title: New cyclopentaquinoline derivatives with fluorobenzoic acid induce G1 arrest and apoptosis in human lung adenocarcinoma cells.
abstract: Non-small cell lung cancer accounts for 80-85% of all lung cancer cases and is the leading cause of cancer death indicating inefficient current treatment. Acridine derivatives interact with DNA and inhibit topoisomerase leading to cell growth arrest or cell death. The aim of this study was to evaluate the effects of new synthesized sixteen 2,3-dihydro-1H-cyclopenta[b]quinoline derivatives (cyclopentaquinoline), a member of acridine-based compounds, on the survival and growth of human lung adenocarcinoma, A549 cells. Anticancer activity of eight new cyclopentaquinoline derivatives with hydrazinonicotinic acid (compounds 1-8) and eight with fluorobenzoic acid (compounds 9-16) were screened using WST-1 assay. Interestingly, cyclopentaquinoline derivatives with fluorobenzoic moiety were found to have a higher anticancer activity than derivatives with hydrazinonicotinic acid. Four out of eight tested compounds with fluorobenzoic acid inhibited 50% cancer cell growth at concentration below 20μM. Moreover, the efficacy of cyclopentaquinoline derivatives containing fluorobenzoic acid correlated with increasing number of carbon atoms in the aliphatic chain. The most effective compounds (6, 15, 16) were selected to determine molecular mechanisms of their anticancer action. The results indicated that inhibition of A549 cell growth by compounds 15 and 16 was associated with a cell cycle arrest at G0/1 phase and with induction of caspase 3-dependent apoptosis. Compound 6 also caused A549 cells death due to apoptosis, however, it had no significant effect on a cell cycle progression. These findings suggest that cyclopentaquinoline derivatives containing fluorobenzoic acid with 8 and 9 carbon atoms in aliphatic chain may be promising candidate for treatment of lung cancer.
authors: Laboratory of Radiopharmacy, Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy, Medical University of Lodz, 1 Muszynskiego Street, 90-151 Lodz, Poland. Electronic address: paulina.olszewska@umed.lodz.pl.
authors: Paulina
authors: P
authors: Olszewska
authors: Central Scientific Laboratory, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, Poland.
authors: Jacek
authors: J
authors: Szymański
authors: Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy, Medical University of Lodz, 1 Muszynskiego Street, 90-151 Lodz, Poland.
authors: Elżbieta
authors: E
authors: Mikiciuk-Olasik
authors: Laboratory of Radiopharmacy, Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy, Medical University of Lodz, 1 Muszynskiego Street, 90-151 Lodz, Poland.
authors: Paweł
authors: P
authors: Szymański
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019817:Benzoic Acid / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D011804:Quinolines; D019817:Benzoic Acid
keywords: Acridine derivatives; Anticancer drug; Cyclopentaquinoline derivatives; DNA intercalation; Lung cancer