The combination of curcumin and salsalate is superior to either agent alone in suppressing pro-cancerous molecular pathways and colorectal tumorigenesis in obese mice

Authors: WU, XIAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KOH, GAR YEE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HUANG, YUEYI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CROTT, JIMMY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BRONSON, RODERICK - Harvard University; MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Molecular Nutrition and Food Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/24/2019
Publication Date: 2/4/2019
Citation: Wu, X., Koh, G., Huang, Y., Crott, J.W., Bronson, R.T., Mason, J.B. 2019. The combination of curcumin and salsalate is superior to either agent alone in suppressing pro-cancerous molecular pathways and colorectal tumorigenesis in obese mice. Molecular Nutrition and Food Research. https://doi.org/10.1002/mnfr.201801097.
DOI: https://doi.org/10.1002/mnfr.201801097

Interpretive Summary: High-fat diets (HFDs) and adiposity increase colorectal cancer risk, in part by elevating inflammation that activates cancer-causing cellular signaling pathways. Curcumin (CUR), a dietary natural compound from turmeric, and salsalate (SAL), a non-steroidal anti-inflammatory drug (NSAID) lacking the side effects of aspirin, each suppress inflammation, but via different mechanisms. Mice are fed a low-fat diet (LFD), a HFD, a HFD containing 0.4% CUR, a HFD containing 0.3% SAL, or a HFD containing both agents (CUR/SAL). Compared to LFD-fed mice, HFD-fed mice display elevated level of inflammation, abnormal cell growth and division, and increased tumor formation. CUR/SAL significantly reduces colonic inflammation, suppresses activation of tumor-causing signaling pathways, activates tumor-suppressive pathways, attenuates abnormal colon cell growth, and reduces tumor metrics, in comparison to the HFD control. In contrast, CUR or SAL alone does not suppress abnormal cell growth or tumor metrics, and is largely ineffective in modifying these signaling pathways. These observations demonstrate the superiority of the CUR/SAL over the individual agents and provide a scientific basis for future clinical studies in obese subjects and/or those habitually consuming HFDs.

Technical Abstract: Scope: High-fat diets (HFDs) and adiposity increase colorectal cancer risk, in part by elevating pro-inflammatory cytokines that activate pro-cancerous signaling pathways. Curcumin (CUR), a dietary polyphenol and salsalate (SAL), an non-steroidal anti-inflammatory drug (NSAID) lacking the gastrotoxicity of aspirin, each suppress inflammatory signaling, but via different cellular pathways. Methods and Results: A/J mice (n = 110) are fed a low-fat diet (LFD, 10% kcal), a HFD (60% kcal), a HFD containing 0.4% CUR, a HFD containing 0.3% SAL, or a HFD containing both agents (CUR/SAL). All mice receive six injections of azoxymethane. Compared to LFD-fed mice, HFD-fed mice display elevated colonic cytokines, crypt cell proliferation, and increased tumorigenesis (p < 0.05). CUR/SAL significantly reduces colonic cytokines (p < 0.01), suppresses activation of the PI3K/Akt/mTOR/NF-kappaB/Wnt pathways (p < 0.01), activates AMPK (p < 0.01), attenuates abnormal proliferation of the colonic mucosa (p < 0.05), and reduces tumor multiplicity and burden (p < 0.05), in comparison to the HFD control. In contrast, CUR or SAL alone does not suppress abnormal crypt cell proliferation or tumor multiplicity, and is largely ineffective in modifying activation of these signaling pathways. Conclusion: These observations demonstrate the superiority of the CUR/SAL over the individual agents and provide a scientific basis for future translational studies in obese subjects and/or those habitually consuming HFDs.