Dimethylfumarate (DMF), a fumaric acid ester, has been used successfully in the treatment of psoriasis for many decades. As previously discovered, DMF partly acts via inhibition of the NF-[kappa]B signalling pathway, one pathway activated constitutively in melanoma playing a critical role in cancer development and progression. Our purpose was therefore to explore in a first study the effect of DMF on human A375 and M24met melanoma cells using severe combined immunodeficient (SCID) mouse models, representing a nodular (A375) and a metastasizing (M24met) tumor model. Here we show that DMF inhibits proliferation, induces apoptosis and regulates the cell cycle in vitro and in vivo and thus reduces melanoma growth and metastasis to lymph nodes and lungs in animal models. In a second study we compared the antitumoral effect of DMF to Dacarbazine (DTIC), the standard chemotherapy in stage IV metastatic melanoma, and to the novel anti-VEGF antibody mAb G6-31, blocking both human and murine VEGF-A. Using our SCID mouse models, we focused on melanoma growth and spontaneous lymphatic and pulmonary metastasis. Single as well as combination therapies with DMF have been used. Primary tumor growth was reduced under all used treatment conditions, however most efficiently under the anti-VEGF antibody mAb G6-31 alone and in combination with DMF.
Pulmonary metastasis was decreased significantly under all used treatment conditions. Our main finding was that sentinel lymph node metastasis could be delayed significantly and most efficiently by DMF in combination with DTIC. Although the combinatory treatment DTIC/ DMF was not found to have a major effect on tumor cell proliferation or apoptosis, this regimen significantly reduced lymphangiogenesis in primary tumors as well as M24met tumor cell migration in vitro and stromal pro-migratory chemo- and cytokine expression in vivo. In summary, DMF might represent a new treatment option in advanced stage melanoma in humans based on its antitumoral and synergistic effect with DTIC, demonstrated here in animal models, and on the long proven good tolerance in patients.