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

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‐κB/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.

Bioactive Components of Polyphenol-Rich and Non-Polyphenol-Rich Cranberry Fruit Extracts and Their Chemopreventive Effects on Colitis-Associated Colon Cancer

“…A large number of studies have demonstrated that colonic inflammation, including obesity-induced low-grade inflammation, and that occurred in IBD could greatly elevate the risk of colon cancer in various experimental settings. ,, Inflammatory cytokines and chemokines promote tumor growth, hinder the differentiation of tumorous cells, and support their survival . Therefore, we next evaluated the anti-inflammatory effects of the cranberry extracts in the colon of AOM/DSS-treated mice by real-time qRT-PCR analysis.…”

Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer

“…Curcumin also prevents the epithelial-mesenchymal transition, positively regulating NKD2 expression [ 123 ]. Furthermore, curcumin induces apoptosis and inhibits tumor cell proliferation and tumor number induced by AOM/DSS protocol by downregulation of the β-catenin protein levels in mice treated orally with 500 mg/kg [ 122 , 124 , 160 ]. AXIN2 (Axin2), a known Wnt target gene, was also downregulated in the same mice.…”

Modulation of TLR/NF-κB/NLRP Signaling by Bioactive Phytocompounds: A Promising Strategy to Augment Cancer Chemotherapy and Immunotherapy

“…The results demonstrated that combination treatment inhibited the growth of liver cancer, reduced the expression of PD-L1, and suppressed the TLR4/NF-κB and NF-κB/matrix metalloproteinase-9 (MMP-9) signaling pathways ( 94 ). Curcumin exerts antineoplastic effects on various in vitro and in vivo cancer models, including lung ( 95 ), colorectal ( 96 – 98 ), bladder ( 99 , 100 ), pancreatic ( 101 , 102 ), and breast ( 103 ) cancers via interfering with the expression of TNF-α, HIF-1α, COX-2, VEGF, NF-κB, Axin2, IL-10, IL-8, and IL-6 and participating in the PI3K/Akt/mTOR/NF-κB/Wnt pathway. Additionally, curcumin promoted apoptosis, inhibited NF-κB, MMP-9, MMP-2, and MAPK, and activated sirtuin 1 (SIRT1) in HNSCC, osteoclastoma, and monocytic leukemia SHI-1 cancer cells ( 104 – 107 ).…”