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Acridine yellow G blocks glioblastoma growth via dual inhibition of epidermal growth factor receptor and protein kinase C kinases

Authors :
Min-Heui Yoo
Hui Tao
Hui Mao
Zhaobin Zhang
Kunyan He
Chi Bun Chan
Haian Fu
Jeffrey J. Olson
Paul S. Mischel
Ge Xiao
Liya Wang
Qi Qi
Keqiang Ye
Suresh S. Ramalingam
Xia Liu
Shi-Yong Sun
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.

Details

ISSN :
1083351X
Volume :
287
Issue :
9
Database :
OpenAIRE
Journal :
The Journal of biological chemistry
Accession number :
edsair.doi.dedup.....99251d89c4a178cf23963afb3c33cf70