title: Novel tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid moiety induce cell cycle arrest and apoptosis in lung cancer cells by activation of DNA damage signaling.
abstract: Lung cancer is still the leading cause of cancer-related death worldwide, indicating a necessity to develop more effective therapy. Acridine derivatives are potential anticancer agents due to their ability to intercalate DNA as well as inhibit enzymes involved in replication and transcription. Recently, we have evaluated anticancer activity of 32 novel acridine-based compounds. We found that the most effective were tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid containing eight and nine carbon atoms in the aliphatic chain. The aim of this study was to determine the molecular mechanisms of compounds-induced cell cycle arrest and apoptosis in human lung adenocarcinoma cells. All compounds activated Ataxia telangiectasia mutated kinase and phosphorylated histone H2A.X at Ser139 indicating DNA damage. Treatment of cells with the compounds increased phosphorylation and accumulation of p53 that regulate cell cycle as well as apoptosis. All compounds induced G0/1 cell cycle arrest by phosphorylation of cyclin-dependent kinase 2 at Tyr15 resulting in attenuation of the kinase activity. In addition, cyclopentaquinoline derivatives induced expression of cyclin-dependent kinase 2 inhibitor, p21; however, tetrahydroacridine derivatives had no significant effect on p21. Moreover, all compounds decreased the mitochondrial membrane potential accompanied by increased expression of Bax and down-regulation of Bcl-2, suggesting activation of the mitochondrial pathway. All compounds also significantly attenuated the migration rates of lung cancer cells. Collectively, our findings suggest a central role of activation of DNA damage signaling in response to new acridine derivatives treatment to induce cell cycle arrest and apoptosis in cancer cells and provide support for their further development as potential drug candidates.
authors.affiliation: 1 Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, Łódź, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Szymański
authors.affiliation: 1 Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, Łódź, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Olszewska
authors.affiliation: 1 Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, Łódź, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Mikiciuk-Olasik
authors.affiliation: 2 Department of Immunobiology of Bacteria, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Łódź, Poland.
authors.forename: Antoni
authors.initials: A
authors.lastname: Różalski
authors.affiliation: 2 Department of Immunobiology of Bacteria, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Łódź, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Maszewska
authors.affiliation: 3 Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Łódź, Poland.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Markiewicz
authors.affiliation: 3 Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Łódź, Poland.
authors.forename: Magda
authors.initials: M
authors.lastname: Cuchra
authors.affiliation: 3 Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Łódź, Poland.
authors.forename: Ireneusz
authors.initials: I
authors.lastname: Majsterek
mesh_terms: D000166:Acridines / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010766:Phosphorylation; D011804:Quinolines / Q000008:administration & dosage* / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000166:Acridines; D009363:Neoplasm Proteins; D011804:Quinolines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C037219:quinoline
keywords: Acridine derivatives; DNA damage signaling; lung cancer