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The in vitro and in vivo anti-tumor effect of KO-202125, a sauristolactam derivative, as a novel epidermal growth factor receptor inhibitor in human breast cancer
- Source :
- Cancer Science. 102:597-604
- Publication Year :
- 2011
- Publisher :
- Wiley, 2011.
-
Abstract
- Epidermal growth factor receptor (EGFR) is one of the most promising targets for cancer therapy. Here, we show the in vitro and in vivo anticancer effects and associated mechanisms of KO-202125, one of the synthesized aristolactam analogs, as a novel EGFR inhibitor, in EGFR-overexpressing cancer cell lines. KO-202125 showed more effective growth inhibition and apoptosis induction than gefitinib, a representative EGFR inhibitor, in various EGFR-overexpressing human cancers including estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells. Epidermal growth factor receptor phosphorylation at Tyr1068 was reduced and, consequently, the association of EGFR with p85 was decreased by KO-202125 treatment in MDA-MB-231 cell lines. This led to inactivation of the PI3K/Akt pathway, and consequently suppression of activation of the Wnt pathway and enhancement of the nuclear import of p27Kip1. KO-202125 treatment in nude mice injected with MDA-MB-231 cells showed inhibition of tumor growth without toxicity. Collectively, our results showed the possibility of KO-202125 as an effective therapy agent of EGFR-overexpressing cancer cells through reduced EGFR activity and downregulation of the Akt pathway.
- Subjects :
- Cancer Research
Estrogen receptor
Antineoplastic Agents
Apoptosis
Breast Neoplasms
Isoindoles
Pharmacology
Biology
Mice
chemistry.chemical_compound
Gefitinib
Cell Line, Tumor
medicine
Animals
Humans
Growth factor receptor inhibitor
Epidermal growth factor receptor
PI3K/AKT/mTOR pathway
Cell Proliferation
EGFR inhibitors
Intracellular Signaling Peptides and Proteins
General Medicine
Xenograft Model Antitumor Assays
ErbB Receptors
Wnt Proteins
Receptors, Estrogen
Oncology
chemistry
biology.protein
Female
Growth inhibition
Proto-Oncogene Proteins c-akt
A431 cells
Cyclin-Dependent Kinase Inhibitor p27
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 13479032
- Volume :
- 102
- Database :
- OpenAIRE
- Journal :
- Cancer Science
- Accession number :
- edsair.doi.dedup.....856e0dd2ac0686ad66b908430dd75f8f