and nuclear factor kappa B (NF-κB), induced cell cycle G2/M arrest and apoptosis, and downregulated the level of phosphorylated epidermal growth factor receptor (EGFR). Most importantly, our data showed that arenobufagin can enhance the sensitivity of PC cells to gemcitabine and 5-fluorouracil (5-FU). Arenobufagin could enhance the effect of gemcitabine and 5-FU on PC cells through targeting multiple key proteins. All above makes arenobufagin a novel agent for combination therapy of pancreatic carcinoma. Citation Format: Tianjiao Wang, Yuhui Yuan. Arenobufagin targets K-Ras downstream to enhance the efficiency of gemcitabine in human pancreatic carcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2696. doi:10.1158/1538-7445.AM2015-2696
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