title: The antimycotic agent clotrimazole inhibits melanogenesis by accelerating ERK and PI3K-/Akt-mediated tyrosinase degradation.
abstract: Azole antimycotic agents are known to have anti-inflammatory and anti-cancer effects, which are mediated through their effects on the p38-cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) pathway, as well as anti-oxidant effects. Furthermore, pyridinyl imidazole compounds, such as SB203580 have recently been shown to inhibit melanogenesis. Accordingly, we hypothesized that azole antifungal agents might affect skin pigmentation. We herein investigated the effect of clotrimazole, the most commonly used azole antifungal agent, on melanogenesis. Intriguingly, clotrimazole reduced the melanin content in human melanocytes and mouse melanocytes, as well as in B16F10 mouse melanoma cells. Clotrimazole reduced levels of tyrosinase protein without altering mRNA expression. Simultaneous treatment with a proteasomal inhibitor restored both the suppression of melanin synthesis, and the downregulation of tyrosinase level, by clotrimazole. Clotrimazole also induced the phosphorylation of extracellular signal-regulated kinase (ERK) and PI3K/Akt, while each inhibitor of these two signals abolished the decrease of melanin synthesis by clotrimazole. Thus, our data suggest that clotrimazole inhibits melanin synthesis by promoting the proteasomal degradation of tyrosinase, which is mediated through activation of the ERK and Akt signaling pathways. These results may indicate a new role for clotrimazole as a molecular-mechanism-based, safe depigmenting agent for topical management of hyper-pigmentary sequelae related to fungal infection, or for other skin inflammatory disorders.
authors.affiliation: Department of Dermatology, College of Medicine, Hallym University Kangnam Sacred Heart Hospital, Seoul, Korea.
authors.forename: Bo Young
authors.initials: BY
authors.lastname: Chung
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Joon Min
authors.initials: JM
authors.lastname: Jung
authors.forename: Chong Hyun
authors.initials: CH
authors.lastname: Won
authors.forename: Jee Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Mi Woo
authors.initials: MW
authors.lastname: Lee
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Chang
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002460:Cell Line; D003022:Clotrimazole / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012880:Skin Pigmentation / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D008543:Melanins; D012333:RNA, Messenger; D014442:Monophenol Monooxygenase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D003022:Clotrimazole
keywords: Akt; clotrimazole; extracellular signal-regulated kinase; melanogenesis; tyrosinase degradation