Jeong Da Eun, Song Hye Jin Jin, Lim Sharon, Lee Se Jeong Jeong, Lim Joung Eun, Nam Do-Hyun, Joo Kyeung Min, Jeong Byong Chang, Jeon Seong Soo, Choi Han Yong, Lee Hye Won
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.
Department of Anatomy and Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Oncotarget. 2015 Oct 20;6(32):33046-64. doi: 10.18632/oncotarget.5422.
Despite advances in the development of molecularly targeted therapies, metastatic renal cell carcinoma (RCC) is still incurable. Artesunate (ART), a well-known anti-malarial drug with low toxicity, exhibits highly selective anti-tumor actions against various tumors through generation of cytotoxic carbon-centered free radical in the presence of free iron. However, the therapeutic efficacy of ART against metastatic RCC has not yet been fully elucidated. In the analysis on a dataset from The Cancer Genome Atlas (TCGA) (n = 469) and a tissue microarray set from Samsung Medical Center (n = 119) from a cohort of patients with clear cell RCC (ccRCC), up-regulation of transferrin receptor 1 (TfR1), which is a well-known predictive marker for ART, was correlated with the presence of distant metastasis and an unfavorable prognosis. Moreover, ART exerted potent selective cytotoxicity against human RCC cell lines (Caki-1, 786-O, and SN12C-GFP-SRLu2) and sensitized these cells to sorafenib in vitro, and the extent of ART cytotoxicity correlated with TfR1 expression. ART-mediated growth inhibition of human RCC cell lines was shown to result from the induction of cell cycle arrest at the G2/M phase and oncosis-like cell death. Furthermore, ART inhibited cell clonogenicity and invasion of human RCC cells and anti-angiogenic effects in vitro in a dose-dependent manner. Consistent with these in vitro data, anti-tumor, anti-metastatic and anti-angiogenic effects of ART were also validated in human 786-O xenografts. Taken together, ART is a promising novel candidate for treating human RCC, either alone or in combination with other therapies.
尽管分子靶向治疗取得了进展，但转移性肾细胞癌（RCC）仍然无法治愈。青蒿琥酯（ART）是一种众所周知的低毒性抗疟药物，通过在游离铁存在下产生细胞毒性的碳中心自由基，对各种肿瘤表现出高度选择性的抗肿瘤作用。然而，ART对转移性RCC的治疗效果尚未完全阐明。在对来自癌症基因组图谱（TCGA）（n = 469）的数据集和三星医疗中心（n = 119）的组织芯片集进行的分析中，在一组透明细胞RCC（ccRCC）患者中，转铁蛋白受体1（TfR1）的上调，这是ART的一个众所周知的预测标志物，与远处转移的存在和不良预后相关。此外，ART对人RCC细胞系（Caki-1、786-O和SN12C-GFP-SRLu2）具有强大的选择性细胞毒性，并在体外使这些细胞对索拉非尼敏感，ART细胞毒性的程度与TfR1表达相关。ART介导的人RCC细胞系生长抑制被证明是由于诱导细胞周期停滞在G2/M期和类胀亡样细胞死亡。此外，ART在体外以剂量依赖性方式抑制人RCC细胞的克隆形成和侵袭以及抗血管生成作用。与这些体外数据一致，ART的抗肿瘤、抗转移和抗血管生成作用也在人786-O异种移植模型中得到验证。综上所述，ART是一种有前途的新型候选药物，可单独或与其他疗法联合用于治疗人类RCC。
