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 Therapeutics

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 2

Clofoctol inhibits GSCs in vitro and in vivo.

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Clofoctol inhibits GSCs in vitro and in vivo. (A) Clofoctol was tested f...
(A) Clofoctol was tested for effects on the cell viability of GSCs (red) and normal human cells (black). Data are representative of 3 wells for more than 3 times. (B) Time course of clofoctol and TMZ treatments in GSCs. (C) Sequential treatment of clofoctol plus TMZ in GSCs (48 hours, n = 3). CI was calculated by CalcuSyn demo version 2.0 software (ComboSyn, Inc). (D) Analysis of tumorsphere formation of GSC2 after clofoctol treatment. (E and F) Limiting dilution assay (E) (n = 10 for each group) and secondary tumorsphere assay (F) of GSC2 cells after pretreatment with clofoctol for 6 hours. (G) Third tumorsphere assay of GSC2 cells collected from second tumorspheres after pretreatment with clofoctol for 6 hours. (H) GSC2 cells were implanted s.c. into nude mice. The mice were treated with vehicle (n = 8) or clofoctol (20 mg/kg) (n = 7) once daily via i.p. injection for 11 days. The tumor volume was calculated using a modified ellipsoid formula. (I) In vivo bioluminescent image (left) and quantitative analysis (right) of GSC2-derived xenografts in mice treated with vehicle and clofoctol (10 mg/kg, daily) i.v. for 13 days from day 7. (J) GSC2 cells were implanted intracranially into nude mice. Mice were treated with vehicle or 10 mg/kg clofoctol i.v. daily for 13 days, and the relative survival curves (control, n = 8; clofoctol-treated, n = 8) are shown. Data are presented as the mean ± SEM. For A, B, D, and F–H, samples were assayed in triplicate. Data in D, F, and G were analyzed by ANOVA. Two-tailed Student’s t test was used in H and I. Mantel-Cox test was used in J. *P < 0.05, **P < 0.01, ***P < 0.001.