Abstract C43: Potential role of isorhamnetin to overcome chemoresistance in gastric cancer

Abstract

Abstract Background: Gastric cancer (GC), including cancer of the esophagogastric junction, is the fourth most common malignant tumor and the second-most common cause of cancer-related death. Though treatment options such as chemotherapy, radiotherapy and surgery are available, only a modest survival rate has been observed, with the most common complications being chemoresistance and tumor recurrence. Majority of gastric adenocarcinomas have been related to chronic inflammation induced by Helicobacter pylori infection. Peroxisome proliferator-activated receptors are ligand-activated intracellular transcription factors that have been implicated in inflammation. Emerging information also implicates that peroxisome proliferator-activated receptor gamma (PPAR-γ) has been found to inhibit cancer cell growth and induce apoptosis in gastric cancer cells. The use of anti-cancer drugs from natural sources have been of major interest since they can help overcome resistance without some of the debilitating side effects of conventional chemotherapy. Isorhamnetin (IH), a derivative of quercetin, is one such compound that has been found to have antioxidative and antiproliferative effects. In our study, we investigate whether IH can modulate the PPAR-γ signaling cascades in gastric cancer cells and help in inhibiting tumor cell growth. Method: Various metastatic gastric cancer cell lines were used in the study. To investigate the effect of IH on gastric cancer cells, we used techniques such as cell proliferation assays, wound healing assay, matrigel invasion assay, western blot analysis, cell cycle analysis and live and dead assay. Whether IH could induce activation of PPAR-γ was investigated by reporter assay. Results: Molecular docking analysis showed that IH formed interactions within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity. This was further confirmed by the reporter assay in which IH was found to induce activation of PPAR-γ. IH also downregulates various PPAR-γ related gene products including survivin, Bcl-2 and Bcl-xL. Isorhamnetin inhibited cell proliferation and was found to increase sub-G1 accumulation in a time-dependent manner suggesting apoptotic induction in gastric cancer cells; IH also reduced the migratory and invasive properties of GC cells effectively as assessed by wound healing assay and matrigel invasion assay. We also observed that IH could potentiate the apoptotic effects of capecitabine. We suggest for the first time that the anti-cancer effects of IH might involve the activation of PPAR-γ by binding to the receptor and affecting its regulated gene products. Conclusion: Our data suggest that isorhamnetin may be a potential candidate in the treatment of gastric cancer through activation of PPAR-γ. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C43.