Abstract
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.
Highlights
40% of all patients with renal cell carcinoma (RCC) die of metastasis
transferrin receptor 1 (TfR1) is up-regulated in clear cell RCC with distant metastases, and high TfR1 expression correlates with poor prognosis
To determine the clinical relevance and therapeutic implication of ART for patients with metastatic RCC, we examined whether TfR1 expression was correlated with any of the clinico-pathological characteristics of clear cell RCC (ccRCC)
Summary
40% of all patients with renal cell carcinoma (RCC) die of metastasis. Metastases are often present at diagnosis, and relapse after nephrectomy is common [1, 2]. There is a renewed interest in the discovery of novel anti-cancer drugs from natural compounds and their derivatives [4]. In addition to its established safety and tolerability in anti-malarial treatment, artesunate (ART), a semi-synthetic derivative of the sesquiterpene artemisinin, has shown promise in crossover usage as an anti-cancer agent for a variety of solid tumors [5,6,7,8,9,10]. Oncosis has regained attention since a number of novel anticancer agents have been identified based on their ability to induce oncotic cell death [17]. ART is a native compound that can induce oncosis in pancreatic [19] and gastric [20] cancer cells
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