title: Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-κB/iNOS signaling pathways.
abstract: 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.
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.|Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Wendan
authors.initials: W
authors.lastname: Yu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Hao
authors.affiliation: Global Life Care Federation, Global Life Care Institute, Hong Kong, China.
authors.forename: Kefang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Bingyi
authors.initials: B
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.|State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Shunbin
authors.initials: S
authors.lastname: Xiong
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.|State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
authors.forename: Wuguo
authors.initials: W
authors.lastname: Deng
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000473:pathology*; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D008550:Melatonin; D005472:Fluorouracil
keywords: 
  AKT
  ; 
  iNOS
  ; 5-fluorouracil; NF-κB; PI3K; colon cancer; melatonin