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Acridine yellow G blocks glioblastoma growth via dual inhibition of epidermal growth factor receptor and protein kinase C kinases
- Source :
- The Journal of biological chemistry. 287(9)
- Publication Year :
- 2012
-
Abstract
- Amplification of the epidermal growth factor receptor (EGFR), frequently expressed as a constitutively active deletion mutant (EGFRvIII), occurs commonly in glioblastoma multiformes (GBM). However, blockade of EGFR is therapeutically disappointing for gliomas with PTEN deletion. To search for small molecules treating this aggressive cancer, we have established a cell-based screening and successfully identified acridine yellow G that preferentially blocks cell proliferation of the most malignant U87MG/EGFRvIII cells over the less malignant U87MG/PTEN cells. Oral administration of this compound markedly diminishes the brain tumor volumes in both subcutaneous and intracranial models. It directly inhibits EGFR and PKCs with IC(50) values of ~7.5 and 5 μM, respectively. It dually inhibits EGFR and PKCs, resulting in a blockade of mammalian target of rapamycin signaling and cell cycle arrest in the G(1) phase, which leads to activation of apoptosis in the tumors. Hence, combinatorial inhibition of EGFR and PKCs might provide proof of concept in developing therapeutic agents for treating malignant glioma and other human cancers.
- Subjects :
- Cell signaling
Mice, Nude
Antineoplastic Agents
Biochemistry
Mice
Glioma
Cell Line, Tumor
medicine
PTEN
Animals
Humans
Epidermal growth factor receptor
Molecular Biology
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Protein Kinase C
biology
integumentary system
Kinase
Cell growth
Aminoacridines
Brain Neoplasms
TOR Serine-Threonine Kinases
G1 Phase
Molecular Bases of Disease
Cell Biology
medicine.disease
Molecular biology
Xenograft Model Antitumor Assays
nervous system diseases
ErbB Receptors
Disease Models, Animal
biology.protein
Female
Signal transduction
Drug Screening Assays, Antitumor
Glioblastoma
Signal Transduction
Subjects
Details
- ISSN :
- 1083351X
- Volume :
- 287
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....99251d89c4a178cf23963afb3c33cf70