1. 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.
- Author
-
Saxena R, Chandra V, Manohar M, Hajela K, Debnath U, Prabhakar YS, Saini KS, Konwar R, Kumar S, Megu K, Roy BG, and Dwivedi A
- Subjects
- Aged, Animals, Antineoplastic Agents pharmacology, Benzopyrans chemistry, Benzopyrans pharmacology, Breast Neoplasms metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Enzyme Activation drug effects, ErbB Receptors chemistry, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Middle Aged, Molecular Docking Simulation, Piperidines chemistry, Piperidines pharmacology, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents administration & dosage, Benzopyrans administration & dosage, Breast Neoplasms drug therapy, ErbB Receptors antagonists & inhibitors, Piperidines administration & dosage
- Abstract
Inhibition of epidermal growth factor receptor (EGFR) signaling is considered to be a promising treatment strategy for estrogen receptor (ER)-negative breast tumors. We have investigated here the anti-breast cancer properties of a novel anti-proliferative benzopyran compound namely, 2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzo(b)pyran (CDRI-85/287) in ER- negative and EGFR- overexpressing breast cancer cells. The benzopyran compound selectively inhibited the EGF-induced growth of MDA-MB 231 cells and ER-negative primary breast cancer cell culture. The compound significantly reduced tumor growth in xenograft of MDA-MB 231 cells in nude mice. The compound displayed better binding affinity for EGFR than inhibitor AG1478 as demonstrated by molecular docking studies. CDRI-85/287 significantly inhibited the activation of EGFR and downstream effectors MEK/Erk and PI-3-K/Akt. Subsequent inhibition of AP-1 promoter activity resulted in decreased transcription activation and expression of c-fos and c-jun. Dephosphorylation of downstream effectors FOXO-3a and NF-κB led to increased expression of p27 and decreased expression of cyclin D1 which was responsible for decreased phosphorylation of Rb and prevented the transcription of E2F- dependent genes involved in cell cycle progression from G1/S phase. The compound induced apoptosis via mitochondrial pathway and it also inhibited EGF-induced invasion of MDA-MB 231 cells as evidenced by decreased activity of MMP-9 and expression of CTGF. These results indicate that benzopyran compound CDRI-85/287 could constitute a powerful new chemotherapeutic agent against ER-negative and EGFR over-expressing breast tumors.
- Published
- 2013
- Full Text
- View/download PDF