Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK.
Mol Cancer Ther. 2010 May;9(5):1219-33. doi: 10.1158/1535-7163.MCT-09-0683.
The dismal prognosis of glioblastoma (GB) indicates the urgent need for new therapies for these tumors. Heat shock protein 90 (HSP90) inhibitors induce the proteasome-mediated degradation of many oncogenic client proteins involved in all of the hallmark characteristics of cancer. Here, we explored the mechanistic potential of the potent synthetic diarylisoxazole amide resorcinol HSP90 inhibitor, NVP-AUY922, in adult and pediatric GB. In vitro antiproliferative potency (nanomolar range) was seen in both adult and pediatric human GB cell lines with different molecular pathologies. A cytostatic effect was observed in all GB lines; more apoptosis was observed at lower concentrations in the SF188 pediatric GB line and at 144 hours in the slower growing KNS42 pediatric GB line, as compared with the adult GB lines U87MG and SF268. In vitro combination studies with inhibitors of phosphoinositide 3-kinase/mammalian target of rapamycin (PI-103) or mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (PD-0325901) supported the hypothesis that sustained inhibition of ERK up to 72 hours and at least temporary inhibition of AKT were necessary to induce apoptosis in GB lines. In athymic mice bearing established s.c U87MG GB xenografts, NVP-AUY922 (50 mg/kg i.p x 3 days) caused the inhibition of ERK1/2 and AKT phosphorylation and induced apoptosis, whereas 17-AAG used at maximum tolerated dose was less effective. NVP-AUY922 antitumor activity with objective tumor regression resulted from antiproliferative, proapoptotic, and antiangiogenic effects, the latter shown by decreased microvessel density and HIF1alpha levels. Our results have established a mechanistic proof of concept for the potential of novel synthetic HSP90 inhibitors in adult and pediatric GB, alone or in combination with phosphoinositide 3-kinase/mammalian target of rapamycin and mitogen-activated protein/ERK kinase inhibitors.
胶质母细胞瘤（GB）的预后不佳，表明迫切需要为这些肿瘤开发新的治疗方法。热休克蛋白 90（HSP90）抑制剂诱导蛋白酶体介导的许多致癌客户蛋白的降解，这些蛋白与癌症的所有标志性特征有关。在这里，我们探索了强效合成二芳基异恶唑酰胺间苯二酚 HSP90 抑制剂 NVP-AUY922 在成人和儿科 GB 中的机制潜力。在具有不同分子病理学的成人和儿科人类 GB 细胞系中均观察到体外抗增殖效力（纳摩尔范围）。在所有 GB 系中均观察到细胞抑制作用；在 SF188 儿科 GB 系中，在较低浓度下观察到更多的细胞凋亡，在生长较慢的 KNS42 儿科 GB 系中在 144 小时时观察到更多的细胞凋亡，与成人 GB 系 U87MG 和 SF268 相比。与磷酸肌醇 3-激酶/雷帕霉素（PI-103）或丝裂原激活的蛋白/细胞外信号调节激酶（ERK）激酶（PD-0325901）抑制剂的体外组合研究支持以下假设：持续抑制 ERK 达 72 小时并至少暂时抑制 AKT 是诱导 GB 系细胞凋亡所必需的。在皮下植入的 U87MG GB 异种移植的裸鼠中，NVP-AUY922（50mg/kg i.p x 3 天）导致 ERK1/2 和 AKT 磷酸化的抑制和凋亡的诱导，而 17-AAG 在最大耐受剂量下的效果较差。NVP-AUY922 的抗肿瘤活性伴有客观的肿瘤消退，是通过抗增殖、促凋亡和抗血管生成作用产生的，后者表现为微血管密度和 HIF1alpha 水平降低。我们的结果为新型合成 HSP90 抑制剂在成人和儿科 GB 中的潜力建立了机制概念证明，单独使用或与磷酸肌醇 3-激酶/雷帕霉素和丝裂原激活的蛋白/ERK 激酶抑制剂联合使用。
