The antibiotic clofoctol suppresses glioma stem cell proliferation by activating KLF13
Yan Hu, … , Wei Han, Xiaozhong Peng
Yan Hu, … , Wei Han, Xiaozhong Peng
Published May 21, 2019
Citation Information: J Clin Invest. 2019;129(8):3072-3085. https://doi.org/10.1172/JCI124979.
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Research Article Oncology

The antibiotic clofoctol suppresses glioma stem cell proliferation by activating KLF13

Abstract

Gliomas account for approximately 80% of primary malignant tumors in the central nervous system. Despite aggressive therapy, the prognosis of patients remains extremely poor. Glioma stem cells (GSCs), considered a potential target of therapy for their crucial role in therapeutic resistance and tumor recurrence, are believed to be key factors in the disappointing outcome. Here, we took advantage of GSCs as the cell model to perform high-throughput drug screening, and the old antibiotic clofoctol was identified as the most effective compound, showing reduction of colony formation and induction of apoptosis of GSCs. Moreover, growth of tumors was obviously inhibited in vivo after clofoctol treatment especially in primary patient-derived xenografts and transgenic xenografts. The anticancer mechanisms demonstrated by analysis of related downstream genes and discovery of the targeted binding protein revealed that clofoctol exhibited the inhibition of GSCs by upregulation of Krüppel-like factor 13 (KLF13), a tumor suppressor gene, through clofoctol’s targeted binding protein, Upstream of N-ras (UNR). Collectively, these data demonstrate that induction of KLF13 expression suppressed growth of gliomas and provide a potential therapy for gliomas targeting GSCs. Importantly, our results also identify the RNA-binding protein UNR as a drug target.

Authors

Yan Hu, Meilian Zhang, Ningyu Tian, Dengke Li, Fan Wu, Peishan Hu, Zhixing Wang, Liping Wang, Wei Hao, Jingting Kang, Bin Yin, Zhi Zheng, Tao Jiang, Jiangang Yuan, Boqin Qiang, Wei Han, Xiaozhong Peng

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Figure 1

High-throughput screening to identify inhibitors of GSCs.

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High-throughput screening to identify inhibitors of GSCs. (A) Compound c...
(A) Compound classification of the MicroSource Spectrum Collection. (B) Schematic representation of the screening process. (C) All 13 compounds used to treat the 4 GSCs for 48 hours with a relative cell viability (vs. control) less than 70%. Data are presented as the mean ± SEM, and samples were assayed in triplicate. (D) Clofoctol concentration in mouse brain following the last treatment of vehicle and clofoctol (10 mg/kg, daily) i.v. for 13 days. Control, n = 4; 5 minutes, n = 3; 15 minutes, n = 4; 45 minutes, n = 4; 90 minutes, n = 4. Data are presented as the mean ± SEM. (E) Selection criteria for compound 12 (clofoctol) as the primary lead compound. In the “IC50” row, “+” indicates that the IC50 values in the 4 GSCs were less than those in normal human cells; “–” indicates that they were not. In “Coculture assay,” “++” and “+” indicate that compounds could selectively inhibit GSC2-GFP and U87MG SLC–GFP cells; “–” indicates not. In “Safety in zebrafish,” “+++,” “++,” and “+” indicate that compounds had almost no, lower, and minor toxicity; “–” indicates that compounds had strong toxicity. In “In vivo effects in zebrafish,” “+” indicates that with compound treatment, the tumors in the zebrafish xenograft model decreased; “–” indicates that this did not occur. In “BBB,” “+” indicates that compounds were predicted to pass through the BBB; “–” indicates that they were not; and “U” indicates undetermined.