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.

Dietary Sources and Bioactivities of Melatonin

“…Melatonin has been known and used to assist sleep disorders [8] or jet lag [69] as a dietary supplement or as a drug, and recently it has also been reported to synergize other drugs as an adjuvant to improve their efficiency or to attenuate their side effects [70]. Herein, the bioavailability of melatonin has been studied by some researchers.…”

“…It has been well documented that the complex interaction of oxidative stress and inflammation results in many diseases. Melatonin could not only reduce the oxidative levels as stated, but also effectively fight against inflammation via different mechanisms such as essential signaling pathways [70,149], the modulation of related genes [150] and the activation membrane receptors [151], as discussed in detail below.…”

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

“…Importantly, our data established the links between Mst1, Drp1-related mitochondrial fission and Parkin-required mitophagy with respect to cell migration. To the best of our knowledge, this is the first study to explore the interactions of the Mst1-Hippo pathway and mitochondrial dynamics [56].…”

Transdermal administration of melatonin coupled to cryopass laser treatment as noninvasive therapy for prostate cancer

“…Melatonin has paracrine, autocrine as well as antioxidant effects, and exerts diverse receptor-dependent and receptor-independent actions, with overall homeostatic functions and pleiotropic effects relevant to cell protection and survival (Srinivasan et al, 2008;Luchetti et al, 2010). Melatonin is known to display oncostatic activity in a variety of tumors including breast (Mao et al, 2016), ovarian (Zhao et al, 2016), colon (Gao et al, 2016), endometrial (Ciortea et al, 2011), gastrointestinal (Wang et al, 2016b), and prostate (Paroni et al, 2014). The link between plasma melatonin and prostate cancer risk is well recognized.…”