Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Trust, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK.
Br J Cancer. 2012 May 8;106(10):1638-47. doi: 10.1038/bjc.2012.131. Epub 2012 Apr 12.
Hypoxia-inducible factor-1 (HIF-1) mediates the transcriptional response to hypoxic stress, promoting tumour progression and survival. This study investigated the acute effects of the small-molecule HIF-pathway inhibitor NSC-134754.
Human PC-3LN5 prostate cancer cells were treated with NSC-134754 for 24 h in hypoxia. Orthotopic prostate tumour-bearing mice were treated with a single dose of NSC-134754 for 6, 24 or 48 h. Treatment response was measured using magnetic resonance spectroscopy and imaging. Ex-vivo histological validation of imaging findings was also sought.
In vitro, NSC-134754 significantly reduced lactate production and glucose uptake (P<0.05), while significantly increasing intracellular glucose (P<0.01) and glutamine uptake/metabolism (P<0.05). Increased glutamine metabolism was independent of c-Myc, a factor also downregulated by NSC-134754. In vivo, a significantly higher tumour apparent diffusion coefficient was determined 24 h post-treatment (P<0.05), with significantly higher tumour necrosis after 48 h (P<0.05). NSC-134754-treated tumours revealed lower expression of HIF-1α and glucose transporter-1, at 6 and 24 h respectively, while a transient increase in tumour hypoxia was observed after 24 h. Vessel perfusion/flow and vascular endothelial growth factor levels were unchanged with treatment.
NSC-134754 induces metabolic alterations in vitro and early anti-tumour activity in vivo, independent of changes in vascular function. Our data support the further evaluation of NSC-134754 as an anti-cancer agent.
缺氧诱导因子-1（HIF-1）介导了对缺氧应激的转录反应，促进肿瘤的进展和存活。本研究探讨了小分子 HIF 通路抑制剂 NSC-134754 的急性作用。
将人 PC-3LN5 前列腺癌细胞在缺氧条件下用 NSC-134754 处理 24 小时。荷瘤原位前列腺癌小鼠用 NSC-134754 单次剂量处理 6、24 或 48 小时。使用磁共振波谱和成像测量治疗反应。还寻求了对成像发现的离体组织学验证。
在体外，NSC-134754 显著降低了乳酸盐的产生和葡萄糖的摄取（P<0.05），同时显著增加了细胞内葡萄糖（P<0.01）和谷氨酰胺的摄取/代谢（P<0.05）。谷氨酰胺代谢的增加与 c-Myc 无关，c-Myc 也是 NSC-134754 下调的一个因素。在体内，治疗后 24 小时肿瘤表观扩散系数显著升高（P<0.05），48 小时后肿瘤坏死显著升高（P<0.05）。NSC-134754 处理的肿瘤在 6 和 24 小时时分别显示出 HIF-1α 和葡萄糖转运蛋白-1 的表达降低，而在 24 小时时观察到肿瘤缺氧的短暂增加。治疗后血管灌注/流量和血管内皮生长因子水平没有变化。
NSC-134754 在体外诱导代谢改变，并在体内早期产生抗肿瘤活性，与血管功能变化无关。我们的数据支持进一步评估 NSC-134754 作为一种抗癌药物。
