title: 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.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Saxena
authors.forename: Vishal
authors.initials: V
authors.lastname: Chandra
authors.forename: Murli
authors.initials: M
authors.lastname: Manohar
authors.forename: Kanchan
authors.initials: K
authors.lastname: Hajela
authors.forename: Utsab
authors.initials: U
authors.lastname: Debnath
authors.forename: Yenamandra S
authors.initials: YS
authors.lastname: Prabhakar
authors.forename: Karan Singh
authors.initials: KS
authors.lastname: Saini
authors.forename: Rituraj
authors.initials: R
authors.lastname: Konwar
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.forename: Kaling
authors.initials: K
authors.lastname: Megu
authors.forename: Bal Gangadhar
authors.initials: BG
authors.lastname: Roy
authors.forename: Anila
authors.initials: A
authors.lastname: Dwivedi
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001578:Benzopyrans / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008875:Middle Aged; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D010880:Piperidines; C066624:CDRI 85-287; C512478:EGFR protein, human; D066246:ErbB Receptors