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

Wu,Jianyue; Wang,Weimin; Shao,Qin; Xiao,Guomin; Cheng,Jun; Yuan,Yunpeng; Zhang,Mei

doi:10.3892/etm.2014.1800

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

Authors:
- Jianyue Wu
- Weimin Wang
- Qin Shao
- Guomin Xiao
- Jun Cheng
- Yunpeng Yuan
- Mei Zhang
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Affiliations: Department of Neurosurgery, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China
Published online on: June 23, 2014 https://doi.org/10.3892/etm.2014.1800
Pages: 893-898

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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.

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1	Thomas L, Di Stefano AL and Ducray F: Predictive biomarkers in adult gliomas: the present and the future. Curr Opin Oncol. 25:689–694. 2013. View Article : Google Scholar : PubMed/NCBI
2	Thon N, Kreth S and Kreth FW: Personalized treatment strategies in glioblastoma: MGMT promoter methylation status. Onco Targets Ther. 6:1363–1372. 2013. View Article : Google Scholar : PubMed/NCBI
3	Chowdhary S and Chamberlain M: Bevacizumab for the treatment of glioblastoma. Expert Rev Neurother. 13:937–949. 2013. View Article : Google Scholar : PubMed/NCBI
4	Tejada S, Aldave G, Marigil M, Gállego Pérez-Larraya J, Domínguez PD and Díez-Valle R: Factors associated with a higher rate of distant failure after primary treatment for glioblastoma. J Neurooncol. 116:169–175. 2014. View Article : Google Scholar : PubMed/NCBI
5	Gaber M, Selim H and El-Nahas T: Prospective study evaluating the radiosensitizing effect of reduced doses of temozolomide in the treatment of Egyptian patients with glioblastoma multiforme. Cancer Manag Res. 5:349–356. 2013.
6	Niyazi M, Schwarz SB, Suchorska B and Belka C: Radiotherapy with and without temozolomide in elderly patients with glioblastoma. Strahlenther Onkol. 188:154–159. 2012. View Article : Google Scholar : PubMed/NCBI
7	Matsumoto H, Hirabayashi Y, Kubota H, et al: A combined therapy with docetaxel and nedaplatin for relapsed and metastatic esophageal carcinoma. Anticancer Res. 32:1827–1831. 2012.PubMed/NCBI
8	Jingu K, Ariga H, Nemoto K, et al: Long-term results of radiochemotherapy for solitary lymph node metastasis after curative resection of esophageal cancer. Int J Radiat Oncol Biol Phys. 83:172–177. 2012. View Article : Google Scholar
9	Zhu H, Huo X, Chen L, Wang H and Yu H: Clinical experience with radio-, chemo- and hyperthermotherapy combined trimodality on locally advanced esophageal cancer. Mol Clin Oncol. 1:1009–1012. 2013.PubMed/NCBI
10	Jolly C and Morimoto RI: Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst. 92:1564–1572. 2000. View Article : Google Scholar : PubMed/NCBI
11	Rérole AL, Jego G and Garrido C: Hsp70: anti-apoptotic and tumorigenic protein. Methods Mol Biol. 787:205–230. 2011.PubMed/NCBI
12	Picard D: Heat-shock protein 90, a chaperone for folding and regulation. Cell Mol Life Sci. 59:1640–1648. 2002. View Article : Google Scholar : PubMed/NCBI
13	Whitesell L and Lindquist SL: HSP90 and the chaperoning of cancer. Nat Rev Cancer. 5:761–772. 2005. View Article : Google Scholar : PubMed/NCBI
14	Neckers L and Neckers K: Heat-shock protein 90 inhibitors as novel cancer chemotherapeutic agents. Expert Opin Emerg Drugs. 7:277–288. 2002. View Article : Google Scholar : PubMed/NCBI
15	Defee MR, Qin Z, Dai L, Toole BP, Isaacs JS and Parsons CH: Extracellular Hsp90 serves as a co-factor for NF-κB activation and cellular pathogenesis induced by an oncogenic herpesvirus. Am J Cancer Res. 1:687–700. 2011.PubMed/NCBI
16	Bandyopadhyay S, Chiang CY, Srivastava J, et al: A human MAP kinase interactome. Nat Methods. 7:801–805. 2010. View Article : Google Scholar : PubMed/NCBI
17	Yang J, Lin Y, Guo Z, et al: The essential role of MEKK3 in TNF-induced NFκB activation. Nat Immunol. 2:620–624. 2001.PubMed/NCBI
18	Wu MX, Ao Z, Prasad KV, Wu R and Schlossman SF: IEX-1L, an apoptosis inhibitor involved in NF-κB-mediated cell survival. Science. 281:998–1001. 1998.
19	Bull EE, Dote H, Brady KJ, et al: Enhanced tumor cell radiosensitivity and abrogation of G2 and S phase arrest by the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin. Clin Cancer Res. 10:8077–8084. 2004. View Article : Google Scholar : PubMed/NCBI
20	Sato S, Fujita N and Tsuruo T: Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci USA. 97:10832–10837. 2000. View Article : Google Scholar : PubMed/NCBI
21	Schulte TW, Blagosklonny MV, Ingui C and Neckers L: Disruption of the Raf-1-Hsp90 molecular complex results in destabilization of Raf-1 and loss of Raf-1-Ras association. J Biol Chem. 270:24585–24588. 1995. View Article : Google Scholar : PubMed/NCBI
22	Ivanov VN and Hei TK: A role for TRAIL/TRAIL-R2 in radiation-induced apoptosis and radiation-induced bystander response of human neural stem cells. Apoptosis. 19:399–413. 2014. View Article : Google Scholar : PubMed/NCBI
23	Carr SD, Green VL, Stafford ND and Greenman J: Analysis of radiation-induced cell death in head and neck squamous cell carcinoma and rat liver maintained in microfluidic devices. Otolaryngol Head Neck Surg. 150:73–80. 2014. View Article : Google Scholar : PubMed/NCBI
24	Ballarini F, Altieri S, Bortolussi S, Giroletti E and Protti N: A model of radiation-induced cell killing: insights into mechanisms and applications for hadron therapy. Radiat Res. 180:307–315. 2013. View Article : Google Scholar : PubMed/NCBI
25	Bao XH, Takaoka M, Hao HF, et al: Antiproliferative effect of the HSP90 inhibitor NVP-AUY922 is determined by the expression of PTEN in esophageal cancer. Oncol Rep. 29:45–50. 2013.PubMed/NCBI
26	Grem JL, Morrison G, Guo XD, et al: Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J Clin Oncol. 23:1885–1893. 2005. View Article : Google Scholar : PubMed/NCBI
27	Guo F, Rocha K, Bali P, et al: Abrogation of heat shock protein 70 induction as a strategy to increase antileukemia activity of heat shock protein 90 inhibitor 17-allylamino-demethoxy geldanamycin. Cancer Res. 65:10536–10544. 2005. View Article : Google Scholar : PubMed/NCBI
28	Brough PA, Barril X, Borgognoni J, et al: Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone. J Med Chem. 52:4794–4809. 2009.PubMed/NCBI
29	Massey AJ, Schoepfer J, Brough PA, et al: Preclinical antitumor activity of the orally available heat shock protein 90 inhibitor NVP-BEP800. Mol Cancer Ther. 9:906–919. 2010. View Article : Google Scholar : PubMed/NCBI
30	Stühmer T, Chatterjee M, Grella E, et al: Anti-myeloma activity of the novel 2-aminothienopyrimidine Hsp90 inhibitor NVP-BEP800. Br J Haematol. 147:319–327. 2009.PubMed/NCBI
31	Niewidok N, Wack LJ, Schiessl S, et al: Hsp90 inhibitors NVP-AUY922 and NVP-BEP800 may exert a significant radiosensitization on tumor cells along with a cell type-specific cytotoxicity. Transl Oncol. 5:356–369. 2012. View Article : Google Scholar
32	Stingl L, Stühmer T, Chatterjee M, Jensen MR, Flentje M and Djuzenova CS: Novel HSP90 inhibitors, NVP-AUY922 and NVP-BEP800, radiosensitise tumour cells through cell-cycle impairment, increased DNA damage and repair protraction. Br J Cancer. 102:1578–1591. 2010. View Article : Google Scholar : PubMed/NCBI