title: Ilimaquinone and ethylsmenoquinone, marine sponge metabolites, suppress the proliferation of multiple myeloma cells by down-regulating the level of β-catenin.
abstract: Deregulation of Wnt/β-catenin signaling promotes the development of a broad range of human cancers, including multiple myeloma, and is thus a potential target for the development of therapeutics for this disease. Here, we used a cell-based reporter system to demonstrate that ilimaquinone and ethylsmenoquinone (formerly smenorthoquinone), sesquiterpene-quinones from a marine sponge, inhibited β-catenin response transcription induced with Wnt3a-conditioned medium, by down-regulating the level of intracellular β-catenin. Pharmacological inhibition of glycogen synthase kinase-3β did not abolish the ilimaquinone and ethylsmenoquinone-mediated β-catenin down-regulation. Degradation of β-catenin was consistently found in RPMI-8226 multiple myeloma cells after ilimaquinone and ethylsmenoquinone treatment. Ilimaquinone and ethylsmenoquinone repressed the expression of cyclin D1, c-myc, and axin-2, which are β-catenin/T-cell factor-dependent genes, and inhibited the proliferation of multiple myeloma cells. In addition, ilimaquinone and ethylsmenoquinone significantly induced G0/G1 cell cycle arrest and apoptosis in RPMI-8266 cells. These findings suggest that ilimaquinone and ethylsmenoquinone exert their anti-cancer activity by blocking the Wnt/β-catenin pathway and have significant potential as therapies for multiple myeloma.
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Korea. qkr092@nate.com.
authors.forename: Seoyoung
authors.initials: S
authors.lastname: Park
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea. yunej@cnu.ac.kr.
authors.forename: Eunju
authors.initials: E
authors.lastname: Yun
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA. inhyun-hwang@uiowa.edu.
authors.forename: In Hyun
authors.initials: IH
authors.lastname: Hwang
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Korea. redsu2@naver.com.
authors.forename: Soojin
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Korea. kimde@konkuk.ac.kr.
authors.forename: Dong-Eun
authors.initials: DE
authors.lastname: Kim
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Korea. beaver131@naver.com.
authors.forename: Ji Seon
authors.initials: JS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea. mkna@cnu.ac.kr.
authors.forename: MinKyun
authors.initials: M
authors.lastname: Na
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea. gysong@cnu.ac.kr.
authors.forename: Gyu-Yong
authors.initials: GY
authors.lastname: Song
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Korea. ohsa@kookmin.ac.kr.
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000302:isolation & purification / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D011161:Porifera / Q000378:metabolism*; D011809:Quinones / Q000302:isolation & purification / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D012717:Sesquiterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D011809:Quinones; D012717:Sesquiterpenes; D051176:beta Catenin; C000594479:ethylsmenoquinone; C467077:ilimaquinone