Chronic hypoxia promotes hypoxia-inducible factor-1α-dependent resistance to etoposide and vincristine in neuroblastoma cells
Chronic hypoxia promotes hypoxia-inducible factor-1α-dependent resistance to etoposide and vincristine in neuroblastoma cells
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DOI：
10.1158/1535-7163.mct-06-0145
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发表时间：
2006-09-01
影响因子：
5.7
通讯作者：
Makin, Guy W. J.
中科院分区：
文献类型：
--
作者：
Hussein, Deema;Estlin, Edward J.;Makin, Guy W. J.
由于肿瘤新生血管结构不佳，实体瘤中普遍存在缺氧现象。直接测量一系列成人肿瘤类型的低氧水平与晚期肿瘤缺氧、化疗和放疗反应差以及预后差相关。对缺氧在儿童肿瘤中的重要性知之甚少；因此，我们评估了缺氧对神经母细胞瘤细胞系SH-EP1和SH-SY5Y对临床相关药物长春新碱、依托泊苷和顺铂的反应的影响。短期低氧(1%OZ(2))长达16小时对药物诱导的细胞凋亡或克隆形成存活没有影响。缺氧1~7天可减少长春新碱和依托泊苷诱导的SH-SY5Y和SH-EP1细胞的凋亡，这反映在这些条件下克隆形成的存活率增加。短期和长期低氧对顺铂诱导的SH-SY5Y细胞克隆形成均无影响。低氧诱导因子-1(HIF-1)α在低氧2小时内在这些细胞系中稳定下来，但在低氧48小时后不再被检测到。碳酸酐酶IX的上调表明HIF-1α在转录上是活跃的。通过短发夹状RNA干扰和小分子3-(5‘-hydroxymethyl-2’-furyl)-1-benzylindazole下调HIF-1α表达可降低缺氧诱导的耐药性。这些结果表明，长期低氧导致神经母细胞瘤对临床相关药物的耐药性，旨在抑制HIF-1a功能的治疗可能有助于克服这种肿瘤的耐药性。
Hypoxia is widespread in solid tumors as a consequence of poorly structured tumor-derived neovasculature. Direct measurement of low oxygen levels in a range of adult tumor types has correlated tumor hypoxia with advanced stage, poor response to chemotherapy and radiotherapy, and poor prognosis. Little is known about the importance of hypoxia in pediatric tumors; therefore, we evaluated the effects of hypoxia on the response of the neuroblastoma cell lines SH-EP1 and SH-SY5Y to the clinically relevant drugs, vincristine, etoposide, and cisplatin. Short periods of hypoxia (1% OZ(2)) of up to 16 hours had no effect on drug-induced apoptosis or clonogenic survival. Prolonged hypoxia of 1 to 7 days leads to reduction in vincristine- and etoposide-induced apoptosis in SH-SY5Y and SH-EP1 cells, and this was reflected in increased clonogenic survival under these conditions. Neither short-term nor prolonged hypoxia had any effect on the clonogenic response to cisplatin in SH-SY5Y cells. Hypoxia-inducible factor-1 (HIF-1) alpha was stabilized in these cell lines within 2 hours of hypoxia but was no longer detectable beyond 48 hours of hypoxia. Up-regulation of carbonic anhydrase IX showed HIF-1 alpha to be transcriptionally active. Downregulation of HIF-1 alpha by short hairpin RNA interference and the small-molecule 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole reduced hypoxia-induced drug resistance. These results suggest that prolonged hypoxia leads to resistance to clinically relevant drugs in neuroblastoma and that therapies aimed at inhibiting HIF-1a function may be useful in overcoming drug resistance in this tumor.