title: Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines.
abstract: Agents stabilizing G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalysed by telomerase or telomerase-independent mechanism and could therefore act as antitumor agents. In this study, we found that quindoline derivatives interacted preferentially with intramolecular G-quadruplex structures and were novel potent telomerase inhibitors. Treatment with quindoline derivatives reproducibly inhibited telomerase activity in human leukemia K562 cells and colon cancer SW620 cells. N'-(10H-Indolo [3,2-b] quinolin-11-yl)-N, N-dimethyl-propane-1,3-diamine (SYUIQ-5), (one of quindoline derivatives), when added to K562 and SW620 cell culture at nonacute cytotoxic concentrations, increased time of population doublings of K562 and SW620 cells, induced a marked cessation in cell growth and cellular senescence phenotype after 35 and 18 days, respectively. Growth cessation was accompanied by a shortening of telomere length, and induction of p16, p21 and p27 protein expression. However, another compound SYUIQ-7 with greater IC(50) for telomerase had no obvious cellular effect in nonacute cytotoxic concentrations. These results indicate that quindoline derivatives as novel potent G-quadruplex interactive agents induce senescence and telomere shortening in cancer cells and therefore are promising agents for cancer treatment.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou.
authors.forename: J-M
authors.initials: JM
authors.lastname: Zhou
authors.forename: X-F
authors.initials: XF
authors.lastname: Zhu
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Lu
authors.forename: R
authors.initials: R
authors.lastname: Deng
authors.forename: Z-S
authors.initials: ZS
authors.lastname: Huang
authors.forename: Y-P
authors.initials: YP
authors.lastname: Mei
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: W-L
authors.initials: WL
authors.lastname: Huang
authors.forename: Z-C
authors.initials: ZC
authors.lastname: Liu
authors.forename: L-Q
authors.initials: LQ
authors.lastname: Gu
authors.forename: Y-X
authors.initials: YX
authors.lastname: Zeng
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D004247:DNA; D054856:G-Quadruplexes; D006147:Guanine / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020014:K562 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011804:Quinolines / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors; D016615:Telomere
chemical_list: D000470:Alkaloids; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007211:Indoles; D011804:Quinolines; D050760:Cyclin-Dependent Kinase Inhibitor p27; C016712:quindoline; D006147:Guanine; D004247:DNA; D019098:Telomerase