Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, 400 Monroe Ave NW, Grand Rapids, MI 49503, USA.
Department of Medical Biology, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Biochem Pharmacol. 2019 Apr;162:237-249. doi: 10.1016/j.bcp.2019.01.007. Epub 2019 Jan 9.
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.
神经母细胞瘤（NB）是婴儿期和幼儿期起源于交感神经系统的肿瘤。复发的高危患者往往对进一步的治疗没有反应，导致这组患者的 5 年生存率低于 5%。因此，仍然迫切需要创新的治疗方法。最近，我们发现柳氮磺胺吡啶（SSZ），一种用于治疗类风湿关节炎和溃疡性结肠炎的 FDA 批准药物，可在 NB 肿瘤细胞中诱导抗增殖作用。最近的研究表明，SSZ 抑制了色氨酸合酶还原酶（SPR），SPR 是一氧化氮（NO）途径中产生四氢生物蝶呤（BH4）的关键酶。在这里，我们在体外测试了 SSZ 对纯化的 SPR 的抑制作用，测量了 SSZ 对一系列 MYCN 扩增和 MYCN 非扩增 NB 细胞系的抗增殖作用，并评估了 SSZ 在 NB 肿瘤异种移植小鼠中的抗肿瘤作用。我们发现，在没有 MYCN 扩增的细胞系中，SPR mRNA 和 SPR 蛋白的表达均显著升高。SSZ 抑制了体外 SPR 酶活性，并在大量源自高危肿瘤的 NB 细胞系中表现出抗增殖活性。重要的是，口服/腹腔内（i.p.）SSZ 联合给药在体内产生了可测量的抗肿瘤作用。SSZ 是一种 FDA 批准的药物，在临床应用中具有良好的耐受性，可重新定位以抑制 NB 中的肿瘤生长。
