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J Clin Invest. 2019 May 21;130. pii: 124979. doi: 10.1172/JCI124979.

The antibiotic clofoctol suppresses glioma stem cell proliferation by activating KLF13.

Author information

1
State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
2
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
3
National Experimental Demonstration Center of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
4
Centralab Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
5
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
6
Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, Kunming, China.

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) which considered as the potential target of therapy for their crucial role in therapeutic resistance and tumor recurrence, are believed to be key factors for 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 inhibited obviously in vivo after clofoctol treatment especially in primary patient-derived xenografts (PDXs) and transgenic xenografts. The anticancer mechanisms demonstrated by analyzing related downstream genes and discovering the targeted binding protein revealed that clofoctol exhibited the inhibition of GSCs by upregulation of Kruppel-like factor 13 (KLF13), a tumor suppressor gene, through clofoctol's targeted binding protein, Upstream of N-ras (UNR). Collectively, these data demonstrated that induction of KLF13 expression suppressed growth of gliomas and provided a potential therapy for gliomas targeting GSCs. Importantly, our results also identified the RNA-binding protein UNR as a drug target.

KEYWORDS:

Brain cancer; Drug screens; Drug therapy; Oncology; Therapeutics

PMID:
31112526
DOI:
10.1172/JCI124979
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