Abstract 3828: Potent curcumin analogues inhibit pancreatic cancer cell growth and angiogenesis

Abstract

Abstract Background: Curcumin, a component of turmeric, has demonstrated anti-cancer properties mediated through inhibition of NF-κB in preclinical models. In clinical trials, curcumin failed to demonstrate activity against pancreatic cancer. The pharmacologic properties, low absorption, and low potency of curcumin may account for this discrepancy between preclinical and clinical results. Using the curcumin molecular model, our group synthesized over 100 analogs. Of these analogs, EF31 and UBS109 demonstrated higher potency in squamous cell cancer xenograft models as well as inhibition of NF-κB signaling pathways. Based on this preclinical data, we hypothesized that these analogs EF-31 and UBS-109 would be more effective in inhibiting growth of pancreatic cell lines than curcumin. Methods: MiaPaCa-2 and PANC-1 cell lines were used in the experiments. Cells were cultured and then treated with nothing (control), curcumin, UBS-109, EF-31, 5FU, or combination. Cell proliferation was evaluated using XTT assay. Western blot was used to evaluate effects on HSP90, HIF-1α, and VEGF levels. Angiogenic effects were measured by tube formation and chicken egg chorioallantoic membrane (Egg CAM) assays. Results: UBS-109 and EF-31 demonstrated significantly improved inhibition of cell proliferation as compared to curcumin. UBS-109 and EF-31 potentiated the growth inhibitory effects of 5FU. UBS-109 and EF-31 resulted in significant inhibition of expression of protein and mRNA for HSP90 and HIF-1α as compared to curcumin. In turn, UBS-109 and EF-31 significantly inhibited VEGF protein and mRNA expression resulting in inhibition of HUVEC tube formation in vitro and also inhibited angiogenesis in vivo using the Egg CAM assay. Conclusion: UBS-109 and EF-31 are more potent analogs of curcumin. Preliminary data demonstrate potentiation of chemotherapy effects as well as antiangiogenic effects. Evaluating UBS-109 and EF-31 in patients with pancreatic cancer is a rational approach to target HSP90 and HIF-1α in this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3828. doi:1538-7445.AM2012-3828