Tumor Biology

, Volume 37, Issue 10, pp 13627–13635 | Cite as

Dimethylfumarate inhibits melanoma cell proliferation via p21 and p53 induction and bcl-2 and cyclin B1 downregulation

  • Irina Kaluzki
  • Igor Hrgovic
  • Tsige Hailemariam-Jahn
  • Monika Doll
  • Johannes Kleemann
  • Eva Maria Valesky
  • Stefan Kippenberger
  • Roland Kaufmann
  • Nadja Zoeller
  • Markus Meissner
Original Article


Recent evidence suggests that dimethylfumarate (DMF), known as a highly potent anti-psoriatic agent, might have anti-tumorigenic properties in melanoma. It has recently been demonstrated that DMF inhibits melanoma proliferation by apoptosis and cell cycle inhibition and therefore inhibits melanoma metastasis. Nonetheless, the underlying mechanisms remain to be evaluated. To elucidate the effects of DMF on melanoma cell lines (A375, SK-Mel), we first performed cytotoxicity assays. No significant lactatedehydogenase (LDH) release could be found. In further analysis, we showed that DMF suppresses melanoma cell proliferation in a concentration-dependent manner. To examine whether these effects are conveyed by apoptotic mechanisms, we studied the amount of apoptotic nucleosomes and caspase 3/7 activity using ELISA analysis. Significant apoptosis was induced by DMF in both cell lines, and this could be paralleled with bcl-2 downregulation and PARP-1 cleavage. We also performed cell cycle analysis and found that DMF induced concentration-dependent arrests of G0/G1 as well as G2/M. To examine the underlying mechanisms of cell cycle arrest, we analyzed the expression profiles of important cell cycle regulator proteins such as p53, p21, cyclins A, B1, and D1, and CDKs 3, 4, and 6. Interestingly, DMF induced p53 and p21 yet inhibited cyclin B1 expression in a concentration-dependent manner. Other cell cycle regulators were not influenced by DMF. The knockdown of DMF induced p53 via siRNA led to significantly reduced apoptosis but had no influence on cell cycle arrest. We examined the adhesion of melanoma cells on lymphendothelial cells during DMF treatment and found a significant reduction in interaction. These data provide evidence that DMF inhibits melanoma proliferation by reinduction of important cell cycle inhibitors leading to a concentration-dependent G0/G1 or G2/M cell cycle arrest and induction of apoptosis via downregulation of bcl-2 and induction of p53 and PARP-1 cleavage. Hence, DMF might be an interesting agent in the treatment of melanoma and is worth further investigation in vivo.


Dimethylfumarate p21 p53 Melanoma Cell cycle arrest Cyclin B1 PARP-1 











Dermal lymphatic endothelial cells



The work was sponsored by the Brigitte und Dr. Konstanze Wegener-Stiftung (M.M.); Dr. Kurt & Eva Herrmann Stipendium, 2013 (I.K.); Nachlässe Maria Christine Held und Erika Hecker (E.V.).

Compliance with ethical standards

Conflicts of interest


Supplementary material

13277_2016_5285_MOESM1_ESM.pdf (114 kb)
ESM 1 (PDF 113 kb)


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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Irina Kaluzki
    • 1
  • Igor Hrgovic
    • 1
  • Tsige Hailemariam-Jahn
    • 1
  • Monika Doll
    • 1
  • Johannes Kleemann
    • 1
  • Eva Maria Valesky
    • 1
  • Stefan Kippenberger
    • 1
  • Roland Kaufmann
    • 1
  • Nadja Zoeller
    • 1
  • Markus Meissner
    • 1
  1. 1.Department of Dermatology, Venereology and AllergologyGoethe-UniversityFrankfurt am MainGermany

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