The in vitro and in vivo anti-tumor effect of KO-202123, a sauristolactam derivative, as a novel EGFR inhibitor in human breast cancer.

Abstract

Aristolactam originated from Saururus chinensis (Lour) Baill and it is phenanthrene lactam alkaloid structurally. Here, we show the in vitro and in vivo anticancer effects and associated mechanisms of KO-202125, one of the synthesized aristolactam analogs, which has had its side chain altered to have the lowest possible toxicity, as a novel EGFR inhibitor, in EGFR-overexpressing cancer cell lines. KO-202125 showed more effective growth inhibition than Gefitinib, a representative EGFR inhibitor, as measured by IC50 values in various EGFR-overexpressing human cancers including MDA-MB-231 human breast cancer cells (1.17 μM and 13.36 μM in MDA-MB-231 cells, respectively). Furthermore, KO-202125 induced apoptosis and affected EGFR-related signaling pathways in MDA-MB-231 cells. EGFR phosphorylation at Tyr1068 was reduced and consequently, the association of EGFR with p85 was decreased by KO-202125 treatment. This led to inactivation of the PI3K/Akt pathway. Akt phosphorylation at Ser473 was reduced and its downstream signals were also inactivated. GSK-3b phosphorylation, b-catenin and c-Myc expressions, and TCF promoter activity were reduced by KO-202125, suggesting the suppression of the Akt-mediated Wnt pathway by KO-202125. Moreover, upon KO-202125 treatment, p27Kip1 phosphorylation at Thr157 was decreased, and consistently, the nuclear import of p27Kip1, which is implicated with increase in functional p27Kip1, was increased. KO-202125 treatment in the 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. .