Obesity increases colorectal cancer (CRC) risk, in part by elevating colonic pro-inflammatory cytokines that activate pro-carcinogenic signaling pathways. We and others have found that curcumin (CUR), a dietary polyphenol, and supplemental vitamin B6 at 4-times the basal requirement, each suppresses inflammatory signaling via different molecular mechanisms. Four-week-old male FVB mice (n=110) were given 6 i.p. injections of azoxymethane, a colonic carcinogen, after a week of acclimation. Mice were then randomized to receive 1 of 5 experimental diets: (1) a low-fat diet (LFD, 10% kcal), (2) a high-fat diet (HFD, 60% kcal), (3) a HFD containing 0.2% CUR, (4) a HFD containing B6 (24 mg/kg, at 4-times the basal requirement), or (5) a HFD containing both agents (B6/CUR). Body composition was determined by rodent MRI, and all mice were sacrificed at 22 weeks after arrival. Mice consuming the HFD without additives (Group 2) achieved a modest, but significant, degree of adiposity compared to the LFD-fed mice (Group 1, p&lt;0.04). Compared to LFD-fed mice, HFD-induced obesity greatly promoted chronic inflammation and colon tumorigenesis, as evidenced by enhanced systemic concentrations of interleukin-6 (p&lt;0.02), fecal calprotectin (p&lt;0.05) and tumor multiplicity (p&lt;0.05). CUR/B6 combination significantly reduced tumor multiplicity and burden (p&lt;0.03), and decreased calprotectin concentration in feces (p&lt;0.01). In contrast, neither agent by itself was sufficient to produce a significant reduction in these tumor metrics. Furthermore, we found that the combination of CUR/B6 significantly down-regulated some critical pro-carcinogenic signaling pathways in the colon, including PI3K, Wnt and NF-κB (p&lt;0.05). Interestingly, LC-MS/MS analysis showed that the CUR/B6 group achieved a significantly higher concentration of pyridoxal phosphate (PLP, the active form of B6) in the colonic mucosa, compared with the B6 intervention alone, suggesting a mechanism by which the synergy of the two agents occurs. The CUR/B6 combination also appeared to alter the metabolic pathway of tryptophan, as evidenced by greater steady-state colonic concentrations of 3-hydroxyanthranillic acid (HAA) and picolinic acid (PA), compared to the HFD-fed control. These observations demonstrate that the combination of B6/CUR is superior to either alone in preventing obesity-promoted CRC. This synergy appears to operate by suppression of cell signaling pathways known to be important in colonic carcinogenesis.

Vitamin B6 and curcumin co-treatment is superior to either agent alone in suppressing obesity-associated colorectal tumorigenesis in mice

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.