Alterations in multiple signaling pathways are a hallmark of most epithelial cancers, including pancreatic (PC) and colon cancers (CC). In principle, agents such as dietary bioactive compounds that affect multiple pathways should exhibit superior effectiveness due to their pleiotrophic actions compared to single pathway targeted therapies. Earlier we had shown that thymoquinone (TQ), a bioactive agent derived from edible black seed plant Nigella Sativa exerts anticancer activity against PC and CC alone or can enhance the effects of chemotherapeutics through mechanisms involving down-regulation of multiple pathways [such as NF-kB, cell cycle, inflammation, anti-apoptosis and angiogenic signaling (Cancer Research 69(13) 2009)]. However, due to poor bioavailability the anti-tumor effects of TQ that are observed at pharmacological high doses (>25 µM in vitro that translates to ∼7.4 g/kg in humans) cannot be considered clinically relevant. To address this problem we have developed a series of potent TQ analogs and among them two (TQ-THB and TQ-TFB patent pending) were found to have greater potency (growth inhibition and apoptosis) than parent TQ (IC50s 5 and 7µM respectively). TQ-THB and TQ-TFB not only show superior in vitro activity against PC, they also demonstrate greater anti-tumor activity in a highly metastatic BxPC-3 pancreatic xenograft model. The analogs are well tolerated and can be given i.v. Most interestingly, these analogs synergize with gemcitabine and FOLFOX that are the standard care for pancreatic and colon cancer respectively. The synergy was found both in cell culture and animal tumor models. Molecular Docking studies revealed that both TQ-THB and TQ-TFB binds very strongly to Cox-2 and NF-kB. This suggests that the analogs work by inhibiting the tumor survival and angiogenic pathways. Based on our novel findings we believe that these dietary analogs hold promise as anticancer agents that warrant further clinical development.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3706. doi:10.1158/1538-7445.AM2011-3706

©2011 American Association for Cancer Research
2011