Department of Radiology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Abdominal Medicine Imaging, Jinan, Shandong 250014, P.R. China.
Department of Radiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Oncol Rep. 2023 Mar;49(3). doi: 10.3892/or.2023.8492. Epub 2023 Feb 3.
Sorafenib is a targeted drug for hepatocellular carcinoma (HCC), however, its efficacy is limited. Nuclear factor erythroid 2‑related factor 2 (Nrf2) contributes to sorafenib resistance. The present study investigated camptothecin (CPT) as a Nrf2 inhibitor to sensitize HCC to sorafenib. The effect of CPT on sorafenib sensitivity in HCC was assessed using H22 mice model (n=32) and VX2 rabbit models (n=32), which were sorted into four treatment groups. The expression levels of Nrf2, its downstream genes, including heme oxygenases‑1 (HO‑1) and NAD(P)H quinone oxidoreductase 1 (NQO1), and the epithelial‑mesenchymal transition markers Snail and N‑cadherin in tumors were determined using immunohistochemical staining and western blotting. Magnetic resonance imaging was used to monitor changes in tumor microcirculation and activity before and after treatment. Mouse body weights, liver and kidney function were monitored to evaluate the safety of combined therapy. The results revealed that the mean tumor size of the combined group was significantly smaller than that of sorafenib group for both models. The expression levels of Nrf2, heme oxygenase‑1, NAD(P)H quinone oxidoreductase 1, Snail, and N‑cadherin in the sorafenib group were significantly higher than control group (P<0.05). However, the expression levels of these genes were decreased in the combined group (P<0.05). Microcirculation perfusion and tumor activity in the combined group were also lower than sorafenib group. There were no significant differences in mouse body weight or liver and kidney function among the four groups. In summary, CPT is a Nrf2 inhibitor that could enhance the efficacy of sorafenib against HCC.
索拉非尼是一种用于治疗肝细胞癌（HCC）的靶向药物，但疗效有限。核因子红细胞 2 相关因子 2（Nrf2）有助于索拉非尼耐药。本研究探讨喜树碱（CPT）作为 Nrf2 抑制剂，以增强 HCC 对索拉非尼的敏感性。采用 H22 小鼠模型（n=32）和 VX2 兔模型（n=32）评估 CPT 对 HCC 索拉非尼敏感性的影响，并将其分为四组进行治疗。采用免疫组化染色和 Western blot 检测肿瘤中 Nrf2 及其下游基因血红素加氧酶-1（HO-1）和 NAD（P）H 醌氧化还原酶 1（NQO1）以及上皮-间充质转化标志物 Snail 和 N-钙黏蛋白的表达水平。采用磁共振成像监测治疗前后肿瘤微循环和活性的变化。监测小鼠体重、肝肾功能，评估联合治疗的安全性。结果显示，两种模型中联合组的平均肿瘤大小均明显小于索拉非尼组。索拉非尼组 Nrf2、血红素加氧酶-1、NAD（P）H 醌氧化还原酶 1、Snail 和 N-钙黏蛋白的表达水平明显高于对照组（P<0.05）。然而，联合组这些基因的表达水平降低（P<0.05）。联合组的微循环灌注和肿瘤活性也低于索拉非尼组。四组小鼠体重、肝肾功能无明显差异。综上所述，CPT 是一种 Nrf2 抑制剂，可增强索拉非尼对 HCC 的疗效。
