title: Antiproliferative and Pro-Apoptotic Effect of Novel Nitro-Substituted Hydroxynaphthanilides on Human Cancer Cell Lines.
abstract: Ring-substituted hydroxynaphthanilides are considered as cyclic analogues of salicylanilides, compounds possessing a wide range of pharmacological activities, including promising anticancer properties. The aim of this study was to evaluate the potential anticancer effect of novel nitro-substituted hydroxynaphthanilides with a special focus on structure-activity relationships. The antiproliferative effect was assessed by Water Soluble Tetrazolium Salts-1 (WST-1) assay, and cytotoxicity was evaluated via dye exclusion test. Flow cytometry was used for cell cycle analysis and detection of apoptosis using Annexin V-FITC/PI assay. Protein expression was estimated by Western blotting. Our data indicate that the potential to cause the antiproliferative effect increases with the shift of the nitro substituent from the ortho- to the para-position. The most potent compounds, 3-hydroxy-N-(3-nitrophenyl)naphthalene-2-carboxamide (2), and 2-hydroxy-N-(4-nitrophenyl)-naphthalene-1-carboxamide (6) showed antiproliferative activity against THP-1 and MCF-7 cancer cells without affecting the proliferation of 3T3-L1 non-tumour cells. Compounds 2 and 6 induced the accumulation of THP-1 and MCF-7 cells in G1 phase associated with the downregulation of cyclin E1 protein levels, while the levels of cyclin B1 were not affected. Moreover, compound 2 was found to exert the pro-apoptotic effect on the THP-1 cells. These results suggest that hydroxynaphthanilides might represent a potential model structure for the development of novel anticancer agents.
authors.affiliation: Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1946/1, 612 42 Brno, Czech Republic. tereza.kauerova@gmail.com.
authors.forename: Tereza
authors.initials: T
authors.lastname: Kauerova
authors.affiliation: Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1946/1, 612 42 Brno, Czech Republic. kosj@vfu.cz.
authors.forename: Jiri
authors.initials: J
authors.lastname: Kos
authors.affiliation: Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1946/1, 612 42 Brno, Czech Republic. t.gonec@seznam.cz.
authors.forename: Tomas
authors.initials: T
authors.lastname: Gonec
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojarov 10, 832 32 Bratislava, Slovakia. josef.jampilek@gmail.com.
authors.forename: Josef
authors.initials: J
authors.lastname: Jampilek
authors.affiliation: Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1946/1, 612 42 Brno, Czech Republic. kollarp@vfu.cz.
authors.forename: Peter
authors.initials: P
authors.lastname: Kollar
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D009284:Naphthols / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000616253:2-hydroxy-N-(4-nitrophenyl)naphthalene-1-carboxamide; D000813:Anilides; D000970:Antineoplastic Agents; D009281:Naphthalenes; D009284:Naphthols; C000616254:3-hydroxy-N-(3-nitrophenyl)naphthalene-2-carboxamide
keywords: anticancer effect; apoptosis; cell proliferation; hydroxynaphthanilides; salicylanilides