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.

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.

Oh M ，Lee JY ，Shin DH ，Park JH ，Oian T ，Kim HJ ，Cho SD ，Oh SH ，Min YK ，Kong G ... -  《-》

Chemotherapeutic Potential of 2-[Piperidinoethoxyphenyl]-3-Phenyl-2H-Benzo(b)pyran in Estrogen Receptor- Negative Breast Cancer Cells: Action via Prevention of EGFR Activation and Combined Inhibition of PI-3-K/Akt/FOXO and MEK/Erk/AP-1 Pathways.

Saxena R ，Chandra V ，Manohar M ，Hajela K ，Debnath U ，Prabhakar YS ，Saini KS ，Konwar R ，Kumar S ，Megu K ，Roy BG ，Dwivedi A ... -  《PLoS One》

Benzopyran derivative CDRI-85/287 induces G2-M arrest in estrogen receptor-positive breast cancer cells via modulation of estrogen receptors α- and β-mediated signaling, in parallel to EGFR signaling and suppresses the growth of tumor xenograft.

In an endeavor to develop novel and improved selective estrogen receptor modulators as anti-breast cancer agents, the benzopyran compounds have been synthesized and identified which act as potent anti-estrogen at uterine level. The present study evaluates the anti-tumor activity of 2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzo(b)pyran (CDRI-85/287) and explores the mechanism of action with a view to describe its potential to inhibit proliferation in ER-positive breast cancer cells MCF-7 and T47D. The compound decreased the expression of ERα while increased the expression of ERβ thereby altering ERα/ERβ ratio in both cell lines. Although the compound showed low binding affinity to ERs, it acted as ERα antagonist and ERβ agonist in decreasing ERE- or AP-1-mediated transcriptional activation in these cells. Transactivation studies in ERα/β-transfected MDA-MB231 cells suggested that at cyclin D1 promoter, compound antagonized the action of ERα-mediated E2 response while acted as estrogen agonist via ERβ. Further, the compound led to decreased expression of ERα-dependent proliferation markers and ERβ-dependent cell cycle progression markers. The expression of cell cycle inhibitory protein p21 was increased leading to G2/M phase arrest. In parallel, compound also interfered with EGFR activation, caused inhibition of PI-3-K/Akt pathway and subsequent induction of apoptosis via intrinsic pathway. A significant reduction in tumor mass and volume was observed in 85/287-treated mice bearing MCF-7 xenograft. We conclude that compound 85/287 exhibits significant anti-tumor activity via modulation of genomic as well as non-genomic mechanisms involved in cellular growth and arrested the cells in G2 phase in both MCF-7 and T47D breast cancer cells. Study suggests that CDRI-85/287 may have therapeutic potential in ER-positive breast cancer.

Saxena R ，Fatima I ，Chandra V ，Blesson CS ，Kharkwal G ，Hussain MK ，Hajela K ，Roy BG ，Dwivedi A ... -  《-》

ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR-2, inhibits MAPK/ERK and AKT/PI3-K and induces apoptosis in breast cancer cells.

Sarkar S ，Mazumdar A ，Dash R ，Sarkar D ，Fisher PB ，Mandal M ... -  《-》

Tamoxifen induces apoptosis through cancerous inhibitor of protein phosphatase 2A-dependent phospho-Akt inactivation in estrogen receptor-negative human breast cancer cells.

Liu CY ，Hung MH ，Wang DS ，Chu PY ，Su JC ，Teng TH ，Huang CT ，Chao TT ，Wang CY ，Shiau CW ，Tseng LM ，Chen KF ... -  《-》