Sulfasalazine inhibits the growth of primary brain tumors independent of nuclear factor-kappaB.
Sulfasalazine inhibits the growth of primary brain tumors independent of nuclear factor-kappaB.
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DOI：
10.1111/j.1471-4159.2009.06129.x
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发表时间：
2009-07
影响因子：
4.7
通讯作者：
Sontheimer H
中科院分区：
文献类型：
--
作者：
Chung WJ;Sontheimer H
核因子-κB（NF-κB）是一种多效性转录因子，其通常增强细胞对凋亡性细胞死亡的抗性。它已被证明在某些癌症中具有组成性活性，并被视为潜在的抗癌靶点。临床上用于治疗克罗恩病的柳氮磺胺吡啶已成为NF-κB的潜在抑制剂，并在两项针对原发性脑肿瘤（神经胶质瘤）的临床前研究中显示出有希望的结果。一旦消化，柳氮磺胺吡啶被结肠细菌裂解成磺胺吡啶和5-氨基水杨酸（5-阿萨;美沙拉嗪），后者也被报道抑制NF-κB活性。我们现在发现，从患者活检或胶质瘤细胞系获得的胶质瘤细胞没有显示出显著的组成型NF-κB活化，除非暴露于炎性细胞因子。当神经胶质瘤植入严重联合免疫缺陷小鼠的大脑时，这一点不会改变。然而，柳氮磺胺吡啶，而不是其裂解形式5-阿萨引起剂量依赖性抑制胶质瘤生长。这种效应完全归因于通过系统xc−胱氨酸-谷氨酸转运蛋白抑制胱氨酸摄取。它可以被S-4-羧基苯甘氨酸（S-4-CPG）模拟，S-4-CPG是一种更特异的系统xc−抑制剂，IκB激酶B b的组成型活性形式的慢病毒表达无法克服柳氮磺胺吡啶或S-4-CPG的生长抑制作用。这两种药物抑制胱氨酸摄取，导致细胞内GSH的慢性消耗，从而损害细胞的氧化还原防御，阻碍肿瘤生长。这些数据表明，系统xc−是神经胶质瘤和其他癌症的一个有前途的治疗靶点，并且可以被FDA批准的药物柳氮磺胺吡啶抑制。
Nuclear factor-κB (NF-κB) is a pleiotropic transcription factor that generally enhances cellular resistance to apoptotic cell death. It has been shown to be constitutively active in some cancers and is being pursued as potential anticancer target. Sulfasalazine which is used clinically to treat Crohn's disease has emerged as a potential inhibitor of NF-κB and has shown promising results in two pre-clinical studies to target primary brain tumors, gliomas. Once digested, sulfasalazine is cleaved into sulfapyridine and 5-aminosalicylic acid (5-ASA; mesalamine) by colonic bacteria, and the latter, too, is reported to suppress NF-κB activity. We now show that glioma cells obtained from patient biopsies or glioma cell lines do not show significant constitutive NF-κB activation, unless exposed to inflammatory cytokines. This does not change when gliomas are implanted into the cerebrum of severe combined immundeficient mice. Nevertheless, sulfasalazine but not its cleaved form 5-ASA caused a dose-dependent inhibition of glioma growth. This effect was entirely attributable to the inhibition of cystine uptake via the system xc− cystine–glutamate transporter. It could be mimicked by S-4-carboxy-phenylglycine (S-4-CPG) a more specific system xc− inhibitor, and lentiviral expression of a constitutively active form of IκB kinase b was unable to overcome the growth retarding effects of sulfasalazine or S-4-CPG. Both drugs inhibited cystine uptake causing a chronic depletion of intracellular GSH and consequently compromised cellular redox defense which stymied tumor growth. This data suggests that system xc− is a promising therapeutic target in gliomas and possibly other cancers and that it can be pharmacologically inhibited by Sulfasalazine, an FDA-approved drug.
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