Irradiation facilitates the inhibitory effect of the heat shock protein 90 inhibitor NVP-BEP800 on the proliferation of malignant glioblastoma cells through attenuation of the upregulation of heat shock protein 70

Abstract

The present study aimed to investigate the effect of NVP-BEP800, a novel heat shock protein (Hsp) 90 inhibitor of the 2-aminothieno[2,3-d]pyrimidine class, in combination with radiation on glioblastoma cells. T98G human glioblastoma cells were treated with dimethyl sulfoxide (DMSO), NVP-BEP800, NVP-BEP800 in combination with X-ray irradiation (10 Gy, 20 min), or X-ray irradiation only, and cultured for 40 h. Cell viability was measured upon completion of the treatments. In addition, apoptosis was measured and immunoblot analysis was performed to analyze the expression levels of cellular protein inhibitory κB kinase β (IKKβ). The combined treatment with NVP-BEP800 and X-ray irradiation resulted in the synergistic destruction of malignant cells. Furthermore, NVP-BEP800 significantly induced apoptosis in the human glioblastoma cells. The immunoblot analysis data indicated that NVP-BEP800 markedly reduced the expression level of IKKβ. The results also revealed that X-ray irradiation significantly attenuated the increase in the level of Hsp70 in cells treated with NVP-BEP800. Since elevated levels of Hsp70 are associated with drug resistance induced by Hsp90 inhibitors, the effects of X-ray irradiation on Hsp70 levels may be associated with the enhanced effect on cells of the presence of irradiation. The results of the current study suggest that irradiation enhances the inhibitory effect of NVP-BEP800 on the proliferation of malignant glioblastoma cells by downregulating the expression level of cellular signaling protein IKKβ and attenuating the upregulation of Hsp70 that is induced by NVP-BEP800.

HSP90 inhibitor NVP-BEP800 affects stability of SRC kinases and growth of T-cell and B-cell acute lymphoblastic leukemias

“…In these experiments, a decrease in the migration and invasion of lung carcinoma and glioblastoma cells was observed 62 , along with apoptosis of myeloma cells cultured on stromal support cells 63 , and a reduced proliferation of other tumor cell lines 64 . HSP90 inhibitors, including NVP-BEP800, increased the sensitivity of tumor cells to ionizing radiation 64 – 66 . In hepatocellular carcinoma, this compound has been found to suppress the vasculogenic networks, which play an important role in tumor malignancy 67 , 68 .…”

HSP90 Inhibition Enhances Antimitotic Drug-Induced Mitotic Arrest and Cell Death in Preclinical Models of Non-Small Cell Lung Cancer

“…Inhibitor binding to HSP90 causes dissociation of active Heat Shock Factor 1 and subsequent transcriptional upregulation of HSP70 which can attenuate the cytotoxic effects of HSP90 inhibitors [17] . In a recent report, X-ray irradiation has been shown to enhance the effects of the HSP90 inhibitor, NVP-BEF800 on glioblastoma through a mechanism involving attenuation of HSP70 upregulation [29] . As predicted, we observed upregulation of HSP70 bound to HSP90 upon treatment of cells with IPI-504.…”

Extracellular Chaperones as Novel Biomarkers of Overall Cancer Progression and Efficacy of Anticancer Therapy

“…Some studies suggested the key role of extracellular Hsp90 in GBM metastasis formation [164][165][166]. These findings translated into in vitro and animal model studies on Hsps inhibitors and Hsp-peptide complex vaccines in GBM treatment [167][168][169][170][171][172]. Some of them recently reached the I and II phases of clinical trials [173][174][175][176].…”