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The antimycotic agent clotrimazole inhibits melanogenesis by accelerating ERK and PI 3K‐/Akt‐mediated tyrosinase degradation
Author(s) -
Chung Bo Young,
Kim Su Yeon,
Jung Joon Min,
Won Chong Hyun,
Choi Jee Ho,
Lee Mi Woo,
Chang Sung Eun
Publication year - 2015
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12669
Subject(s) - tyrosinase , clotrimazole , mapk/erk pathway , pi3k/akt/mtor pathway , chemistry , protein kinase b , pharmacology , melanin , biochemistry , biology , signal transduction , microbiology and biotechnology , enzyme , antifungal
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 ( PGE 2) pathway, as well as anti‐oxidant effects. Furthermore, pyridinyl imidazole compounds, such as SB 203580 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 PI 3K/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.