Leflunomide reduces proliferation and induces apoptosis in neuroblastoma cells in vitro and in vivo

PLoS One. 2013 Aug 9;8(8):e71555. doi: 10.1371/journal.pone.0071555. eCollection 2013.

Abstract

Leflunomide as an immunosuppressive drug is generally used in the treatment of rheumatoid arthritis. It inhibits DHODH (dihydroorotate dehydrogenase ), which is one of the essential enzymes in the de novo pyrimidine biosynthetic pathway. Here we showed that leflunomide significantly reduced cell proliferation and self-renewal activity. Annexin V-FITC/PI staining assay revealed that leflunomide induced S-phase cell cycle arrest, and promoted cell apoptosis. In vivo xenograft study in SCID mice showed that leflunomide inhibited tumor growth and development. We also observed that DHODH was commonly expressed in neuroblastoma. When treated with leflunomide, the neuroblastoma cell lines BE(2)-C, SK-N-DZ, and SK-N-F1 showed dramatic inhibition of DHODH at mRNA and protein levels. Considering the favorable toxicity profile and the successful clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in neuroblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dihydroorotate Dehydrogenase
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Humans
  • Isoxazoles / pharmacology*
  • Leflunomide
  • Mice
  • Mice, SCID
  • Neuroblastoma / enzymology
  • Neuroblastoma / pathology*
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism
  • S Phase / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Dihydroorotate Dehydrogenase
  • Isoxazoles
  • Oxidoreductases Acting on CH-CH Group Donors
  • Leflunomide

Grants and funding

The authors are grateful for Dr. Han-fei Ding for the invaluable support. This study was supported by the National Basic Research Program of China (number 2012cb114600), the National Natural Science Foundation of China (numbers 31172268 and 31271462). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.