Combined Supplementation with Vitamin B-6 and Curcumin is Superior to Either Agent Alone in Suppressing Obesity-Promoted Colorectal Tumorigenesis in Mice.

Abstract

BACKGROUND\nObesity increases the colorectal cancer risk, in part by elevating colonic proinflammatory cytokines. Curcumin (CUR) and supplemental vitamin B-6 each suppress colonic inflammation.\n\n\nOBJECTIVES\nWe examined whether the combination of CUR and vitamin B-6 amplifies each supplement s effects and thereby suppress obesity-promoted tumorigenesis.\n\n\nMETHODS\nMale Friend Virus B (FVB) mice (4-week-old; n\xa0=\xa0110) received 6 weekly injections of azoxymethane beginning 1 week after arrival. Thereafter, they were randomized to receive a low-fat diet (10% energy from fat), a high-fat diet (HFD; 60% energy from fat), a HFD containing 0.2% CUR, a HFD containing supplemental vitamin B-6 (24\xa0mg pyridoxine HCl/kg), or a HFD containing both CUR and supplemental vitamin B-6 (C\xa0+\xa0B) for 15 weeks. Colonic inflammation, assessed by fecal calprotectin, and tumor metrics were the primary endpoints. The anti-inflammatory efficacy of the combination was also determined in human colonic organoids.\n\n\nRESULTS\nHFD-induced obesity produced a 2.6-fold increase in plasma IL-6 (P\xa0<\xa00.02), a 1.9-fold increase in fecal calprotectin (P\xa0<\xa00.05), and a 2.2-fold increase in tumor multiplicity (P\xa0<\xa00.05). Compared to the HFD group, the C\xa0+\xa0B combination, but not the individual agents, decreased fecal calprotectin (66%; P\xa0<\xa00.01) and reduced tumor multiplicity and the total tumor burden by 60%-80% (P\xa0<\xa00.03) in an additive fashion. The combination of C\xa0+\xa0B also significantly downregulated colonic phosphatidylinositol-4,5-bisphosphate 3-kinase, Wnt, and NF-κB signaling by 31%-47% (P\xa0<\xa00.05), effects largely absent with the single agents. Observations that may explain how the 2 agents work additively include a 2.8-fold increased colonic concentration of 3-hydroxyanthranillic acid (P\xa0<\xa00.05) and a 1.3-fold higher colonic concentration of the active coenzymatic form of vitamin B-6 (P\xa0<\xa00.05). In human colonic organoids, micromolar concentrations of CUR, vitamin B-6, and their combination suppressed secreted proinflammatory cytokines by 41%-93% (P\xa0<\xa00.03), demonstrating relevance to humans.\n\n\nCONCLUSIONS\nIn this mouse model, C\xa0+\xa0B is superior to either agent alone in preventing obesity-promoted colorectal carcinogenesis. Augmented suppression of procancerous signaling pathways may be the means by which this augmentation occurs.