TREATMENT OF MELANOMA-CELLS WITH THE SYNTHETIC RETINOID CD437 INDUCESAPOPTOSIS VIA ACTIVATION OF AP-1 IN-VITRO, AND CAUSES GROWTH-INHIBITION IN XENOGRAFTS IN-VIVO

Citation
D. Schadendorf et al., TREATMENT OF MELANOMA-CELLS WITH THE SYNTHETIC RETINOID CD437 INDUCESAPOPTOSIS VIA ACTIVATION OF AP-1 IN-VITRO, AND CAUSES GROWTH-INHIBITION IN XENOGRAFTS IN-VIVO, The Journal of cell biology, 135(6), 1996, pp. 1889-1898
Citations number
49
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell Biology
Journal title
ISSN journal
0021-9525
Volume
135
Issue
6
Year of publication
1996
Part
2
Pages
1889 - 1898
Database
ISI
SICI code
0021-9525(1996)135:6<1889:TOMWTS>2.0.ZU;2-O
Abstract
Human malignant melanoma is notoriously resistant to pharmacological m odulation, We describe here for the first time that the synthetic reti noid CD437 has a strong dose-dependent antiproliferative effect on hum an melanoma cells (IC50: 5 x 10(-)6 M) via the induction of programmed cell death, as judged by analysis of cell morphology, electron micros copical features, and DNA fragmentation. Programmed cell death was pre ceded by a strong activation of the AP-1 complex in CD437-treated cell s as demonstrated by gel retardation and chloramphenicol transferase ( CAT) assays. Northern blot analysis showed a time-dependent increase i n the expression of c-fos and c-jun encoding components of AP-1, where as bcl-2 and p53 mRNA levels remained constant. CD437 also exhibited a strong growth inhibitory effect on MeWo melanoma cells in a xenograft model,ln tissue sections of CD437-treated MeWo tumors from these anim als, apoptotic melanoma cells and c-fos overexpressing cells were colo calized 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 upregula tes the transcription factor AP-1, leading eventually to programmed ce ll death of exposed human melanoma cells in vitro and in vivo. Further studies are needed to evaluate whether synthetic retinoids such as CD 437 represent a new class of retinoids, which may open up new ways to a more effective therapy of malignant melanoma.