Repurposing the anti-malarial drug artesunate as a novel therapeutic agent for metastatic renal cell carcinoma due to its attenuation of tumor growth, metastasis, and angiogenesis.
Repurposing the anti-malarial drug artesunate as a novel therapeutic agent for metastatic renal cell carcinoma due to its attenuation of tumor growth, metastasis, and angiogenesis.
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DOI：
10.18632/oncotarget.5422
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Lee HW
中科院分区：
文献类型：
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作者：
Jeong DE;Song HJ;Lim S;Lee SJ;Lim JE;Nam DH;Joo KM;Jeong BC;Jeon SS;Choi HY;Lee HW
尽管分子靶向治疗的发展取得了进展，但转移性肾细胞癌（RCC）仍然无法治愈。青蒿琥酯（ART）是一种著名的低毒抗疟疾药物，在游离铁存在下通过产生细胞毒性的碳中心自由基，对多种肿瘤表现出高度选择性的抗肿瘤作用。然而，ART对转移性肾细胞癌的治疗效果尚未完全阐明。在对癌症基因组图谱 (TCGA) (n = 469) 的数据集和三星医疗中心 (n = 119) 透明细胞肾细胞癌 (ccRCC) 患者队列的组织微阵列集进行分析时，转铁蛋白受体 1 (TfR1) 的上调（TfR1）是众所周知的 ART 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）发挥有效的选择性细胞毒性，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 细胞系生长抑制是由于诱导细胞周期停滞在 G2/M 期和肿瘤样细胞死亡所致。此外，ART 以剂量依赖性方式抑制人肾细胞癌细胞的细胞克隆形成和侵袭以及体外抗血管生成作用。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类 786-O 异种移植物中得到了验证。总而言之，ART 是治疗人类肾细胞癌的一种有前途的新型候选药物，无论是单独使用还是与其他疗法联合使用。
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.