Dimethylfumarate impairs melanoma growth and metastasis.
Dimethylfumarate (DMF) inhibits signals transmitted by Rel proteins and is used for the treatment of inflammatory skin diseases such as psoriasis, but potential effects of DMF on tumor progression have yet not been analyzed. We show that DMF reduced melanoma growth and metastasis in severe combined immunodeficient mouse models. To identify targets of DMF action, we analyzed mRNA expression in DMF-treated melanomas by gene chip arrays. Using BiblioSphere software for data analysis, significantly regulated genes were mapped to Gene Ontology terms cell death, cell growth, and cell cycle. Indeed, we found that DMF inhibited proliferation of human melanoma cells A375 and M24met in vitro. The cell cycle was arrested at the G(2)-M boundary. Moreover, DMF was proapoptotic, as shown by cell cycle analysis and by Annexin V and Apo2.7 staining. These results were confirmed in vivo. DMF reduced proliferation rates of tumor cells as assessed by Ki-67 immunostaining and increased apoptosis as assessed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining. In conclusion, DMF is antiproliferative and proapoptotic and reduces melanoma growth and metastasis in animal models.
Loewe
Robert
R
Department of Dermatology, Division of General Dermatology, Medical University of Vienna, Vienna, Austria.
Valero
Teresa
T
Kremling
Silvia
S
Pratscher
Barbara
B
Kunstfeld
Rainer
R
Pehamberger
Hubert
H
Petzelbauer
Peter
P
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D000069462:Dimethyl Fumarate; D005260:Female; D005650:Fumarates / Q000627:therapeutic use*; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology / Q000517:prevention & control; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D005650:Fumarates; D011838:Radiation-Sensitizing Agents; D000069462:Dimethyl Fumarate