Melatonin synergizes the chemotherapeutic effect of 5‐fluorouracil in colon cancer by suppressing PI3K/AKT and NF‐κB/iNOS signaling pathways

• Published in: Journal of pineal research Vol. 62; no. 2; pp. np - n/a
• Main Authors: Gao, Yue, Xiao, Xiangsheng, Zhang, Changlin, Yu, Wendan, Guo, Wei, Zhang, Zhifeng, Li, Zhenglin, Feng, Xu, Hao, Jiaojiao, Zhang, Kefang, Xiao, Bingyi, Chen, Miao, Huang, Wenlin, Xiong, Shunbin, Wu, Xiaojun, Deng, Wuguo
• Format: Journal Article
• Language: English
• Published: England 01.03.2017
• Subjects: 5‐fluorouracil; AKT; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Blotting, Western; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chromatin Immunoprecipitation; colon cancer; Colonic Neoplasms - pathology; Drug Synergism; Fluorouracil - pharmacology; Humans; Immunohistochemistry; iNOS; melatonin; Melatonin - pharmacology; Mice; Mice, Nude; Microscopy, Confocal; NF-kappa B - metabolism; NF‐κB; Nitric Oxide Synthase Type II - metabolism; Phosphatidylinositol 3-Kinases - metabolism; PI3K; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Xenograft Model Antitumor Assays; 5-fluorouracil; NF-κB; PI3K; colon cancer; iNOS; AKT; melatonin
• ISSN: 0742-3098; 1600-079X
• DOI: 10.1111/jpi.12380

5‐Fluorouracil (5‐FU) is one of the most commonly used chemotherapeutic agents in colon cancer treatment, but has a narrow therapeutic index limited by its toxicity. Melatonin exerts antitumor activity in various cancers, but it has never been combined with 5‐FU as an anticolon cancer treatment to improve the chemotherapeutic effect of 5‐FU. In this study, we assessed such combinational use in colon cancer and investigated whether melatonin could synergize the antitumor effect of 5‐FU. We found that melatonin significantly enhanced the 5‐FU‐mediated inhibition of cell proliferation, colony formation, cell migration and invasion in colon cancer cells. We also found that melatonin synergized with 5‐FU to promote the activation of the caspase/PARP‐dependent apoptosis pathway and induce cell cycle arrest. Further mechanism study demonstrated that melatonin synergized the antitumor effect of 5‐FU by targeting the PI3K/AKT and NF‐κB/inducible nitric oxide synthase (iNOS) signaling. Melatonin in combination with 5‐FU markedly suppressed the phosphorylation of PI3K, AKT, IKKα, IκBα, and p65 proteins, promoted the translocation of NF‐κB p50/p65 from the nuclei to cytoplasm, abrogated their binding to the iNOS promoter, and thereby enhanced the inhibition of iNOS signaling. In addition, pretreatment with a PI3K‐ or iNOS‐specific inhibitor synergized the antitumor effects of 5‐FU and melatonin. Finally, we verified in a xenograft mouse model that melatonin and 5‐FU exerted synergistic antitumor effect by inhibiting the AKT and iNOS signaling pathways. Collectively, our study demonstrated that melatonin synergized the chemotherapeutic effect of 5‐FU in colon cancer through simultaneous suppression of multiple signaling pathways.