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.

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.

• Authors: Ruchi Saxena, Vishal Chandra, Murli Manohar, Kanchan Hajela, Utsab Debnath, Yenamandra S Prabhakar, Karan Singh Saini, Rituraj Konwar, Sandeep Kumar, Kaling Megu, Bal Gangadhar Roy, Anila Dwivedi
• Journal: PloS one (PLoS One) Vol. 8 Issue 6 Pg. e66246 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23840429 (Publication Type: Journal Article, Retracted Publication)

Chemical References

• Antineoplastic Agents
• Benzopyrans
• Piperidines
• CDRI 85-287
• EGFR protein, human
• ErbB Receptors

Topics

• Aged
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Benzopyrans (administration & dosage, chemistry, pharmacology)
• Breast Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Enzyme Activation (drug effects)
• ErbB Receptors (antagonists & inhibitors, chemistry)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Middle Aged
• Molecular Docking Simulation
• Piperidines (administration & dosage, chemistry, pharmacology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays