Abstract
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 one of these agents, which has been demonstrated to possess antitumor activities and as an inhibitor of NF-κB. 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-κB-regulated genes in the 5-Fu-resistant cells. Obviously, aspirin completely eradicated the 5-Fu-induced NF-κB 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-κB activation, suggesting that aspirin may be a promising adjuvant therapeutic agent for CRC.
Highlights
Colorectal cancer (CRC), one of the most common malignancies, accounts for the second leading cause of cancer-related deaths in the USA1
The results showed that aspirin reduced cell viability in a dose-dependent manner, and no obvious difference was observed between 5-Fu-resistant cells and their parental cells, suggesting no cross-resistance between aspirin and 5-Fu (Fig. 1A–C)
5-Fu treatment alone had a minimal effect on preventing the metastasis of chemoresistant colorectal cancer (CRC) cells, aspirin treatment dramatically enhanced the efficacy of 5-Fu in a synergistic manner, and the greatest effect was observed in the combined treatment group
Summary
Colorectal cancer (CRC), one of the most common malignancies, accounts for the second leading cause of cancer-related deaths in the USA1. One recent study demonstrates that aspirin probably improves the clinical outcomes of metastatic CRC patients receiving capecitabine, a derivative of 5-Fu, after the failure of standard chemotherapy[9]. Such results suggested that aspirin potentially boosted the chemosensitivity of CRC to 5-Fu-based chemotherapy. Our results suggested that aspirin, as a sensitizer, reversed the chemoresistance of CRC cells to 5-Fu and enhanced the antitumor effects of 5-Fu both in vivo and in vitro, without inducing additional toxicity, and such effects were achieved by abolishing the 5-Fu-induced NF-κB activation
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