Anti-tumor effect of sulfasalazine in neuroblastoma

• Published in: Biochemical pharmacology 2019-04, Vol.162, p.237-249
• Main Authors: Mooney, Marie R., Geerts, Dirk, Kort, Eric J., Bachmann, André S.
• Format: Article
• Language: English
• Subjects: Alcohol Oxidoreductases - antagonists & inhibitors; Alcohol Oxidoreductases - chemistry; Alcohol Oxidoreductases - metabolism; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; DFMO; Humans; Male; Mice; Mice, Nude; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - metabolism; Neuroblastoma - pathology; Novel target; Protein Structure, Secondary; SPR; Sulfasalazine; Sulfasalazine - pharmacology; Sulfasalazine - therapeutic use; Xenograft Model Antitumor Assays - methods
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2019.01.007

An active metabolic pathway in neuroblastoma (NB) converts sepiapterin into tetrahydro-biopterin (BH4) through the enzyme sepiapterin reductase (SPR). The FDA-approved drug sulfasalazine (SSZ) inhibits SPR and suppresses NB growth. Design by Marie Mooney. [Display omitted] 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.