Radiofrequency ablation-induced upregulation of hypoxia-inducible factor-1α can be suppressed with adjuvant bortezomib or liposomal chemotherapy.
Radiofrequency ablation-induced upregulation of hypoxia-inducible factor-1α can be suppressed with adjuvant bortezomib or liposomal chemotherapy.
复制标题
DOI：
10.1016/j.jvir.2014.08.025
复制
发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Ahmed M
中科院分区：
文献类型：
--
作者：
Moussa M;Goldberg SN;Kumar G;Sawant RR;Levchenko T;Torchilin V;Ahmed M
旨在表征射频 (RF) 消融后缺氧诱导因子 (HIF)-1α 的上调，以及辅助 HIF-1α 抑制剂（硼替佐米）和纳米药物对调节射频消融上调缺氧途径的影响。使用 Fisher 344 只大鼠 (n = 68)。首先，在正常肝脏或皮下 R3230 肿瘤（14-16 mm）中评估射频消融诱导的消融周围 HIF-1α 表达。接下来，在 R3230 肿瘤中研究了不同射频消融热剂量（改变尖端温度 50°C–90°C，持续 2–20 分钟）对 HIF-1α 表达的影响。第三，在不使用或使用辅助 HIF-1α 抑制剂硼替佐米（单次腹膜内剂量 0.1 mg/kg）的情况下对 R3230 肿瘤进行射频消融。最后，评估了射频消融和已知会增加围消融细胞毒性的静脉脂质体化疗药物（阿霉素、紫杉醇和槲皮素）的组合对围消融 HIF-1α 的影响。结果测量包括 HIF-1α 和热休克蛋白 70（非致死性热损伤标记物）的免疫组织化学分析。射频消融增加了正常肝脏和 R3230 肿瘤中消融周围的 HIF-1α，在 24-72 小时达到峰值。与肝脏射频消融相比，肿瘤射频消融具有相似的 HIF-1α 边缘厚度，但细胞阳性率显着更高 (P < .001)。无论热剂量如何，消融后的 HIF-1α 都是相同的。硼替佐米抑制了 HIF-1α（边缘厚度，单独射频消融为 68.7 μm ± 21.5 对比 210.3 μm ± 85.1；P < .02）并增加消融尺寸（单独射频消融为 11.0 mm ± 1.5 对比 7.7 mm ± 0.6；P < .002）。最后，所有三种纳米药物均抑制射频消融诱导的 HIF-1α（即边缘厚度和细胞阳性；所有比较的 P < .02），其中脂质体阿霉素对 HIF-1α 的抑制作用最大（P < .03）。射频消融以与温度无关的方式上调正常肝脏和肿瘤中的 HIF-1α。这种促生长、缺氧途径可以通过辅助 HIF-1α 特异性抑制剂、硼替佐米或非 HIF-1α 特异性脂质体化疗成功抑制。
To characterize upregulation of hypoxia-inducible factor (HIF)-1α after radiofrequency (RF) ablation and the influence of an adjuvant HIF-1α inhibitor (bortezomib) and nanodrugs on modulating RF ablation–upregulated hypoxic pathways. Fisher 344 rats (n = 68) were used. First, RF ablation–induced periablational HIF-1α expression was evaluated in normal liver or subcutaneous R3230 tumors (14–16 mm). Next, the effect of varying RF ablation thermal dose (varying tip temperature 50°C–90°C for 2–20 minutes) on HIF-1α expression was studied in R3230 tumors. Third, RF ablation was performed in R3230 tumors without or with an adjuvant HIF-1α inhibitor, bortezomib (single intraperitoneal dose 0.1 mg/kg). Finally, the combination RF ablation and intravenous liposomal chemotherapeutics with known increases in periablational cellular cytotoxicity (doxorubicin, paclitaxel, and quercetin) was assessed for effect on periablational HIF-1α. Outcome measures included immunohistochemistry of HIF-1α and heat shock protein 70 (marker of nonlethal thermal injury). RF ablation increased periablational HIF-1α in both normal liver and R3230 tumor, peaking at 24–72 hours. Tumor RF ablation had similar HIF-1α rim thickness but significantly greater percent cell positivity compared with hepatic RF ablation (P < .001). HIF-1α after ablation was the same regardless of thermal dose. Bortezomib suppressed HIF-1α (rim thickness, 68.7 μm ± 21.5 vs 210.3 μm ± 85.1 for RF ablation alone; P < .02) and increased ablation size (11.0 mm ± 1.5 vs 7.7 mm ± 0.6 for RF ablation alone; P < .002). Finally, all three nanodrugs suppressed RF ablation–induced HIF-1α (ie, rim thickness and cell positivity; P < .02 for all comparisons), with liposomal doxorubicin suppressing HIF-1α the most (P < .03). RF ablation upregulates HIF-1α in normal liver and tumor in a temperature-independent manner. This progrowth, hypoxia pathway can be successfully suppressed with an adjuvant HIF-1α-specific inhibitor, bortezomib, or non–HIF-1α-specific liposomal chemotherapy.