Curcumin and Salsalate Suppresses Colonic Inflammation and Procarcinogenic Signaling in High-Fat-Fed, Azoxymethane-Treated Mice

Abstract

High-fat diets (HFDs) and excess adiposity increase proinflammatory cytokines in the colon, altering gene expression in a manner that promotes the development of colorectal cancer (CRC). Thus, compounds that reduce this biochemical inflammation are potential chemopreventive agents. Curcumin (CUR), a dietary polyphenol, and salsalate (SAL), a non-steroidal anti-inflammatory drug, are both anti-inflammatories. We investigated the inhibitory effects of CUR with or without SAL on inflammatory cytokines and procarcinogenic signaling in azoxymethane (AOM)-treated A/J mice. A sub-tumorigenic AOM dose was chosen to produce a biochemical and molecular procarcinogenic colonic environment without tumors. Mice were fed either a HFD (60% of kilocalories) or low-fat diet (LFD) (10% of kilocalories). One HFD treatment group received 0.2% CUR in the diet; one received 0.2% CUR + 0.15% SAL; and one received 0.4% CUR + 0.3% SAL. The HFD mice developed 30% greater fat mass than the LFD mice (p < 0.05). The colonic concentrations of interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the HFD mice were decreased by 50-69% by the high-dose combination regimen (p < 0.015). Only the combination regimens significantly suppressed phosphorylation of protein kinase B (Akt) and nuclear factor-κB (NF-κB) p65 (p < 0.044). The combination of CUR and SAL reduces the concentration of proinflammatory cytokines and diminishes activation of Akt and NF-κB more effectively than CUR alone, providing a scientific basis for examining whether this combination mitigates the risk of CRC in obese individuals.

Dietary fats promote inflammation in Wistar rats as well as induce proliferation, invasion of SKOV3 ovarian cancer cells

“…IL1β and TNFα are also important cytokines induced by inflammatory processes, which are involved in the ovarian cancer development (Gupta, Babic, Beck, & Terry, 2016; Norman & Brännström, 1996; Schauer et al, 2013). The contribution of IL6, IL1β, and TNFα in dietary fat‐mediated cancer development has been reported in several studies (Chen et al, 2016; Duan et al, 2014; Hu et al, 2018; Liu et al, 2016; Olivo‐Marston et al, 2014; Wu, Pfalzer, et al, 2017). In a study, Xu et al revealed the high levels of IL1β, IL6, and TNFα in HFD TRAMP mice demonstrating crucial roles of these pro‐inflammatory cytokines in the development of prostate cancer (Xu et al, 2015).…”

The Combination of Curcumin and Salsalate is Superior to Either Agent Alone in Suppressing Pro‐Cancerous Molecular Pathways and Colorectal Tumorigenesis in Obese Mice

“…SAL (2‐carboxyphenyl salicylate, >98% pure) was purchased from TCI America (Portland, OR, USA). CUR was a gift from the Sabinsa Corporation (East Windsor, NJ, USA), the purity of which was >99%, as confirmed by HPLC . The V‐PLEX Proinflammatory Panel 1 (mouse) Kit and Tris Lysis Buffer containing 150 m m NaCl, 20 m m Tris, pH 7.5, 1 m m EDTA, 1m m EGTA, 1% Triton X‐100 were obtained from Meso Scale Discovery (Rockville, MD, USA).…”

“…CUR, which by itself can suppress pro‐inflammatory cytokines as well as downstream inflammatory pathways, has previously been shown to suppress tumorigenesis in rodent models, and to diminish aberrant crypt foci, an intermediary biomarker of CRC, in humans . It is therefore relevant that the abovementioned rodent study demonstrated that several aspects of the suppressive effects on colonic cytokines and signaling were greater with the combination of the two agents compared to CUR alone.…”

“…Further, the dose of each individual agent in the combination can often be reduced, minimizing side‐effects . Previously, we have demonstrated that the novel combination regimen of curcumin (CUR) and salsalate (SAL) suppresses colonic cytokines and the activation of Akt and NF‐κB pathways in the colonic mucosa of high‐fat diet (HFD)‐fed mice . CUR, which by itself can suppress pro‐inflammatory cytokines as well as downstream inflammatory pathways, has previously been shown to suppress tumorigenesis in rodent models, and to diminish aberrant crypt foci, an intermediary biomarker of CRC, in humans .…”

Incremental Elevations in TNFα and IL6 in the Human Colon and Procancerous Changes in the Mucosal Transcriptome Accompany Adiposity

“…TNFa, IL1b, and IL6 protein levels were measured in duplicate in plasma and colon using a chemiluminescence system [MesoScale Discovery (MSD)]. The choice of these cytokines was based on prior work indicating that these three cytokines are the most reliably elevated in the colons of obese mice (19,23,24). Colonic cytokine and total protein concentrations were measured in lysate preparations isolated from 2-3 colonic biopsies.…”