Oral administration of curcumin and salsalate attenuates high fat diet-induced up-regulation of pro-inflammatory colonic cytokines and suppresses Akt/NF kappa B signaling in azoxymethane-treated mice

Background Obesity, a robust risk factor for colorectal cancer (CRC), is known to elevate the concentrations of pro‐inflammatory cytokines in the murine colon. Also, signaling through the Akt pathway, which is known to be activated by pro‐inflammatory cytokines, is thought to play a role in colorectal carcinogenesis, in part by enhancing NFκB signaling. Further, we have previously demonstrated that high fat diets (HFD) and excess adiposity each alter the expression of the regulators of colonic Akt signaling in a pattern suggestive of Akt activation. Objective We sought to determine whether the combination of a pharmacologic agent and a dietary component that each possesses anti‐inflammatory properties might suppress obesity‐induced elevations in colonic cytokines and Akt/NFκB signaling, with the ultimate intent of mitigating the cancer‐promoting effect of obesity. Methods Curcumin (CUR), a natural polyphenol in turmeric, and salsalate (SAL) a non‐steroidal anti‐inflammatory drug (NSAID) that lacks the gastrointestinal toxicity of other NSAIDs, were tested alone and in combination in the azoxymethane (AOM) model of colonic carcinogenesis in 110 A/J mice, randomized to five groups including a control group receiving a low‐fat diet. AOM (7 mg/kg body weight, 4 weekly injections) in combination with a HFD that contained 60% kcals as fat was used induce a pro‐tumorigenic milieu in the colons of mice. Results The results showed that HFD‐mice had 30.4% greater fat mass and a lower lean mass than did low‐fat diet (10% kcal fat, LFD, p<0.005)‐mice. In the colonic mucosa of the obese mice addition of CUR and SAL (0.2% and 0.15% w/w, respectively) to the diet significantly diminished concentrations of IL‐1β and IL‐6 (p<0.015). Moreover, CUR/SAL co‐treatments also profoundly suppressed phosphorylation of Akt (p<0.044) and concurrently suppressed NF‐κB p65 signaling (p<0.042). Conclusions Our results demonstrate, for the first time, that co‐administration of CUR and SAL in very low, well‐tolerated, concentrations attenuates inflammatory cytokine levels, Akt activation, and NFkB signaling in the colons of AOM/HFD mice, providing a scientific rationale for using this combination as a chemopreventive regimen to mitigate the risk of obesity‐associated colon cancer. Support or Funding Information Tufts Collaborates Grant; United States Department of Agriculture, Cooperative Agreements #58‐1950‐0‐014 and #58‐1950‐4‐003