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.
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.
Schadendorf
D
D
Department of Dermatology, Virchow Klinikum, Humboldt Universität zu Berlin, Germany.
Kern
M A
MA
Artuc
M
M
Pahl
H L
HL
Rosenbach
T
T
Fichtner
I
I
Nürnberg
W
W
Stüting
S
S
von Stebut
E
E
Worm
M
M
Makki
A
A
Jurgovsky
K
K
Kolde
G
G
Henz
B M
BM
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
C099555:CD 437; D006131:Growth Inhibitors; D012333:RNA, Messenger; D012176:Retinoids; D018808:Transcription Factor AP-1; D015500:Chloramphenicol O-Acetyltransferase