Inactivation of survival pathways such as NF-κB, cyclooxygenase (COX-2) or epidermal growth factor receptor (EGFR) signaling individually may not be sufficient for the treatment of advanced pancreatic cancer (PC). Since these pathways are well known in the pathogenesis and aggressiveness of PC, we hypothesized that a multitargeted approach for the inhibition of NF-κB, COX-2 and EGFR may therefore be useful to improve the outcome of anti-EGFR therapies and will also potentiate the anti-tumor effects of gemcitabine. In this study, we determined the cell viability in seven PC cell lines with 3,3′-diindolylmethane (B-DIM), erlotinib or gemcitabine alone or in combination using MTT assay. Significant inhibition in cell viability and induction in apoptosis was observed in PC cells expressing high levels of COX-2, EGFR, and NF-κB proteins. A significant down-regulation in the expression of COX-2, NF-κB and EGFR in BxPC-3, COLO-357 and HPAC cells was observed, suggesting that multi-targeting of EGFR, NF-κB and COX-2 is more effective than targeting either signaling pathway separately. Most importantly, our in vivo results using animal model showed that B-DIM in combination with erlotinib and gemcitabine was significantly more effective than individual agents and these results were consistent with in vitro findings. Based on our pre-clinical in vitro and in vivo results, we conclude that this multi-targeted combination could be developed for the treatment of PC patients whose tumors express high levels of COX-2, EGFR and NF-κB.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5420.