RHPS4 G-Quadruplex Ligand Induces Anti-Proliferative Effects in Brain Tumor CellsReportar como inadecuado




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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-quino4,3,2-klacridinium 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.



Autor: Sunil Lagah, I-Li Tan, Priya Radhakrishnan, Robert A. Hirst, Jennifer H. Ward, Chris O’Callaghan, Stuart J. Smith, Malcolm F. G

Fuente: http://plos.srce.hr/



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