Abstract Title:

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

Abstract Source:

J Pineal Res. 2016 Nov 19. Epub 2016 Aug 19. PMID: 27865009

Abstract Author(s):

Yue Gao, Xiangsheng Xiao, Changlin Zhang, Wendan Yu, Wei Guo, Zhifeng Zhang, Zhenglin Li, Xu Feng, Jiaojiao Hao, Kefang Zhang, Bingyi Xiao, Miao Chen, Wenlin Huang, Shunbin Xiong, Xiaojun Wu, Wuguo Deng

Article Affiliation:

Yue Gao


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 anti-tumor activity in various cancers, but it has never been combined with 5-FU as an anti-colon cancer treatment to improve the chemotherapeutic effect of 5-FU. In this study, we assessed such combinational use in colon cancer and investigated if melatonin could synergize the anti-tumor 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 anti-tumor effect of 5-FU by targeting the PI3K/AKT and NF-κB/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 ofiNOS signaling. In addition, pretreatment with a PI3K- or iNOS-specific inhibitor synergized the anti-tumor effects of 5-FU and melatonin. Finally, we verified in a xenograft mouse model that melatonin and 5-FU exerted synergistic anti-tumor effect by inhibiting the AKT and iNOS signaling pathway.Collectively, our study demonstrated that melatonin synergized the chemotherapeutic effect of 5-FU in colon cancer through simultaneous suppression of multiple signaling pathways. This article is protected by copyright. All rights reserved.

Study Type : In Vitro Study

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