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RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells

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

Authors

Sunil Lagah

I-Li Tan

Priya Radhakrishnan

Robert A. Hirst

Jennifer H. Ward

Chris O'Callaghan

Stuart J. Smith

Malcolm F.G. Stevens

Richard G. Grundy

Ruman Rahman

Abstract

Background
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.
Methods
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.
Results
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.
Conclusion
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.

Journal Article Type Article
Publication Date Jan 15, 2014
Journal PLoS ONE
Electronic ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 9
Issue 1
Article Number e86187
Institution Citation Lagah, S., Tan, I., Radhakrishnan, P., Hirst, R. A., Ward, J. H., O'Callaghan, C., …Rahman, R. (2014). RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells. PLoS ONE, 9(1), doi:10.1371/journal.pone.0086187
DOI https://doi.org/10.1371/journal.pone.0086187
Publisher URL http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086187
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0




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