title: 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.
authors.affiliation: Biologie et Pathologie des Cellules Mélanocytaire: de la Pigmentation Cutanée au Mélanome, Equipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, U1065, INSERM, Nice, France; UFR de Médecine, Université de Nice Sophia Antipolis, Nice, France.
authors.forename: Abdelali
authors.initials: A
authors.lastname: Lehraiki
authors.affiliation: Biologie et Pathologie des Cellules Mélanocytaire: de la Pigmentation Cutanée au Mélanome, Equipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, U1065, INSERM, Nice, France; UFR de Médecine, Université de Nice Sophia Antipolis, Nice, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Abbe
authors.affiliation: Biologie et Pathologie des Cellules Mélanocytaire: de la Pigmentation Cutanée au Mélanome, Equipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, U1065, INSERM, Nice, France; UFR de Médecine, Université de Nice Sophia Antipolis, Nice, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Cerezo
authors.affiliation: Biologie et Pathologie des Cellules Mélanocytaire: de la Pigmentation Cutanée au Mélanome, Equipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, U1065, INSERM, Nice, France; UFR de Médecine, Université de Nice Sophia Antipolis, Nice, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Rouaud
authors.affiliation: UFR de Médecine, Université de Nice Sophia Antipolis, Nice, France; Equipe 12, U1065, INSERM, Nice, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Regazzetti
authors.affiliation: Plastic, Reconstructive and Hand Surgery Department, Saint Roch Hospital, Nice, France.
authors.forename: Bérengère
authors.initials: B
authors.lastname: Chignon-Sicard
authors.affiliation: UFR de Médecine, Université de Nice Sophia Antipolis, Nice, France; Equipe 12, U1065, INSERM, Nice, France; Service de Dermatologie, Hôpital Archet II, CHU, Nice, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Passeron
authors.affiliation: Biologie et Pathologie des Cellules Mélanocytaire: de la Pigmentation Cutanée au Mélanome, Equipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, U1065, INSERM, Nice, France; UFR de Médecine, Université de Nice Sophia Antipolis, Nice, France; Service de Dermatologie, Hôpital Archet II, CHU, Nice, France.
authors.forename: Corine
authors.initials: C
authors.lastname: Bertolotto
authors.affiliation: Biologie et Pathologie des Cellules Mélanocytaire: de la Pigmentation Cutanée au Mélanome, Equipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, U1065, INSERM, Nice, France; UFR de Médecine, Université de Nice Sophia Antipolis, Nice, France; Service de Dermatologie, Hôpital Archet II, CHU, Nice, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Ballotti
authors.affiliation: Biologie et Pathologie des Cellules Mélanocytaire: de la Pigmentation Cutanée au Mélanome, Equipe 1, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, U1065, INSERM, Nice, France; UFR de Médecine, Université de Nice Sophia Antipolis, Nice, France; Service de Dermatologie, Hôpital Archet II, CHU, Nice, France. Electronic address: srocchi@unice.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Rocchi
mesh_terms: D000818:Animals; D001706:Biopsy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D012880:Skin Pigmentation / Q000187:drug effects; D013997:Time Factors
chemical_list: D007004:Hypoglycemic Agents; C497234:MITF protein, human; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D008687:Metformin; D000242:Cyclic AMP
references.citation: J Transl Med. 2011 May 24;9:76
references.pmid: 21609436
references.citation: Exp Cell Res. 1998 Oct 10;244(1):117-24
references.pmid: 9770355
references.citation: Biochem Biophys Res Commun. 2010 Jul 16;398(1):135-9
references.pmid: 20599746
references.citation: Pigment Cell Res. 1994 Aug;7(4):227-34
references.pmid: 7855068
references.citation: Oncogene. 2014 May 8;33(19):2531-9
references.pmid: 23728343
references.citation: Eur J Pharmacol. 2011 Oct 15;668(3):373-82
references.pmid: 21806981
references.citation: Dermatol Clin. 2005 Apr;23(2):209-26
references.pmid: 15837152
references.citation: J Biol Chem. 2010 Mar 5;285(10):7288-99
references.pmid: 20053998
references.citation: Science. 2005 Dec 9;310(5754):1642-6
references.pmid: 16308421
references.citation: Mol Cancer Ther. 2013 Aug;12(8):1605-15
references.pmid: 23741061
references.citation: J Clin Invest. 2001 Oct;108(8):1167-74
references.pmid: 11602624
references.citation: Clin Dermatol. 2005 Jan-Feb;23(1):56-67
references.pmid: 15708290
references.citation: Biofactors. 2009 Mar-Apr;35(2):193-9
references.pmid: 19449448
references.citation: Pigment Cell Res. 2006 Dec;19(6):550-71
references.pmid: 17083484
references.citation: Pigment Cell Res. 2000 Apr;13(2):60-9
references.pmid: 10841026
references.citation: Cell Death Dis. 2011 Sep 01;2:e199
references.pmid: 21881601
references.citation: Mol Cancer Ther. 2010 May;9(5):1092-9
references.pmid: 20442309
references.citation: J Cell Biol. 1996 Aug;134(3):747-55
references.pmid: 8707852
references.citation: Chem Biol. 2012 Oct 26;19(10):1222-36
references.pmid: 23102217
references.citation: Ann Dermatol Venereol. 2012 Dec;139 Suppl 4:S148-52
references.pmid: 23522630
references.citation: J Invest Dermatol. 2009 May;129(5):1208-18
references.pmid: 19177142
references.citation: Nature. 2013 Feb 14;494(7436):256-60
references.pmid: 23292513
references.citation: Cancer Prev Res (Phila). 2010 Sep;3(9):1060-5
references.pmid: 20810670