The nonsteroidal anti-inflammatory drug celecoxib suppresses the growth and induces apoptosis of human glioblastoma cells via the NF-κB pathway
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Gliomas are devastating primary tumors of the central nervous system and tend to recur even after standard therapy. Celecoxib, the selective COX-2 nonsteroidal anti-inflammatory drug, has anti-neoplastic activity against several malignancies. Accumulating evidence suggests that several COX-2-independent mechanisms may also be involved in the anti-tumor effects of celecoxib. Deregulation of the NF-κB signaling pathway contributes to enhanced glioma cell survival, proliferation, and chemoresistance. In this study, we examined the efficacy of celecoxib in suppressing the growth of glioblastoma cell lines. We observed that treatment with celecoxib significantly reduced the proliferation of a variety of GBM cell lines in a dose-dependent manner and also induced apoptosis, which was evident from enhanced caspase-3 and 8 activity, PARP cleavage, and TUNEL positive cells. Celecoxib treatment significantly down-regulated TNF-α induced NF-κB nuclear translocation, NF-κB DNA binding activity, and NF-κB-dependent reporter gene expression in U373 and T98G cells in a dose-dependent manner. Furthermore, celecoxib suppressed IκBα degradation and phosphorylation and reduced IKK activity in a dose-dependent manner. This study provides evidence that celecoxib suppresses the growth of GBM cell lines partly by inhibiting the NF-κB signaling pathway.
KeywordsCelecoxib NF-κB Glioblastoma p50 p65 IKK IκBα
We greatly acknowledge the Professor P. Reddanna (University of Hyderabad, India) for providing celecoxib. DBT, DST, CSIR, and ICMR are acknowledged for funding the laboratory, and CSIR, New Delhi, India (fellowship to GRS) is also acknowledged. We acknowledge Dr Syed Maqbool Ahmed, in charge of the CIL facility, UoH, and technical assistance of Miss Nalini for the confocal microscopy.
- 16.Kim KS, Yoon JH, Kim JK, Baek SJ, Eling TE, Lee WJ, Ryu JH, Lee JG, Lee JH, Yoo JB (2004) Cyclooxygenase inhibitors induce apoptosis in oral cavity cancer cells by increased expression of nonsteroidal anti-inflammatory drug-activated gene. Biochem Biophys Res Commun 325:1298–1303PubMedCrossRefGoogle Scholar
- 22.Waskewich C, Blumenthal RD, Li H, Stein R, Goldenberg DM, Burton J (2009) Celecoxib exhibits the greatest potency amongst cyclooxygenase (COX) inhibitors for growth inhibition of COX-2-negative hematopoietic and epithelial cell lines. Cancer Res 62:2029–2033Google Scholar
- 25.Shishodia S, Koul D, Aggarwal BB (2004) Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-kappa B activation through inhibition of activation of I kappa B kinase and Akt in human non-small cell lung carcinoma: correlation with suppression of COX-2 synthesis. J Immunol 173:2011–2022PubMedGoogle Scholar
- 45.Kardosh A, Golden EB, Pyrko P, Uddin J, Hofman FM, Chen TC, Louie SG, Petasis NA, Schonthal AH (2008) Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma by bortezomib in combination with celecoxib or its non-coxib analogue, 2, 5-dimethyl-celecoxib. Cancer Res 68:843–851PubMedCrossRefGoogle Scholar
- 49.Kesari S, Schiff D, Henson JW, Muzikansky A, Gigas DC, Doherty L, Batchelor TT, Longtine JA, Ligon KL, Weaver S, Laforme A, Ramakrishna N, Black PM, Drappatz J, Ciampa A, Folkman J, Kieran M, Wen PY (2008) Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults. Neuro Oncol 10:300–308PubMedCrossRefGoogle Scholar
- 52.Kern MA, Haugg AM, Koch AF, Schilling T, Breuhahn K, Walczak H, Fleischer B, Trautwein C, Michalski C, Schulze-Bergkamen H, Friess H, Stremmel W, Krammer PH, Schirmacher P, Muller M (2006) Cyclooxygenase-2 inhibition induces apoptosis signaling via death receptors and mitochondria in hepatocellular carcinoma. Cancer Res 66:7059–7066PubMedCrossRefGoogle Scholar