RHPS4 G-Quadruplex Ligand Induces Anti-Proliferative Effects in Brain Tumor Cells

• Published in: PloS one Vol. 9; no. 1; p. e86187
• Main Authors: Lagah, Sunil, Tan, I-Li, Radhakrishnan, Priya, Hirst, Robert A., Ward, Jennifer H., O’Callaghan, Chris, Smith, Stuart J., Stevens, Malcolm F. G., Grundy, Richard G., Rahman, Ruman
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.01.2014; Public Library of Science (PLoS)
• Subjects: Acridines - chemistry; Acridines - pharmacology; Animals; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferatives; Biology; Brain; Brain cancer; Brain Neoplasms; Brain research; Brain tumors; c-Myc protein; Cancer; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Central nervous system; Cilia - drug effects; Cilia - physiology; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA structure; Drug Screening Assays, Antitumor; Endothelial cells; Endothelial Cells - drug effects; Ependyma - pathology; G-Quadruplexes; Glioblastoma; Glioblastoma cells; Glioma cells; Gliomas; Humans; Immunotherapy; In vivo methods and tests; Inhibitory Concentration 50; Ligands; Medical research; Medicine; Medulloblastoma; Melanoma; Myc protein; Nervous system; Pediatrics; Proteins; Proto-Oncogene Proteins c-myc - metabolism; Rats; Taq Polymerase - antagonists & inhibitors; Telomerase; Telomerase - antagonists & inhibitors; Telomerase - chemistry; Telomere Homeostasis - drug effects; Telomeres; Toxicity; Tumor cells; United Kingdom > UK
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0086187

Telomeric 3' overhangs can fold into a four-stranded DNA structure termed G-quadruplex (G4), a formation which inhibits telomerase. As telomerase activation is crucial for telomere maintenance in most cancer cells, several classes of G4 ligands have been designed to directly disrupt telomeric structure. We exposed brain tumor cells to the G4 ligand 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) and investigated proliferation, cell cycle dynamics, telomere length, telomerase activity and activated c-Myc levels. Although all cell lines tested were sensitive to RHPS4, PFSK-1 central nervous system primitive neuroectodermal cells, DAOY medulloblastoma cells and U87 glioblastoma cells exhibited up to 30-fold increased sensitivity compared to KNS42 glioblastoma, C6 glioma and Res196 ependymoma cells. An increased proportion of S-phase cells were observed in medulloblastoma and high grade glioma cells whilst CNS PNET cells showed an increased proportion of G1-phase cells. RHPS4-induced phenotypes were concomitant with telomerase inhibition, manifested in a telomere length-independent manner and not associated with activated c-Myc levels. However, anti-proliferative effects were also observed in normal neural/endothelial cells in vitro and ex vivo. This study warrants in vivo validation of RHPS4 and alternative G4 ligands as potential anti-cancer agents for brain tumors but highlights the consideration of dose-limiting tissue toxicities.