title: Treatment of melanoma cells with the synthetic retinoid CD437 induces apoptosis via activation of AP-1 in vitro, and causes growth inhibition in xenografts in vivo.
abstract: Human malignant melanoma is notoriously resistant to pharmacological modulation. We describe here for the first time that the synthetic retinoid CD437 has a strong dose-dependent antiproliferative effect on human melanoma cells (IC50: 5 x 10(-6) M) via the induction of programmed cell death, as judged by analysis of cell morphology, electron microscopical features, and DNA fragmentation. Programmed cell death was preceded by a strong activation of the AP-1 complex in CD437-treated cells as demonstrated by gel retardation and chloramphenicol transferase (CAT) assays. Northern blot analysis showed a time-dependent increase in the expression of c-fos and c-jun encoding components of AP-1, whereas bcl-2 and p53 mRNA levels remained constant. CD437 also exhibited a strong growth inhibitory effect on MeWo melanoma cells in a xenograft model. In tissue sections of CD437-treated MeWo tumors from these animals, apoptotic melanoma cells and c-fos overexpressing cells were colocalized by TdT-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL) staining and in situ hybridization. Taken together, this report identifies CD437 as a retinoid that activates and upregulates the transcription factor AP-1, leading eventually to programmed cell death of exposed human melanoma cells in vitro and in vivo. Further studies are needed to evaluate whether synthetic retinoids such as CD437 represent a new class of retinoids, which may open up new ways to a more effective therapy of malignant melanoma.
authors.affiliation: Department of Dermatology, Virchow Klinikum, Humboldt Universität zu Berlin, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Schadendorf
authors.forename: M A
authors.initials: MA
authors.lastname: Kern
authors.forename: M
authors.initials: M
authors.lastname: Artuc
authors.forename: H L
authors.initials: HL
authors.lastname: Pahl
authors.forename: T
authors.initials: T
authors.lastname: Rosenbach
authors.forename: I
authors.initials: I
authors.lastname: Fichtner
authors.forename: W
authors.initials: W
authors.lastname: Nürnberg
authors.forename: S
authors.initials: S
authors.lastname: Stüting
authors.forename: E
authors.initials: E
authors.lastname: von Stebut
authors.forename: M
authors.initials: M
authors.lastname: Worm
authors.forename: A
authors.initials: A
authors.lastname: Makki
authors.forename: K
authors.initials: K
authors.lastname: Jurgovsky
authors.forename: G
authors.initials: G
authors.lastname: Kolde
authors.forename: B M
authors.initials: BM
authors.lastname: Henz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015152:Blotting, Northern; D015500:Chloramphenicol O-Acetyltransferase; D053938:DNA Fragmentation; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D008545:Melanoma; D051379:Mice; D008819:Mice, Nude; D008854:Microscopy, Electron; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure
chemical_list: C099555:CD 437; D006131:Growth Inhibitors; D012333:RNA, Messenger; D012176:Retinoids; D018808:Transcription Factor AP-1; D015500:Chloramphenicol O-Acetyltransferase