title: A novel adamantyl benzylbenzamide derivative, AP736, inhibits melanogenesis in B16F10 mouse melanoma cells via glycogen synthase kinase 3β phosphorylation.
abstract: Recently, much effort has been made to develop effective dermatological depigmenting compounds. In this study, we investigated the novel candidate compound, AP736 (an adamantyl benzylbenzamide derivative), and its effects on melanogenesis in B16F10 melanoma cells, as well as the mechanisms involved. AP736 has been reported to exert anti-melanogenic effects in melanocytes in vitro and in artificial skin equivalents through the inhibition of key melanogenic enzymes and the suppression of the cAMP-protein kinase A (PKA)-cAMP response element‑binding protein (CREB) signaling pathway. Thus, we examined another pathway of melanogenesis involving the effects of AP736 on the glycogen synthesis kinase 3β (GSK3β) pathway. Melanin content and tyrosinase activity were measured using a spectrophotometer after the cells were treated with AP736. The AP736-induced activation of signaling pathways was examined by western blot analysis. We confirmed that AP736 decreased melanin production in a dose-dependent manner; however, it did not directly inhibit tyrosinase, the rate-limiting melanogenic enzyme. The expression of microphthalmia-associated transcription factor, tyrosinase, and related signal transduction pathways was also investigated. The Wnt signaling pathway is deeply involved in melanogenesis; therefore, phosphorylation by GSK3β was assessed following treatment with AP736. AP736 induced GSK3β phosphorylation (inactivation), but it did not alter the level of β-catenin. Furthermore, the expression of α-melanocyte-stimulating hormone-induced tyrosinase was downregulated by AP736. Our data suggest that AP736 exerts hypopigmentary effects through the downregulation of tyrosinase via GSK3β phosphorylation.
authors.affiliation: Medical Beauty Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
authors.forename: Hong-Ju
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: Department of Dermatology, Chung-Ang University College of Medicine, Seoul 156-756, Republic of Korea.
authors.forename: Chang Taek
authors.initials: CT
authors.lastname: Oh
authors.affiliation: Department of Dermatology, Chung-Ang University College of Medicine, Seoul 156-756, Republic of Korea.
authors.forename: Tae-Rin
authors.initials: TR
authors.lastname: Kwon
authors.affiliation: Skin Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
authors.forename: Heung Soo
authors.initials: HS
authors.lastname: Beak
authors.affiliation: Skin Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
authors.forename: Yung Hyup
authors.initials: YH
authors.lastname: Joo
authors.affiliation: Medical Beauty Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
authors.forename: Jeong-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Medical Beauty Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
authors.forename: Chang Seok
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Skin Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
authors.forename: John Hwan
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Dermatology, Chung-Ang University College of Medicine, Seoul 156-756, Republic of Korea.
authors.forename: Beom Joon
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: Skin Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
authors.forename: Song Seok
authors.initials: SS
authors.lastname: Shin
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 440-746, Republic of Korea.
authors.forename: Eun-Seok
authors.initials: ES
authors.lastname: Park
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects*; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D008546:Melanoma, Experimental / Q000175:diagnosis* / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D014442:Monophenol Monooxygenase; D010766:Phosphorylation / Q000187:drug effects*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: C000592311:5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxybenzamide; D001549:Benzamides; D017362:Cyclic AMP Response Element-Binding Protein; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D051176:beta Catenin; D014442:Monophenol Monooxygenase; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000218:Adamantane