title: 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.
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.
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: Miyun
authors.initials: M
authors.lastname: Oh
authors.forename: Jeong-Yeon
authors.initials: JY
authors.lastname: Lee
authors.forename: Dong-Hui
authors.initials: DH
authors.lastname: Shin
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Park
authors.forename: Tingting
authors.initials: T
authors.lastname: Oian
authors.forename: Hyun-Jun
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sung-Dae
authors.initials: SD
authors.lastname: Cho
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Oh
authors.forename: Young Ki
authors.initials: YK
authors.lastname: Min
authors.forename: Gu
authors.initials: G
authors.lastname: Kong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D054833:Isoindoles / Q000494:pharmacology*; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011960:Receptors, Estrogen / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D054833:Isoindoles; C547823:KO 202125; D011960:Receptors, Estrogen; D051153:Wnt Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt