Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-κB/iNOS signaling pathways.
J Pineal Res. 2016 Nov 19. Epub 2016 Aug 19. PMID: 27865009
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.