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J Cancer Res Ther. 2019;15(4):889-898. doi: 10.4103/jcrt.JCRT_564_18.

Anticancer effects of FL34 through the inhibition of GLI1 in glioblastoma.

Author information

1
Department of Pharmacology, Institute of Material Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2
Department of Synthetic Medicinal Chemistry, Beijing Key Laboratory of Active Substance Discovery and Drug ability Evaluation, Institute of Material Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
3
Department of Neurosurgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Abstract

Background:

The hedgehog (HH) signaling pathway is abnormally activated in glioblastoma (GBM); thus, its downstream effector GLI1 may be a suitable target for the treatment of GBM. The aim of the present study was to evaluate the antitumor activities of a novel compound, FL34, in GBM through the inhibition of GLI1.

Methods:

The effect of FL34 on suppressing the proliferation, angiogenesis, and invasion of GBM cells was investigated in vitro using proliferation, invasion, tube formation, flow cytometry, GLI1 dual luciferase, reverse transcription-quantitative polymerase chain reaction, and western blot assays. A subcutaneously transplanted and orthotopic U-87 MG GBM cell xenograft model was used to study the effect of FL34 on tumor growth in vivo.

Results:

The results of the present study demonstrated that FL34 markedly inhibited the proliferation, invasion, and angiogenesis of GBM, in addition to decreasing the transcriptional activity and expression of GLI1, resulting in the downregulation of GLI1 target genes, including B-cell lymphoma-2, vascular endothelial growth factor, and matrix metalloproteinases. Furthermore, FL34 inhibited the activation of GLI1 without influencing upstream canonical HH/Smoothened signaling or through crosstalk with other oncogenic pathways, including Ras/ERK and AKT signaling. At a dose of 30.0 mg/kg, FL34 suppressed tumor growth by 78.74% in tumor weight in subcutaneously transplanted U-87 MG xenograft models and by 64.24% in volume in orthotopic U-87 MG GBM xenograft models.

Conclusions:

These data suggested that FL34 exerted antitumor activity mediated by the inhibition of GLI1 and that FL34 may be a potential antitumor candidate compound that could be used to develop new antitumor drugs for the treatment of GBM.

KEYWORDS:

Antitumor; GLI1; glioblastoma; hedgehog

PMID:
31436248
DOI:
10.4103/jcrt.JCRT_564_18
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