Inhibition of Mek 1/2 kinase activity and stimulation of melanogenesis by 5,7-dimethoxycoumarin treatment of melanoma cells

Abstract

Abstract. In this study, the processes of differentiation and melanogenesis induced by 5,7-dimethoxycoumarin in murine (B16) and human (A375) melanoma cells were investigated.Taking into account the previously demonstrated antiproliferative and differentiation activities of this compound, we examined Ras/Raf/Mek/Erk mitogen-activated protein kinase activity following treatment; inhibition of Mek 1/2 kinase activity and subsequent reduction in Erk 1/2 activation were detected in both cell types. We observed melanogenesis induction associated to an increase in cAMP-response elementbinding protein (CREB) and microphthalmia-associated transcription factor (Mitf) expression, both involved in its regulation. Mitf is fundamental for development, survival and differentiation of melanocyte and melanoma, since it regulates transcription of genes encoding for proteins involved in cell cycle progression or in melanogenesis, such as the enzyme tyrosinase. A significant increase of tyrosinase activity was revealed following treatment in B16 but not in A375 cells, although a strong synthesis of melanin was induced by 5,7-dimethoxycoumarin in both cell lines. The treatment induced protoporphyrine IX accumulation involved in melanogenesis since it promotes stability of cAMP. Finally, the Mek 1/2 inhibitor U0126 significantly potentiated growth inhibition of B16 cells triggered by 5,7-dimethoxycoumarin, suggesting that down-regulation of Raf/Mek/Erk pathway sensitizes melanoma cells to 5,7-dimethoxycoumarin treatment.

Coumarins from Jinhua Finger Citron: Separation by Liquid–Liquid Chromatography and Potential Antitumor Activity

“…In addition, Annexin V-PI staining confirmed an increased rate of apoptosis in HeLa cells treated with compound I, in a concentration-dependent manner (Figure 4D). The previous reports indicated that compound I realized the inhibition on melanomas through the inhibition of mitogen-activated extracellular signal-regulated kinase (MEK) [31][32][33]. Therefore, the anticancer activity of compound I had potential in medicinal treatments, and the improvement on its productivity with liquid-liquid chromatography in this work was beneficial for realizing its practical utilization.…”

Zebrafish in dermatology: a comprehensive review of their role in investigating abnormal skin pigmentation mechanisms

“…Beyond its role in heme synthesis, PPIX has been recognized for its diverse biological functions, including promoting cell respiration, enhancing protein and glucose metabolism, and inhibiting complement binding (Thapar and Bonkovsky, 2008;Dailey and Meissner, 2013). Recent studies have illuminated its potential in melanogenesis, particularly in melanoma cells, where it acts as a stimulator of melanogenesis (Kim et al, 2006;Kim et al, 2016 B.-H.;Alesiani et al, 2009).…”

Insights into the Chemical Compositions and Health Promoting Effects of Wild Edible Mushroom Chroogomphus rutilus

“…Among them, 5a, 8a-epidioxyergosta-6,22-dien-3b-ol, 3b, 5a-dihydroxy-(22E,24R)-ergosta-7,22-dien-6-one, and 6-hydroxy-5,7-dimethoxycoumarin have anti-OECM-1 tumor activity [ 55 , 56 ]. 5,7-Dimethoxycoumarin can stimulate melanogenesis and inhibit melanoma by inhibiting Mek 1/2 kinase activity [ 57 ]. Ergosta-4,6,8(14) and 22-tetraen-3-one induced G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells, which reduced the incidence of liver cancer and the growth rate of liver cancer cells [ 62 ].…”