Combined supplementation with vitamin b-6 and curcumin is superior to either agent alone in suppressing obesity-promoted colorectal tumorigenesis in mice

Authors: WU, XIAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; UELAND, PER - University Of Bergen; ROPER, JATIN - Duke University; KOH, GAR YEE - Texas State University; LIANG, XU - Massachusetts Institute Of Technology; CROTT, JIMMY - Boston University; YILMAZ, OMER - Massachusetts Institute Of Technology; BRONSON, RODERICK - Harvard University; MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/30/2021
Publication Date: 9/29/2021
Citation: Wu, X., Ueland, P.M., Roper, J., Koh, G., Liang, X., Crott, J.W., Yilmaz, O.H., Bronson, R.T., Mason, J.B. 2021. Combined supplementation with vitamin b-6 and curcumin is superior to either agent alone in suppressing obesity-promoted colorectal tumorigenesis in mice. Journal of Nutrition. https://doi.org/10.1093/jn/nxab320.
DOI: https://doi.org/10.1093/jn/nxab320

Interpretive Summary: Obesity increases the risk of developing colorectal cancer, and it does so largely by producing a low-grade level of inflammation in the lining of the colon. Therefore, agents that have anti-inflammatory effects might feasibly diminish the development of cancers in obese individuals. We examined the utility of a combination of vitamin B6 and curcumin to prevent tumor development in a mouse model of obesity-promoted colon cancer. Supplemental levels of these two agents at well-tolerated doses were added to the mouse diets in a five-arm study. The results showed that a high-fat diet did indeed produce obesity and increased tumor development compared to a low-fat diet and incited inflammation in the lining of the intestine. Supplemental curcumin alone, as well as B6 alone in obese mice diminished tumor development to a small, non-significant degree but the combination of the two diminished tumor development by 60-80%, a highly significant decrease. Similarly, only the combination significantly reduced inflammation and pro-cancerous biochemical pathways in the intestinal lining. Relevance to human biology was demonstrated by showing that the curcumin/B6 combination also diminished inflammation in colonies of colonic cells derived from the biopsies of individuals with obesity. These observations suggest that the combination of curcumin and vitamin B6 may provide cancer-preventive properties in overweight and obese individuals and provides the rationale for human trials.

Technical Abstract: Obesity increases the colorectal cancer risk, in part by elevating colonic proinflammatory cytokines. Curcumin (CUR) and supplemental vitamin B-6 each suppress colonic inflammation. We therefore examined whether the combination of CUR and vitamin B-6 amplifies each supplement's effects and thereby suppress obesity-promoted tumorigenesis. Male Friend Virus B (FVB) mice (4-week-old; n = 110) 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 mg pyridoxine HCl/kg), or a HFD containing both CUR and supplemental vitamin B-6 (C + B) 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. HFD-induced obesity produced a 2.6-fold increase in plasma IL-6 (P < 0.02), a 1.9-fold increase in fecal calprotectin (P < 0.05), and a 2.2-fold increase in tumor multiplicity (P < 0.05). Compared to the HFD group, the C + B combination, but not the individual agents, decreased fecal calprotectin (66%; P < 0.01) and reduced tumor multiplicity and the total tumor burden by 60%-80% (P < 0.03) in an additive fashion. The combination of C + B also significantly downregulated colonic phosphatidylinositol-4,5-bisphosphate 3-kinase, Wnt, and NF-?B signaling by 31%-47% (P < 0.05), 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 < 0.05) and a 1.3-fold higher colonic concentration of the active coenzymatic form of vitamin B-6 (P < 0.05). In human colonic organoids, micromolar concentrations of CUR, vitamin B-6, and their combination suppressed secreted proinflammatory cytokines by 41%-93% (P < 0.03), demonstrating relevance to humans. In this mouse model, C + B 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.