Abstract 3723: Tangeretin enhances sensitivity of human pancreatic cancer cells to gemcitabine through targeting the reprogramming of stemness.

Abstract

Abstract Background: As a single agent, gemcitabine (2′,2′-difluorodeoxycytidine) has shown only a modest improvement in survival in patients with pancreatic ductal adenocarcinoma (PDAC). Our recent studies found CCN1 (a member of CCN family of growth factor) as an important factor in determining PDAC aggressiveness as it promotes epithelial to mesenchymal transition, tumor stemness, migration and tumorigenicity in xenograft model, possibly through the regulation of multiple miRNAs that are known to link with the progression of cancers and survival and the maintenance of cancer stem cells. Targeting CCN1 may lead to the development of novel therapeutic approaches for human cancers. Here, we examined the effects of tangeretin, a polymethoxylated flavonoid compound produced by citrus fruits in combination of gemcitabine on CCN1-sonic hedgehog (SHh) signaling in pancreatic cancer cells, and assessed the therapeutic potential of tangeretin with gemcitabine for the treatment and/or prevention of pancreatic cancer. Methodology/Principal Findings: Cell viability and apoptosis were measured by crystal violet staining assay and annexinV/PI staining assay, respectively. Gene and protein expressions were measured by Western blot analysis, respectively. We found that tangeretin in combination with gemcitabine significantly decreased cell survival, clonogenicity, wound-healing capacity, sphere-forming capacity (pancreatospheres) in pancreatic cell lines. Tangeretin also decreased the expression of cancer stem cells (CSC) markers, CD44, Notch-1, Nanog, Oct-4, ABCG2, SHh and CCN1. Conclusions: Collectively, these studies clearly suggest that tangeretin helps in sensitizing pancreatic cancer cells to gemcitabine by reprogramming the CSC-specific markers. Thus tangeretin could be useful for overcoming therapeutic resistance of pancreatic cancer cells. Citation Format: Inamul Haque, Sushanta K. Banerjee, Snigdha Banerjee. Tangeretin enhances sensitivity of human pancreatic cancer cells to gemcitabine through targeting the reprogramming of stemness. [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 3723. doi:10.1158/1538-7445.AM2013-3723