Pomegranate By-Products in Colorectal Cancer Chemoprevention: Effects in Apc-Mutated Pirc Rats and Mechanistic Studies in vitro and ex vivo.

Scope: To investigate the effect of pomegranate mesocarp, a polyphenol-rich by-product of juice production, in colorectal cancer (CRC) chemoprevention. Methods and results: A mesocarp decoction (PMD) is administered for 6 weeks in the diet to Pirc rats, mutated in Apc, a key-gene in CRC. Mucin-depleted foci (MDFs), as CRC biomarkers, are reduced in PMD-fed rats compared to controls (MDF/colon: 344 versus 47 +/- 3, p = 0.02). There is an increase in apoptosis in MDFs from PMD-treated rats compared to controls (2.5 +/- 0.2 versus 1.6 +/- 0.2, p < 0.01). To elucidate the involved mechanisms, two colon-relevant metabolites of the polyphenolic and fiber PMD components, urolithin-A (u-A) and sodium butyrate (SB), are tested alone or in combination in vitro (colon cancer cells), and ex vivo in adenoma (AD) and normal mucosa (NM) from Pirc rats. u-A 25 mu m plus SB 2.5 mm (USB) causes a significant reduction in COX-2 protein expression compared to untreated controls (about -70% in cancer cell cultures, AD, and NM), and a strong increase in C-CASP-3 expression in cells (about ten times), in AD and NM (+74 and +69%). Conclusion: These data indicate a chemopreventive activity of PMD due, at least in part, to pro-apoptotic and anti-inflammatory action of its metabolites that could be exploited in high-risk patients.