title: Quinoline-Based Compound BPIQ Exerts Anti-Proliferative Effects on Human Retinoblastoma Cells via Modulating Intracellular Reactive Oxygen Species.
abstract: Retinoblastoma (Rb) is the most common primary intraocular malignant tumor of childhood. It is important to develop the strategy for Rb treatment. We have tested a quinolone derivative 2,9-bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-11H-indeno[1,2-c]quinolin-11-one (BPIQ) for its anti-cancer effects against Rb via cultured human Rb cell line Y79. Our results showed that BPIQ significantly inhibits cell growth of Y79. Furthermore, the flow cytometer-based assays and Western blotting showed that BPIQ induces the apoptosis of Y79 via increasing the level of reactive oxygen species (ROS). Besides, the activation of γH2AX, a DNA damage sensor in human Y79 cells was also observed, indicating the potential of BPIQ for causing DNA damage of Rb cells. On the contrary, BPIQ-induced apoptosis of Y79 cells was attenuated significantly by N-acetyl-L-cysteine (NAC), an ROS scavenger. The results of Western blot showed that BPIQ down-regulates the levels of anti-apoptotic proteins Bcl-2, survivin and XIAP while up-regulates the pro-apoptotic proteins Bad, Bax and Bid. Our present study demonstrated the anti-proliferative effect of BPIQ in human Y79 cells. The inhibitory effect of BPIQ on the proliferation of Y79 cells is, at least, partly mediated by the regulation of ROS and DNA damage pathway. In conclusion, BPIQ may provide an alternative option in the chemotherapeutics or chemoprevention on the Rb therapy in the future.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Ophthalmology, Kaohsiung Municipal Hsiao-kang Hospital, Kaohsiung, Taiwan.|Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Kai-Chun
authors.initials: KC
authors.lastname: Cheng
authors.affiliation: Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Ophthalmology, Yuan's General Hospital, Kaohsiung, 807, Taiwan.
authors.forename: Chun-Tzu
authors.initials: CT
authors.lastname: Hung
authors.affiliation: Department of Ophthalmology, Kaohsiung Municipal Hsiao-kang Hospital, Kaohsiung, Taiwan.
authors.forename: Kuo-Jen
authors.initials: KJ
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Ophthalmology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
authors.forename: Wen-Chuan
authors.initials: WC
authors.lastname: Wu
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jau-Ling
authors.initials: JL
authors.lastname: Suen
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Ophthalmology, Kaohsiung Municipal Hsiao-kang Hospital, Kaohsiung, Taiwan.|Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Ophthalmology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
authors.forename: Cheng-Hsien
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
authors.forename: Chi-Yu
authors.initials: CY
authors.lastname: Lu
authors.affiliation: School of Pharmacy, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
authors.forename: Chih-Hua
authors.initials: CH
authors.lastname: Tseng
authors.affiliation: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. yeloch@kmu.edu.tw.
authors.forename: Yeh-Long
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. cchiu@kmu.edu.tw.|Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Kaohsiung, 807, Taiwan. cchiu@kmu.edu.tw.|Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. cchiu@kmu.edu.tw.
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Chiu
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012175:Retinoblastoma / Q000188:drug therapy*; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C512698:8-((3-bromophenyl)amino)-3-methyl-3H-imidazo(4,5-g)quinazoline; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D006131:Growth Inhibitors; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D017382:Reactive Oxygen Species; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000111:Acetylcysteine
keywords: Apoptosis; BPIQ; DNA damage; Quinoline; Reactive oxygen species; Retinoblastoma