1. 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
- Author
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Jeong-Yeon Lee, Sung-Dae Cho, Hyun-Jun Kim, Mi-Yun Oh, Gu Kong, Seung Hyun Oh, Ji-Hye Park, Young Ki Min, Tingting Oian, and Dong Hui Shin
- 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 - 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.
- Published
- 2011