Anti-tumor effect of sulfasalazine in neuroblastoma

Biochem Pharmacol. 2019 Apr;162:237-249. doi: 10.1016/j.bcp.2019.01.007. Epub 2019 Jan 9.

Abstract

Neuroblastoma (NB) is a tumor arising from the sympathetic nervous system during infancy and early childhood. High-risk patients who relapse often fail to respond to further therapy, which results in 5-year survival rate for this patient group below 5%. Therefore, there continues to be an urgent need for innovative treatments. Recently, we found that sulfasalazine (SSZ), an FDA-approved drug for the treatment of rheumatoid arthritis and ulcerative colitis induces anti-proliferative effects in NB tumor cells. SSZ was recently shown to inhibit sepiapterin reductase (SPR), a key enzyme that produces tetrahydrobiopterin (BH4) in the nitric oxide (NO) pathway. Here we tested SSZ against purified SPR in vitro, measured the anti-proliferative effect of SSZ on a panel of MYCN amplified and MYCN non-amplified NB cell lines, and assessed the anti-tumor effect of SSZ in NB tumor-xenografted mice. We found that the expression of both SPR mRNA and SPR protein was significantly higher in cell lines without MYCN amplification. SSZ inhibited SPR enzyme activity in vitro and exhibits anti-proliferative activity in a large number of NB cell lines derived from high-risk tumors. Importantly, oral/intraperitoneal (i.p.) SSZ co-administration resulted in measureable anti-tumor effects in vivo. The FDA-approved drug SSZ, a well-tolerated drug in clinical use, could be repositioned to inhibit tumor growth in NB.

Keywords: DFMO; Neuroblastoma; Novel target; SPR; Sulfasalazine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / antagonists & inhibitors*
  • Alcohol Oxidoreductases / chemistry
  • Alcohol Oxidoreductases / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neuroblastoma / drug therapy
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Protein Structure, Secondary
  • Sulfasalazine / pharmacology
  • Sulfasalazine / therapeutic use*
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antineoplastic Agents
  • Sulfasalazine
  • Alcohol Oxidoreductases
  • sepiapterin reductase