Interrogation of gossypol therapy in glioblastoma implementing cell line and patient-derived tumour models

Abstract

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.