Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-B/iNOS signaling pathways
Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-B/iNOS signaling pathways
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褪黑激素通过抑制 PI3K/AKT 和 NF-kappaB/iNOS 信号通路来协同 5-氟尿嘧啶对结肠癌的化疗作用。
DOI：
10.1111/jpi.12380
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发表时间：
2017-03-01
影响因子：
10.3
通讯作者：
Deng, Wuguo
中科院分区：
文献类型：
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作者：
Gao, Yue;Xiao, Xiangsheng;Deng, Wuguo
5-氟尿嘧啶（5-FU）是结肠癌治疗中最常用的化疗药物之一，但其毒性限制了其治疗指数。褪黑激素在多种癌症中发挥抗肿瘤活性，但它从未与5-FU组合作为抗结肠癌治疗以改善5-FU的化疗效果。在这项研究中，我们评估了这种联合使用在结肠癌和调查是否褪黑激素可以协同5-FU的抗肿瘤作用。我们发现，褪黑激素显着增强5-FU介导的抑制细胞增殖，集落形成，细胞迁移和侵袭在结肠癌细胞。我们还发现，褪黑激素与5-FU协同促进caspase/PARP依赖的凋亡途径的激活，并诱导细胞周期阻滞。进一步的机制研究表明，褪黑素可能通过靶向PI 3 K/AKT和NF-B/诱导型一氧化氮合酶（iNOS）信号通路协同5-FU的抗肿瘤作用。褪黑素与5-FU联用显著抑制PI 3 K、AKT、IKK、IB和p65蛋白的磷酸化，促进NF-B p50/p65从细胞核易位到细胞质，消除它们与iNOS启动子的结合，从而增强对iNOS信号传导的抑制。此外，用PI 3 K或iNOS特异性抑制剂预处理可协同5-FU和褪黑激素的抗肿瘤作用。最后，我们在异种移植小鼠模型中验证了褪黑素和5-FU通过抑制AKT和iNOS信号通路发挥协同抗肿瘤作用。总的来说，我们的研究表明，褪黑激素协同化疗效果的5-FU在结肠癌通过同时抑制多种信号通路。
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-B/inducible nitric oxide synthase (iNOS) signaling. Melatonin in combination with 5-FU markedly suppressed the phosphorylation of PI3K, AKT, IKK, IB, and p65 proteins, promoted the translocation of NF-B 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.