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Malignant gliomas can be converted to non‑proliferating glial cells by treatment with a combination of small molecules

Authors
 Jinsoo Oh  ;  Yongbo Kim  ;  Daye Baek  ;  Yoon Ha 
Citation
 Oncology Reports, Vol.41(1) : 361-368, 2019 
Journal Title
 Oncology Reports 
ISSN
 1021-335X 
Issue Date
2019
MeSH
2',3'-Cyclic Nucleotide 3'-Phosphodiesterase/genetics ; Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology* ; Brain Neoplasms/drug therapy ; Brain Neoplasms/genetics* ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Reprogramming ; Colforsin/pharmacology ; Drug Therapy, Combination ; Gene Expression Profiling/methods ; Gene Expression Regulation, Neoplastic ; Glial Fibrillary Acidic Protein/genetics ; Glioma/drug therapy ; Glioma/genetics* ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Humans ; Neuroglia/chemistry ; Neuroglia/cytology* ; Oligonucleotide Array Sequence Analysis/methods ; Rats ; Sirolimus/pharmacology ; Small Molecule Libraries/pharmacology*
Abstract
Gliomas, the most highly malignant central nervous system tumors, are associated with an extremely poor patient survival rate. Given that gliomas are derived from mutations in glial precursor cells, a considerable number of them strongly react with glial precursor cell‑specific markers. Thus, we investigated whether malignant gliomas can be converted to glial cells through the regulation of endogenous gene expression implicated in glial precursor cells. In the present study, we used three small‑molecule compounds, [cyclic adenosine monophosphate (cAMP) enhancer, a mammalian target of rapamycin (mTOR) inhibitor, and a bromodomain and extra‑terminal motif (BET) inhibitor] for glial reprogramming. Small‑molecule‑induced gliomas (SMiGs) were not only transformed into exhibiting a glial‑specific morphology, but also showed positive reactions with glial‑specific markers such as glial fibrillary acidic protein (GFAP), 2',3'‑cyclic nucleotide 3'‑phosphohydrolase (CNP) and anti‑oligodendrocyte (RIP). A microarray analysis indicated that SMiGs exhibited a marked increase in specific gene levels, whereas that of a malignant cancer‑specific gene was greatly decreased. Moreover, proliferation of the cells was markedly suppressed after the conversion of malignant glioma cells into glial cells. Our findings confirmed that malignant gliomas can be reprogrammed to non‑proliferating glial cells, using a combination of small molecules, and their proliferation can be regulated by their differentiation. We suggest that our small‑molecule combination (with forskolin, rapamycin and I‑BET151) may be the next generation of anticancer agents that act by reprogramming malignant gliomas to differentiate into glial cells.
Full Text
https://www.spandidos-publications.com/or/41/1/361
DOI
10.3892/or.2018.6824
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
Yonsei Authors
하윤(Ha, Yoon)
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/167310
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