title: Telomere targeting with a novel G-quadruplex-interactive ligand BRACO-19 induces T-loop disassembly and telomerase displacement in human glioblastoma cells.
abstract: Interference with telomerase and telomere maintenance is emerging as an attractive target for anticancer therapies. Ligand-induced stabilization of G-quadruplex formation by the telomeric DNA 3'-overhang inhibits telomerase from catalyzing telomeric DNA synthesis and from capping telomeric ends, making these ligands good candidates for chemotherapeutic purposes. BRACO-19 is one of the most effective and specific ligand for telomeric G4. It is shown here that BRACO-19 suppresses proliferation and reduces telomerase activity in human glioblastoma cells, paralleled by the displacement of telomerase from nuclear to cytoplasm. Meanwhile, BRACO-19 triggers extensive DNA damage response at telomere, which may result from uncapping and disassembly of telomeric T-loop structure, characterized by the formation of anaphase bridge and telomere fusion, as well as the release of telomere-binding protein from telomere. The resulting dysfunctional telomere ultimately provokes p53 and p21-mediated cell cycle arrest, apoptosis and senescence. Notably, normal primary astrocytes do not respond to the treatment of BRACO-19, suggesting the agent's good selectivity for cancer cells. These results reinforce the notion that G-quadruplex binding compounds can act as broad inhibitors of telomere-related processes and have potential as selective antineoplastic drugs for various tumors including malignant gliomas.
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Guangtong
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Xinrui
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Yunqian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Songbai
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000166:Acridines / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054697:Cytostatic Agents / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D016615:Telomere / Q000737:chemistry* / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D000166:Acridines; D054697:Cytostatic Agents; C509186:TERT protein, human; D019098:Telomerase; C454064:BRACO-19
keywords: DNA damage; G-quadruplex; T-loop; telomerase; telomere