Abstract
Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy.
Highlights
Melanoma is one of the most aggressive forms of skin cancer, which has been occurring with an increased incidence faster than that of any other cancer in the world [1,2,3]
The combinational treatment of the cells with melatonin (1.0 mM) with fisetin (0 mM–250 mM) significantly enhanced the inhibition of cell viability as compared with the cells treated with fisetin alone (Fig. 1C, 1D)
The co-treatment with fisetin and melatonin following pretreatment of inducible NO synthases (iNOS)-selective inhibitor 1400w in MeWo and Sk-mel-28 cells did not obviously elevate cell viability inhibition compared with fisetin and melatonininduced anti-proliferation ability (Fig. 5E, 5F). These results indicate that the enhanced antitumor effect of the combinational treatment might partially be mediated through inactivating COX2 and iNOS signalings
Summary
Melanoma is one of the most aggressive forms of skin cancer, which has been occurring with an increased incidence faster than that of any other cancer in the world [1,2,3]. Melanoma in early stage is curable, the prognosis and overall survival for patients with metastasized melanoma is unfavourable. Patients in metastasis even have a median survival of only 6–10 months [4]. Melanoma is characterized by the forming of resistance to cytotoxic agents during the progression, and the effective treatment options for it are very few. Discovering and confirming new cytotoxic agents exerting anti-melanoma activities becomes very important. More and more natural products extracted from plants and animals have been shown to contribute to decrease cancer risks, and some of them even have been applied in cancer chemoprevention and malignancy suppression due to their high efficiency, low toxicity and wide variety of sources [5,6,7]
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