Interrogation of gossypol therapy in glioblastoma implementing cell line and patient-derived tumour models.
BACKGROUND
Glioblastoma (GBM), being a highly vascularised and locally invasive tumour, is an attractive target for anti-angiogenic and anti-invasive therapies. The GBM/endothelial cell response to gossypol/temozolomide (TMZ) treatment was investigated with a particular aim to assess treatment effects on cancer hallmarks.


METHODS
Cell viability, endothelial tube formation and GBM tumour cell invasion were variously assessed following combined treatment in vitro. The U87MG-luc2 subcutaneous xenograft model was used to investigate therapeutic response in vivo. Viable tumour response to treatment was interrogated using immunohistochemistry. Combined treatment protocols were also tested in primary GBM patient-derived cultures.


RESULTS
An endothelial/GBM cell viability inhibitory effect, as well as an anti-angiogenic and anti-invasive response, to combined treatment have been demonstrated in vitro. A significantly greater anti-proliferative (P=0.020, P=0.030), anti-angiogenic (P=0.040, P<0.0001) and pro-apoptotic (P=0.0083, P=0.0149) response was observed when combined treatment was compared with single gossypol/TMZ treatment response, respectively. GBM cell line and patient-specific response to gossypol/TMZ treatment was observed.


CONCLUSIONS
Our results indicate that response to a combined gossypol/TMZ treatment is related to inhibition of tumour-associated angiogenesis, invasion and proliferation and warrants further investigation as a novel targeted GBM treatment strategy.
Department of Physiology and Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
M A
MA
Jarzabek
1] Molecular Therapeutics for Cancer Ireland, Dublin City University, Dublin 9, Ireland [2] All Ireland Cooperative Oncology Research Group, Dublin 2, Ireland.
V
V
Amberger-Murphy
1] UCD School of Veterinary Medicine, University College Dublin, Dublin 4, Ireland [2] Ross School of Veterinary Medicine, Basseterre, St Kitts, West Indies.
J J
JJ
Callanan
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
C
C
Gao
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland.
A M
AM
Zagozdzon
Department of Physiology and Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
L
L
Shiels
Department of Biomedicine, University of Bergen, Bergen, Norway.
J
J
Wang
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
K L
KL
Ligon
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
B E
BE
Rich
PHS Department of Epidemiology and Public Health Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
P
P
Dicker
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland.
W M
WM
Gallagher
Department of Physiology and Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
J H M
JH
Prehn
1] Department of Physiology and Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland [2] UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland.
A T
AT
Byrne
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006072:Gossypol / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D023041:Xenograft Model Antitumor Assays
D006072:Gossypol