HIF-1α activation mediates resistance to anti-angiogenic therapy in neuroblastoma xenografts.
HIF-1α activation mediates resistance to anti-angiogenic therapy in neuroblastoma xenografts.
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DOI：
10.1016/j.jpedsurg.2012.10.016
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发表时间：
2013-01
影响因子：
2.4
通讯作者：
Davidoff, Andrew M.
中科院分区：
文献类型：
--
作者：
Hartwich, Joseph;Orr, W. Shannon;Ng, Catherine Y.;Spence, Yunyu;Morton, Christopher;Davidoff, Andrew M.
血管生成抑制剂的抗肿瘤活性通常受到对这些药物产生耐药性的限制。在这里，我们确定HIF-1α是神经母细胞瘤异种移植物耐药发展的主要因素。通过将未修饰的SKNAS或NB-1691细胞（2×106个细胞）或其中HIF-1α表达已被shRNA敲低的细胞注射到SCID小鼠的腹膜后间隙中来建立神经母细胞瘤异种移植物。已建立肿瘤的治疗包括贝伐珠单抗（5 mg/kg q2 wk）、舒尼替尼（40 mg/kg qd）或托泊替康（0.5 mg/kg qd）单独或联合治疗共2周。与对照肿瘤相比，NB-1691异种移植物在HIF-1α敲低的相对生长方面没有差异（73.33±7.90 vs 79.94±6.15，p=0.528）。然而，当用贝伐珠单抗（35.88±4.24 vs 53.57±6.61，p=0.0544）或舒尼替尼（12.46±2.59 vs 36.36±4.82，p=0.0024）治疗时，HIF-1α敲减显示相对最终体积显著低于未修饰的肿瘤。用贝伐单抗、舒尼替尼或托泊替康单药治疗未修饰的异种移植物在很大程度上无效。在舒尼替尼+托泊替康（4.78±0.77 vs 39.17±2.44 [舒尼替尼单药]，p=0.011）和贝伐珠单抗+托泊替康（13.63±1.55 vs 48.16±9.94 [贝伐珠单抗单药]，p=0.014）治疗的队列中，NB-1691异种移植物的相对最终体积显著较小。HIF-1α的上调似乎是神经母细胞瘤对抗血管生成治疗耐药的重要机制。在小鼠模型中，用低剂量拓扑替康抑制HIF-1α可增强抗血管生成药物的作用。
The anti-tumor activity of angiogenesis inhibitors is often limited by the development of resistance to these drugs. Here we establish HIF-1α as a major factor in the development of this resistance in neuroblastoma xenografts. Neuroblastoma xenografts were established by injecting unmodified SKNAS or NB-1691 cells (2×106 cells), or cells in which HIF-1α expression had been knocked down with shRNA, into the retroperitoneal space of SCID mice. Treatment of established tumors included bevacizumab (5mg/kg q2wk), sunitinib (40mg/kg qd), or topotecan (0.5mg/kg qd) alone or in combination for a total of two weeks. NB-1691 xenografts showed no difference in relative growth in HIF-1α knockdowns compared to control tumors (73.33±7.90 vs 79.94±6.15, p=0.528). However, HIF-1α knockdowns demonstrated relative final volumes that were significantly lower than unmodified tumors when both were treated with bevacizumab (35.88±4.24 vs 53.57±6.61, p=0.0544) or sunitinib (12.46±2.59 vs 36.36±4.82, p=0.0024). Monotherapy of unmodified xenografts with bevacizumab, sunitinib, or topotecan was largely ineffective. Relative final volumes of NB-1691 xenografts were significantly less in cohorts treated with sunitinib+topotecan (4.78±0.77 vs 39.17±2.44 [sunitinib alone], p=0.011) and bevacizumab+topotecan (13.63±1.55 vs 48.16±9.94 [bevacizumab alone], p=0.014). Upregulation of HIF-1α appears to be a significant mechanism of resistance to antiangiogenic therapies in neuroblastoma. Suppressing HIF-1α with low-dose topotecan potentiates the effects of the antiangiogenic drugs in a mouse model.
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