The in vivo preventive and therapeutic properties of curcumin in bile reflux-related oncogenesis of the hypopharynx

Abstract

Bile at strongly acidic pH exerts a carcinogenic effect on the hypopharynx, based upon recent pre-clinical studies that support its role as an independent risk factor. We recently demonstrated in vitro that curcumin can prevent oncogenic profile of bile in human hypopharyngeal cells, by inhibiting NF-κB. We hypothesize that topically applied curcumin to the hypopharynx can similarly block early oncogenic molecular events of bile, by inhibiting NF-κB and consequently altering the expression of genes with oncogenic function. Using Mus musculus (C57Bl/6J), we topically applied curcumin (250 μmol/L; three times per day; 10 days) to the hypopharynx, 15 minutes before, 15 minutes after or in combination with bile acids (pH 3.0). Immunohistochemical analysis and qPCR revealed that topically applied curcumin either before, after or in combination with acidic bile exposure significantly suppressed its induced NF-κB activation in regenerating epithelial cells, and overexpression of Rela, Bcl2, Egfr, Stat3, Wnt5a, Tnf, Il6, Ptgs2. Akt1 was particularly inhibited by curcumin when applied simultaneously with bile. We provide novel evidence into the preventive and therapeutic properties of topically applied curcumin in acidic bile-induced early oncogenic molecular events in hypopharyngeal mucosa, by inhibiting NF-κB, and shaping future translational development of effective targeted therapies using topical non-pharmacologic inhibitors of NF-κB.

Keywords: Bcl2; Egfr; Stat3; NF-κB; bile; curcumin; hypopharyngeal cancer; laryngopharyngeal reflux.