In vitro studies on the lymphoma growth-inhibitory activity of sulfasalazine
In vitro studies on the lymphoma growth-inhibitory activity of sulfasalazine
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DOI：
10.1097/00001813-200301000-00004
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发表时间：
2003-01-01
影响因子：
2.3
通讯作者：
Robertson, MC
中科院分区：
文献类型：
--
作者：
Gout, PW;Simms, CR;Robertson, MC
柳氮磺胺吡啶（sulfasalazine，SASP）是一种新型的、有效的细胞胱氨酸摄取抑制剂，它通过x（c）（-）胱氨酸/谷氨酸逆向转运蛋白介导。类肉瘤细胞不能合成半胱氨酸，并且依赖于从其微环境中摄取半胱氨酸来生长。我们以前表明，SASP（0.2 mM）可以废除淋巴瘤细胞增殖体外特异性抑制x（c）（-）介导的胱氨酸摄取。腹腔注射SASP对Noble大鼠显著抑制Nb 2-U17大鼠淋巴瘤移植生长，对宿主无明显毒性。由于Nb2-U17细胞是x（c）（-）-缺陷的，生长停滞显然不是由于SASP-肿瘤细胞相互作用，而是可能干扰体细胞的x（c）（-）-介导的半胱氨酸分泌。在这项研究中，我们发现，x（c）（-）-缺陷型Nb 2 - 11淋巴瘤细胞的复制可以在体外持续，在没有胱氨酸摄取增强剂，通过与IMR-90成纤维细胞已知分泌半胱氨酸共培养。SASP，在0.15和0.2 mM，逮捕复制成纤维细胞驱动的Nb 2 - 11细胞分别为93%和100%，而不妨碍成纤维细胞增殖。添加2-巯基乙醇（60 μ M），一种胱氨酸摄取增强剂，几乎完全阻止了这种生长停滞，表明SASP特异性抑制成纤维细胞的半胱氨酸分泌，这是一个基于xc-介导的胱氨酸摄取的过程。有人提出，在体内的淋巴瘤生长抑制活性的SASP涉及抑制半胱氨酸分泌的肿瘤相关的体细胞（巨噬细胞，树突状细胞），导致半胱氨酸饥饿的肿瘤细胞和凋亡。淋巴瘤细胞和成纤维细胞对SASP治疗敏感性的差异与SASP无明显副作用的显著抗肿瘤作用一致。Anti-Cancer Drugs 14：21 - 29（C）2003 Lippincott威廉姆斯威尔金斯。
Sulfasalazine (SASP) is a novel, potent inhibitor of cellular cystine uptake mediated by the x(c)(-) cystine/glutamate antiporter. Lymphoid cells cannot synthesize cyst(e)ine and depend for growth on its uptake from their micro-environment. We previously showed that SASP (0.2 mM) can abrogate lymphoma cell proliferation in vitro by specifically inhibiting x(c)(-)-mediated cystine uptake. Intraperitoneal administration of SASP to Noble rats markedly suppressed Nb2-U17 rat lymphoma transplant growth, notably without major toxicity to the hosts. Since Nb2-U17 cells are x(c)(-)-deficient, the growth arrest was apparently not due to SASP-tumor cell interaction, but possibly to interference with x(c)(-)-mediated cysteine secretion by somatic cells. In this study we found that replication of x(c)(-)-deficient Nb2-11 lymphoma cells can be sustained in vitro, in the absence of cystine uptake enhancers, by co-culturing with IMR-90 fibroblasts known to secrete cysteine. SASP, at 0.15 and 0.2 mM, arrested replication of fibroblast-driven Nb2-11 cells by 93 and 100%, respectively, without impeding fibroblast proliferation. Addition of 2-mercaptoethanol (60 muM), a cystine uptake enhancer, almost completely prevented this growth arrest, indicating that SASP specifically inhibited cysteine secretion by the fibroblasts, a process based on xc--mediated cystine uptake. It is proposed that the lymphoma growth-inhibitory activity of SASP in vivo involves inhibition of cysteine secretion by tumor-associated somatic cells (macrophages, dendritic cells), leading to cysteine starvation of the tumor cells and apoptosis. The difference between the lymphoma cells and fibroblasts in sensitivity to SASP treatment is consistent with the marked antitumor effect of SASP lacking significant side effects. Anti-Cancer Drugs 14:21-29 (C) 2003 Lippincott Williams Wilkins.