Evaluation of the cytotoxic, apoptosis inducing activity and molecular docking of spiroquinazolinone benzamide derivatives in MCF-7 breast cancer cells. (25th December 2016)

• Record Type: Journal Article
• Authors: Mahdavi, Majid; Lavi, Malihe Mohseni; Yekta, Reza; Moosavi, Mohammad Amin; Nobarani, Mahnaz; Balalaei, Saeed; Arami, Sanam; Rashidi, Mohammad Reza
• Is Part Of: Chemico-biological interactions. Volume 260(2016)
• Page Start: 232
• Page End: 242
• Publication Date: 2016-12-25
• Subjects: Apoptosis -- Survivin -- Spiroquinazolinone benzamide -- MCF-7 cells; 4t-CHQB N-(4-tert-butyl-4'-oxo-1′H-spiro[cyclohexane-1, 2'-quinazoline]-3′(4′H)-yl)benzamide -- Caspases cysteine-aspartic proteases -- IAPs inhibitor of apoptosis proteins -- XIAP X-Linked Inhibitor of Apoptosis Protein -- cIAP cellular inhibitor of apoptosis protein -- NAIP neuronal apoptosis inhibitory protein -- BIR baculoviral IAP repeat -- MTT Thiazolyl blue tetrazolium bromide -- TNF tumor necrosis factor -- EGFR Epidermal growth factor receptor -- VEGFR Vascular endothelial growth factor receptor; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2016.10.004
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Previous studies have suggested that quinazolinone derivatives are potent apoptosis-inducing agents in various cancer cell lines. In the present study, we have investigated cytotoxic, apoptosis induction, and molecular docking activities of the spiroquinazolinone benzamide derivatives family on MCF-7 human breast cancer cells. The MTT cytotoxicity assays and docking studies showed that 4t-CHQB was the most active compound among the prepared spiroquinazolinone benzamide compounds with IC50 of 50 ± 1.2 μM and was selected for further assessments. Apoptosis, as the mechanism of cell death, was assessed morphologically by acridine orange/ethidium bromide (AO/EtBr) double staining, evaluation of the cell surface phosphatidylserine (PS) expression through annexin V/PI technique and, the formation of DNA ladder. Down regulation of survivin was evaluated in protein level after cell treatment with 4t-CHQB using western blotting method. Molecular modeling experiments involving 4t-CHQB binding site of survivin showed several strong hydrogen bonds and hydrophobic interactions between many important amino acid residues. Overall, the obtained data suggest that the assessed spiroquinazolinone benzamide compounds may provide a novel therapeutic approach for further evaluation, as an effective chemotherapeutic family acting through down regulation of survivin and apoptosis induction in breast cancer. Graphical abstract: Highlights: The spiroquinazolinone benzamides reduce viability in MCF-7 cells. The 4t-CHQB is the most active compound among these compound series. This compound causes Sub-G1 cell cycle arrest and apoptosis induction in the cells. The 4t-CHQB leads to down-regulation of survivin in a dose-dependent manner. Molecular docking studies show the highest affinity to survivin inhibition.