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 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.


CONCLUSIONS
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.
Children's Brain Tumour Research Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom.
Sunil
S
Lagah
Children's Brain Tumour Research Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom.
I-Li
IL
Tan
Department of Infection, Immunity and Inflammation, Leicester Royal Infirmary, University of Leicester, Leicester, United Kingdom.
Priya
P
Radhakrishnan
Department of Infection, Immunity and Inflammation, Leicester Royal Infirmary, University of Leicester, Leicester, United Kingdom.
Robert A
RA
Hirst
Children's Brain Tumour Research Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom.
Jennifer H
JH
Ward
Department of Respiratory Medicine, Portex Unit, Institute of Child Health, University College London and Great Ormond Street Hospital, London, United Kingdom.
Chris
C
O'Callaghan
Children's Brain Tumour Research Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom.
Stuart J
SJ
Smith
School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, United Kingdom.
Malcolm F G
MF
Stevens
Children's Brain Tumour Research Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom.
Richard G
RG
Grundy
Children's Brain Tumour Research Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom.
Ruman
R
Rahman
D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001932:Brain Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002923:Cilia / Q000187:drug effects / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects; D004805:Ependyma / Q000473:pathology; D054856:G-Quadruplexes; D006801:Humans; D020128:Inhibitory Concentration 50; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051381:Rats; D019914:Taq Polymerase / Q000037:antagonists & inhibitors; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000737:chemistry; D059505:Telomere Homeostasis / Q000187:drug effects
C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D000970:Antineoplastic Agents; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D019914:Taq Polymerase; D019098:Telomerase