Dataset Information

Aspirin suppresses chemoresistance and enhances antitumor activity of 5-Fu in 5-Fu-resistant colorectal cancer by abolishing 5-Fu-induced NF-?B activation.

ABSTRACT: Chemoresistance to 5-fluorouracil (5-Fu)-based chemotherapy is a leading obstacle in achieving effective treatment for colorectal cancer (CRC). Typically, NF-?B activation induced by the chemotherapeutics themselves is an important cause resulting in chemoresistance. Specifically, NF-?B activation can inhibit tumor cell apoptosis and induce chemoresistance. Drugs that can prevent NF-?B activation induced by chemotherapeutics are urgently needed to overcome chemoresistance. Obviously, aspirin is one of these agents, which has been demonstrated to possess antitumor activities and as an inhibitor of NF-?B. The current study aimed to investigate whether aspirin was able to overcome the chemoresistance to 5-Fu in CRC, together with the potential synergistic mechanisms. Our results suggested that aspirin remarkably potentiated the inhibitory effect of 5-Fu on the growth and invasion of resistant cells in vitro. In vivo, aspirin markedly enhanced the antitumor activity of 5-Fu in suppressing tumor growth and metastasis, and down-regulating the expression of NF-?B-regulated genes in the 5-Fu-resistant cells. Obviously, aspirin completely eradicated the 5-Fu-induced NF-?B activation, without inducing pronounced adverse effects. Taken together, findings in this study suggest that aspirin can reverse chemoresistance and potentiate the antitumor effect of 5-Fu, which is achieved through abolishing the 5-Fu-induced NF-?B activation, suggesting that aspirin may be a promising adjuvant therapeutic agent for CRC.

SUBMITTER: Fu J

PROVIDER: S-EPMC6858464 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Aspirin suppresses chemoresistance and enhances antitumor activity of 5-Fu in 5-Fu-resistant colorectal cancer by abolishing 5-Fu-induced NF-κB activation.

Fu Jinbo J Xu Yiming Y Yang Yushan Y Liu Yun Y Ma Lulu L Zhang Yiyao Y

Scientific reports 20191115 1

Chemoresistance to 5-fluorouracil (5-Fu)-based chemotherapy is a leading obstacle in achieving effective treatment for colorectal cancer (CRC). Typically, NF-κB activation induced by the chemotherapeutics themselves is an important cause resulting in chemoresistance. Specifically, NF-κB activation can inhibit tumor cell apoptosis and induce chemoresistance. Drugs that can prevent NF-κB activation induced by chemotherapeutics are urgently needed to overcome chemoresistance. Obviously, aspirin is ...[more]

PMID: 31729451

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Project description:Alpha-ketoglutarate (AKG) is a critical nutritional factor in the maintenance of intestinal homeostasis. However, the relative mechanism of AKG has not been well understood. It was recently shown that the interaction between nuclear factor kappa B (NF-κB)-mediated inflammatory pathway and pregnane X receptor (PXR)-regulated detoxification pathway is a check and balance mechanism for keeping the homeostatic state of the intestine, preventing the onset of intestinal inflammation which may lead to cancer. In the current study we used lipopolysaccharide (LPS)-challenged piglet and intestinal porcine epithelial cells-J2 models to investigate the effects of dietary AKG supplementation on the intestinal immune system and PXR regulated target expression. We found that LPS induced significant activation of the NF-κB-mediated inflammatory pathway with concomitant impairment of intestinal nutrient absorption. AKG administration increased intracellular AKG and its metabolite concentrations and enhanced the mRNA expression of alpha-ketoglutarate dehydrogenase in vivo and in vitro. Thus dietary AKG supplementation reversed the adverse effects induced by LPS. We also found a strong inhibitory effects on the NF-κB-mediated inflammatory pathway, especially, in the AKG-treated intestinal tissues, LPS-induced NF-κB phosphorylation was inhibited and TNF-α was suppressed. Interestingly, AKG has potent effects in regulating the PXR and its downstream targets such as CYP3As and CYP2Bs in vivo and in vitro, although AKG is not a known PXR ligand. One potential mechanism for the up-regulation of the PXR pathway is through the down-regulation of NF-κB pathway which in turn de-represses the PXR-regulated target expression. Taken together, our results suggest that AKG improves intestinal immune system through modulating the interaction between PXR and NF-κB. Our findings have important implications for the prevention and treatment of intestinal inflammatory diseases in neonates.

Dataset Information

Aspirin suppresses chemoresistance and enhances antitumor activity of 5-Fu in 5-Fu-resistant colorectal cancer by abolishing 5-Fu-induced NF-?B activation.

Publications

Aspirin suppresses chemoresistance and enhances antitumor activity of 5-Fu in 5-Fu-resistant colorectal cancer by abolishing 5-Fu-induced NF-κB activation.

Similar Datasets

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