title: Cytotoxicity and mode of action of aeroplysinin-1 and a related dienonefrom the sponge Aplysina aerophoba.
abstract: Aeroplysinin-1 (1) and the structurally related dienone 2 were cytotoxic to Ehrlich ascites tumor (EAT) cells and HeLa tumor cells in the microculture tetrazolium (MTT) and clonogenic assays. Both compounds are bromotyrosine derivatives, isolated from the marine spong Aplysina aerophoba. As the effective concentrations in the MTT assay were lower than in the clonogenic assay, 1 and 2 are able to cause growth inhibition as well as actual cell death in these cell lines. With an IC50 value of 8.2 microM (MTT assay, 2-h incubation, EAT cells), 1 was the more toxic compound. When the cells were depleted of glutathione by pretreatment with buthionine sulfoximine, they were significantly more sensitive toward 1 and 2 in the MTT assay. A dose-enhancement factor as high as 11.8 was found in EAT cells after 2-h incubation with 2. Using electron paramagnetic resonance we were able to measure free radical formation of 1 and 2, yielding the semiquinone structures 3 and 4, respectively, in a culture medium with tumor cells. It is concluded that free radicals are, at least in part, responsible for the cytotoxicity of 1 and 2. This conclusion is in line with expectations derived from the chemical structures of both compounds.
authors.affiliation: Department of Pharmaceutical Biology, Groningen Institute for Drug Studies (GIDS), University of Groningen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Koulman
authors.forename: P
authors.initials: P
authors.lastname: Proksch
authors.forename: R
authors.initials: R
authors.lastname: Ebel
authors.forename: A C
authors.initials: AC
authors.lastname: Beekman
authors.forename: W
authors.initials: W
authors.lastname: van Uden
authors.forename: A W
authors.initials: AW
authors.lastname: Konings
authors.forename: J A
authors.initials: JA
authors.lastname: Pedersen
authors.forename: N
authors.initials: N
authors.lastname: Pras
authors.forename: H J
authors.initials: HJ
authors.lastname: Woerdenbag
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D000097:Acetonitriles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D053138:Cyclohexenes; D004354:Drug Screening Assays, Antitumor; D004578:Electron Spin Resonance Spectroscopy; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D011161:Porifera / Q000737:chemistry*; D013778:Tetrazolium Salts; D013844:Thiazoles; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D000081:Acetamides; D000097:Acetonitriles; D000970:Antineoplastic Agents; D016227:Benzoquinones; D053138:Cyclohexenes; D013778:Tetrazolium Salts; D013844:Thiazoles; C058102:dienone B; C042151:aeroplysinin I; C022616:thiazolyl blue; D005978:Glutathione