Noscapine crosses the blood-brain barrier and inhibits glioblastoma growth
Noscapine crosses the blood-brain barrier and inhibits glioblastoma growth
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DOI：
10.1158/1078-0432.ccr-04-0360
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发表时间：
2004-08-01
影响因子：
11.5
通讯作者：
Archer, DR
中科院分区：
文献类型：
--
作者：
Landen, JW;Han, V;Archer, DR
鸦片生物碱诺斯卡因是欧洲、亚洲和南美洲常用的镇咳药。虽然它抑制咳嗽的机制目前尚不清楚，但据推测它涉及中枢神经系统。除了镇咳作用外，诺斯汀还与微管蛋白结合，并在体外和体内改变微管动力学。在这项研究中，我们发现诺斯汀在体外抑制大鼠C6胶质瘤细胞的增殖(IC50=100微米)，并有效地通过血脑屏障，其速度与吗啡和[Met]脑啡肽等具有强大中枢神经系统活性的药物相似(P<或等于0.05)。对立体定向种植大鼠C6胶质母细胞瘤的免疫缺陷小鼠，每日口服诺伐他汀(300 mg/kg)可显著缩小肿瘤体积(P：50.05)。通过对十二指肠、脾、肝或造血细胞的病理显微镜检查和流式细胞术检测，结果表明该方法对十二指肠、脾、肝或造血细胞无明显毒性。此外，从抑制神经突起生长的角度来看，诺伐他汀对背根神经节培养几乎没有毒性的证据，也没有发现动物周围神经病变的证据。然而，在诺伐他汀治疗的脑组织中观察到了血管扩张的证据。这些独特的特性，包括它能够穿越血脑屏障，干扰微管动力学，阻止肿瘤细胞分裂，减少肿瘤生长，以及对其他分裂组织和周围神经的最小影响，值得进一步研究其治疗潜力。
The opium alkaloid noscapine is a commonly used antitussive agent available in Europe, Asia, and South America. Although the mechanism by which it suppresses coughing is currently unknown, it is presumed to involve the central nervous system. In addition to its antitussive action, noscapine also binds to tubulin and alters microtubule dynamics in vitro and in vivo. In this study, we show that noscapine inhibits the proliferation of rat C6 glioma cells in vitro (IC50 = 100 muM) and effectively crosses the blood-brain barrier at rates similar to the ones found for agents such as morphine and [Met]enkephalin that have potent central nervous system activity (P less than or equal to 0.05). Daily oral noscapine treatment (300 mg/kg) administered to immunodeficient mice having stereotactically implanted rat C6 glioblasoma into the striatum revealed a significant reduction of tumor volume (P :5 0.05). This was achieved with no identifiable toxicity to the duodenum, spleen, liver, or hematopoietic cells as determined by pathological microscopic examination of these tissues and flow cytometry. Furthermore, noscapine treatment resulted in little evidence of toxicity to dorsal root ganglia cultures as measured by inhibition of neurite outgrowth and yielded no evidence of peripheral neuropathy in animals. However, evidence of vasodilation was observed in noscapine-treated brain tissue. These unique properties of noscapine, including its ability to cross the blood-brain barrier, interfere with microtubule dynamics, arrest tumor cell division, reduce tumor growth, and minimally affect other dividing tissues and peripheral nerves, warrant additional investigation of its therapeutic potential.