Inhibition of Melanogenesis by the Antidiabetic Metformin

Abstract

Several reports have demonstrated the inhibitory effect of metformin, a widely used drug in the treatment of type 2 diabetes, on the proliferation of many cancers including melanoma. Recently, it has been shown that metformin is able to modulate the cAMP level in the liver. As cAMP has a crucial role in melanin synthesis and skin pigmentation, we investigated the effect of metformin on melanogenesis both in vitro and in vivo. We showed that metformin led to reduced melanin content in melanoma cells and in normal human melanocytes by decreasing cAMP accumulation and cAMP-responsive element-binding protein phosphorylation. This inhibitory effect is correlated with decreased expression of master genes of melanogenesis, microphthalmia-associated transcription factor, tyrosinase, dopachrome tautomerase, and tyrosinase-related protein 1. Furthermore, we demonstrated that the antimelanogenic effect of metformin is independent of the AMPK pathway. Interestingly, topical application of metformin induced tail whitening in mice. Finally, we confirmed the antimelanogenic effect of metformin on reconstituted human epidermis and on human skin biopsies. These data emphasize the depigmenting effect of metformin and suggest a clinical strategy for using metformin in the topical treatment of hyperpigmentation disorders.

p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing

“…The observation of the requirement of a low dose of Met (1 mg/kg BW per mouse) to be effective in vivo as opposed to a much higher concentration (10 mM) in cultured decidual cells was perhaps due to higher expression of Oct1 and Oct3 in tissues in vivo as compared with much lower expression in cultured cells; OCTs serve as transporters to deliver Met inside the cell. In this respect, several studies used Met at 10 mM to be effective (13,47,48). Our present results also show a relationship between p53-sestrin and AMPK/mTORC1 signaling and their integration to optimize decidual function.…”

Skin Whitening Cosmetics: Feedback and Challenges in the Development of Natural Skin Lighteners

“…However, these systems are expensive and their implementation is difficult. Skin explants sampled from volunteers or stemming from surgical waste, as well as commercially available skin equivalent models (SEM) constituted of human epidermal cells, may be preferred for in vitro systems for testing skin whitening substances [88,91,92].…”

“…• in vivo assays and clinical trials: Mammalian skin is generally preferred to evaluate the efficacy and innocuousness of a given substance [93]: several animal models, more reliable than in vitro tests, have been used, e.g., the mouse [92,94], the zebrafish [94][95][96], the guinea pig [97,98], and the Yucatan swine [99,100]. The zebrafish presents several advantages, including easy maintenance and handling of the animals, short generation times, and high efficiency of drug penetration through the skin [96,101,102].…”

Callicarpa longissima extract, carnosol-rich, potently inhibits melanogenesis in B16F10 melanoma cells

“…In contrast to CBP/p300, AMPK is proposed to suppress CREB activity in the liver via the phosphorylation-dependent inhibition of other coactivator CRTCs (CREB-related transcription coactivators) [29], and CRTC1 promotes MITF gene expression in melanocytes [6]. Although the AMPK activator metformin was found to suppress CREB activity in human melanocytes by reducing cAMP levels [30], the metformin-dependent suppression of melanogenesis did not require AMPK, suggesting that AMPK is not essential for the suppressed melanogenesis found for the C. longissima extract. b-Catenin also acts as a co-activator of the LEF/TCF complex, which up-regulates MITF gene expression in Wnt signaling [31].…”