Acridine yellow G blocks glioblastoma growth via dual inhibition of epidermal growth factor receptor and protein kinase C kinases.
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.
Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Qi
Q
Qi
Kunyan
K
He
Min-Heui
MH
Yoo
Chi-Bun
CB
Chan
Xia
X
Liu
Zhaobin
Z
Zhang
Jeffrey J
JJ
Olson
Ge
G
Xiao
Liya
L
Wang
Hui
H
Mao
Haian
H
Fu
Hui
H
Tao
Suresh S
SS
Ramalingam
Shi-Yong
SY
Sun
Paul S
PS
Mischel
Keqiang
K
Ye
D000609:Aminoacridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000609:Aminoacridines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C410723:epidermal growth factor receptor VIII; C546842:MTOR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C; C025902:acridine yellow