RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells
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 tel...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
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Public Library of Science
2014
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| Online Access: | https://eprints.nottingham.ac.uk/31762/ |
| _version_ | 1848794268029681664 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Lagah, Sunil |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:13:29Z |
| format | Article |
| id | nottingham-31762 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:13:29Z |
| publishDate | 2014 |
| publisher | Public Library of Science |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-317622020-05-04T16:41:42Z https://eprints.nottingham.ac.uk/31762/ 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 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. Public Library of Science 2014-01-15 Article PeerReviewed 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. and Rahman, Ruman (2014) RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells. PLoS ONE, 9 (1). e86187/1-e86187/11. ISSN 1932-6203 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086187 doi:10.1371/journal.pone.0086187 doi:10.1371/journal.pone.0086187 |
| spellingShingle | 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 RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells |
| title | RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells |
| title_full | RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells |
| title_fullStr | RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells |
| title_full_unstemmed | RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells |
| title_short | RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells |
| title_sort | rhps4 g-quadruplex ligand induces anti-proliferative effects in brain tumor cells |
| url | https://eprints.nottingham.ac.uk/31762/ https://eprints.nottingham.ac.uk/31762/ https://eprints.nottingham.ac.uk/31762/ |