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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

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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 3

Clofoctol inhibits growth of gliomas in vivo in PDXs and transgenic xenografts.

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Clofoctol inhibits growth of gliomas in vivo in PDXs and transgenic xeno...
(A) Tumor volumes of PDXs over time. The mice were treated with 20 mg/kg clofoctol or vehicle by i.p. administration. PDX1, clofoctol (n = 5), vehicle (n = 5); PDX2, clofoctol (n = 9), vehicle (n = 9); PDX3, clofoctol (n = 9), vehicle (n = 9). Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 compared with control by 2-tailed Student’s t test at each time point. (B and C) Glioblastomas were induced by injection with pTomo-Ras-sip53 lentivirus in C57BL/6 mice. MRI analysis after 12 days of injection was used for grouping (C, left), and then drug effects were valued after treatment with vehicle or 10 mg/kg clofoctol i.v. daily for 10 days (C, right), and MRI graphs of 3 samples for each group are shown (B). *P < 0.05 compared with control by 2-tailed Student’s t test. (D) Immunohistochemical analysis of sections from tumors induced by injection with pTomo-Ras-sip53 lentivirus after clofoctol treatment stained with antibody against CD133. Three individual samples were analyzed. Scale bars: 100 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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