NF-κB inhibitor reverses temozolomide resistance in human glioma TR/U251 cells

Wang,Xuan; Jia,Lili; Jin,Xiaohua; Liu,Qian; Cao,Wei; Gao,Xiangdong; Yang,Mingfeng; Sun,Baoliang

doi:10.3892/ol.2015.3130

NF-κB inhibitor reverses temozolomide resistance in human glioma TR/U251 cells

Authors:
- Xuan Wang
- Lili Jia
- Xiaohua Jin
- Qian Liu
- Wei Cao
- Xiangdong Gao
- Mingfeng Yang
- Baoliang Sun
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Affiliations: Department of Neurology, The Sixth People's Hospital of Jinan, Jinan, Shandong 250200, P.R. China, Key Laboratory of Cerebral Microcirculation Taishan Medical University, Tai'an, Shangdong 271000, P.R. China
Published online on: April 21, 2015 https://doi.org/10.3892/ol.2015.3130
Pages: 2586-2590

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Abstract

Glioblastoma multiforme (GBM) demonstrates an unsatisfactory clinical prognosis due to the intrinsic or acquired resistance to temozolomide (TMZ) exhibited by the tumors. One possible cause of TMZ resistance in GBM is the overexpression of O6‑methylguanine‑DNA methyltransferase (MGMT), which can repair the TMZ‑induced guanine damage in DNA. Additionally, excessive activated NF‑κB is reported to be a component of the major inflammatory transcription pathway that is associated with TMZ resistance in GBM. However, the association between the NF‑κB pathway and MGMT expression in GBM cells is unknown. Therefore, in the present study, the TMZ resistant (TR) U251 cell line (TR/U251) was successfully constructed to detect how the TR/U251 cell line and the parental U251 cell line each interact with TMZ in vitro. The TR/U251 cells were approximately five times more resistant to TMZ compared with the parental cells. Furthermore, it was found that the NF‑κB inhibitor BAY 11‑7082 suppressed the expression of MGMT in TR/U251 cells and enhanced TMZ‑induced cytotoxicity and apoptosis, thereby indicating that the NF‑κB pathway and MGMT interact to promote TMZ resistance. The inhibition of NF‑κB may be a promising strategy to reverse drug resistance in TR glioma cells. The present results propose a potential mechanism for using the NF‑κB inhibitor BAY 11‑7082 as a potential therapy for the treatment of TR glioma. Although BAY 11‑7082 is a well‑known NF‑ κB inhibitor, the present study further investigated its underlying mechanisms through a series of new experiments.

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1	Tate MC and Aghi MK: Biology of angiogenesis and invasion in glioma. Neurotherapeutics. 6:447–457. 2009. View Article : Google Scholar : PubMed/NCBI
2	Grauer OM, Wesseling P and Adema GJ: Immunotherapy of diffuse gliomas: biological background, current status and future developments. Brain Pathol. 19:674–693. 2009. View Article : Google Scholar : PubMed/NCBI
3	Mason WP: Emerging drugs for malignant glioma. Exprt Opin Emerg Drugs. 13:81–94. 2008. View Article : Google Scholar
4	Auger N, Thillet J, Wanherdrick K, et al: Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line. Mol Cancer Ther. 5:2182–2192. 2006. View Article : Google Scholar : PubMed/NCBI
5	Hegi ME, Diserens AC, Godard S, et al: Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res. 10:1871–1874. 2004. View Article : Google Scholar : PubMed/NCBI
6	Kumar A, Takada Y, Boriek AM, et al: Nuclear factor-kappaB: its role in health and disease. J Mol Med (Berl). 82:434–448. 2004. View Article : Google Scholar : PubMed/NCBI
7	Senftleben U, Cao Y, Xiao G, et al: Activation by IKKalpha of a second, evolutionary conserved, NF-kappaB signaling pathway. Science. 293:1495–1499. 2001. View Article : Google Scholar : PubMed/NCBI
8	Naugler WE and Karin M: NF-kappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev. 18:19–26. 2008. View Article : Google Scholar : PubMed/NCBI
9	Kapoor GS, Zhan Y, Johnson GR and O'Rourke DM: Distinct domains in the SHP-2 phosphatase differentially regulate epidermal growth factor receptor/NF-kappaB activation through Gab1 in glioblastoma cells. Mol Cell Biol. 24:823–836. 2004. View Article : Google Scholar : PubMed/NCBI
10	Bredel M, Bredel C, Juric D, et al: Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 24:274–287. 2006. View Article : Google Scholar : PubMed/NCBI
11	Crinière E, Kaloshi G, Laigle-Donadey F, et al: MGMT prognostic impact on glioblastoma is dependent on therapeutic modalities. J Neuro-oncol. 83:173–179. 2007. View Article : Google Scholar
12	Bottero V, Busuttil V, Loubat A, et al: Activation of nuclear factor kappaB through the IKK complex by the topoisomerase poisons SN38 and doxorubicin A brake to apoptosis in HeLa human carcinoma cells. Cancer Res. 61:7785–7791. 2001.PubMed/NCBI
13	Cusack JC Jr, Liu R and Baldwin AS Jr: Inducible chemoresistance to 7-ethyl-10 [4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11) in colorectal cancer cells and a xenograft model is overcome by inhibition of nuclear factor-κB Activation. Cancer Res. 60:2323–2330. 2000.PubMed/NCBI
14	Ma J, Murphy M, O'Dwyer PJ, et al: Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. Biochem Pharmacol. 63:1219–1228. 2002. View Article : Google Scholar : PubMed/NCBI
15	Martinez R, Schackert G, Yaya-Tur R, et al: Frequent hypermethylation of the DNA repair gene MGMT in long-term survivors of glioblastoma multiforme. J Neuro-oncol. 83:91–93. 2007. View Article : Google Scholar
16	Rodriguez FJ, Thibodeau SN, Jenkins RB, et al: MGMT immunohistochemical expression and promoter methylation in human glioblastoma. Appl Immunohistochem Mol Morphol. 16:59–65. 2008.PubMed/NCBI
17	Kasuga C, Ebata T, Kayagaki N, et al: Sensitization of human glioblastomas to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by NF-kappaB inhibitors. Cancer Sci. 95:840–844. 2004. View Article : Google Scholar : PubMed/NCBI
18	Nogueira L, Ruiz-Ontañon P, Vazquez-Barquero A, et al: The NFκB pathway: a therapeutic target in glioblastoma. Oncotarget. 2:646–653. 2011.PubMed/NCBI
19	Lavon I, Fuchs D, Zrihan D, et al: Novel mechanism whereby nuclear factor κB mediates DNA damage repair through regulation of O(6)-methylguanine-DNA-methyltransferase. Cancer Res. 67:8952–8959. 2007. View Article : Google Scholar : PubMed/NCBI
20	Huang H, Lin H, Zhang X, et al: Resveratrol reverses temozolomide resistance by downregulation of MGMT in T98G glioblastoma cells by the NF-κB-dependent pathway. Oncol Rep. 27:2050–2056. 2012.PubMed/NCBI