The nonsteroidal anti-inflammatory drug celecoxib suppresses the growth and induces apoptosis of human glioblastoma cells via the NF-κB pathway

Abstract

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-jB 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-a induced NF-jB nuclear translocation, NF-jB DNA binding activity, and NF-jB-dependent reporter gene expression in U373 and T98G cells in a dose-dependent manner. Furthermore, celecoxib suppressed IjBa degradation and phosphorylation and reduced IKK activity in a dosedependent manner. This study provides evidence that celecoxib suppresses the growth of GBM cell lines partly by inhibiting the NF-jB signaling pathway.

Cadherin-11 in poor prognosis malignancies and rheumatoid arthritis: common target, common therapies

“…The cycloxygenase-2 (COX-2) selective NSAIDS such as celecoxib (Celebrex™) and the now discontinued rofecoxib (Vioxx™) are treatments of for patients with RA. Celecoxib also has well known anti-cancer properties [30-33] and RA patients treated with celecoxib or rofecoxib have a lower risk of breast, prostate and colorectal cancers [34;35]. However, although there is no doubt that celecoxib is an excellent inhibitor of COX-2 there is much debate over its COX-2 independent activities and if these could play a role in its anti-inflammatory and anti-cancer effects [36-39].…”

3d metal complexes with meloxicam as therapeutic agents in the fight against human glioblastoma multiforme and cervical carcinoma

“…Promising data have been reported, such as the ability of celecoxib (a COX-2 selective NSAID) to inhibit the proliferation of various glioblatoma cell lines in vitro [65] and to induce apoptosis via the NF-kB pathway. [66] In addition, several case control studies have suggested that NSAIDs reduce the risk for this aggressive brain cancer, but findings from a large prospective study did not support an inverse association between NSAIDs and risk of glioma and glioblastoma. [67] The NSAID sulindac has been reported to induce specific degradation of the Human papilomavirus oncoprotein E7 and to cause growth arrest (inhibition of the G1 to S transition of the cell cycle) and apoptosis in HeLa cervical carcinoma cells.…”

Alveolar rhabdomyosarcoma: morphoproteomics and personalized tumor graft testing further define the biology of PAX3-FKHR(FOXO1) subtype and provide targeted therapeutic options

“…In this context, the following agents should act to address the biology of ARMS by acting at genomic and proteomic levels: 1) Entinostat by virtue of its ability to: a) inhibit class I HDAC [32] and thereby, to interrupt the YY1-EZH2-HDAC1 inhibition of miR-29b2 and mir-29c allowing arrest of ARMS cell proliferation and promoting differentiation [11–17, 28]; and b) its ability to effect direct transcriptional supression of PAX3:FOXO1 [33] and to inhibit the phosphorylative activation of PAX3—FOXO1 by polo-like kinase (PLK)1 [29, 34, 35]; 2) celecoxib inhibits the NF-kappaB pathway at multiple points [36] and should reduce the overproduction of YY1; 3) sulforaphane, a nutraceutical suppresses polycomb group protein level including EZH2 [37] and this should promote alveolar rhabdomyosarcoma's differentiation to a more benign form, induce apoptosis in the tumor cells [38] and reduce the survival of alveolar rhabdomyosarcoma leading to elimination of the tumor (in the latter study, sulforaphane was also shown to decrease the mRNA and protein levels of PAX3-FKHR, MYCN and MET in ARMS cells); 4) retinoic acid upregulates miR-214 which downregulates EZH2 protein in embryonic stem cells and miR-214-mediated EZH2 protein reduction accelerates skeletal muscle cell differentiation [39] (Both all-trans retinoic acid, ATRA and 9-cis retinoic acid suppressed the cell growth of alveolar rhabdomyosarcoma with evidence of a differentiating effect [40]. ATRA increased the expression of some genes associated with muscle differentiation and slowed the proliferation and promoted a more differentiated myogenic phenotype in ARMS cell lines [41].…”