RETRACTED: Cyclooxygenase-2 (COX-2) expression in high-risk premalignant oral lesions

114

Nuclear Factor‐κB (NF‐κB) activation and COX‐2 overexpression have been reported in head and neck cancer, but the relationship between these proteins remains to be investigated. To determine the relationship between NF‐κB and COX‐2 in Smokeless Tobacco (ST) associated oral tumorigenesis, we performed immunohistochemistry in serial sections from 107 OSCCs, 78 oral precancerous lesions (OPLs) (58 hyperplasias, 20 dysplasias) and 15 histologically normal oral tissues and correlated with clinicopathological data. Significant increase in NF‐κB and COX‐2 immunopositivity was observed from normal oral mucosa to OPLs to OSCCs (p = 0.009 and p = 0.002 respectively). Upregulation of NF‐κB and COX‐2 was observed as early as in hyperplasia [p = 0.006; OR = 6.1 and p = 0.003; OR = 7.6, respectively]. Expression of both proteins was found to be significantly associated in OPLs (p = 0.000; OR = 12.6) and OSCCs (p = 0.001; OR = 4.0). Intriguingly, khaini consumption correlated with NF‐κB immunopositivity in OPLs (p = 0.05, OR = 3.8) and OSCCs (p = 0.01, OR = 3.4) and with COX‐2 expression in OPLs (p = 0.03; OR = 4.3). In vitro experimental system of ST associated oral carcinogenesis was used to demonstrate ST (khaini) and NNK mediated activation of NF‐κB and COX‐2, supporting the clinical data. In conclusion, this study demonstrates correlation between over expression of NF‐κB and COX‐2 in early precancerous stages of development of oral cancer and sustained elevation down the tumorigenic pathway, underscoring their potential as targets for early intervention. In vitro studies demonstrated that NNK may be one of the carcinogenic components of ST (khaini) inducing activation of NF‐κB and COX‐2 in oral precancer and cancer cells, suggesting plausible role in ST‐induced oral carcinogenesis. © 2007 Wiley‐Liss, Inc.

Section: Discussionmentioning

confidence: 99%

Expression of NF‐κB parallels COX‐2 expression in oral precancer and cancer: Association with smokeless tobacco

Sawhney

Rohatgi

Kaur

et al. 2007

114

“…3,38,39 While much of the anticancer activity has been ascribed to COX-2 activity, the mechanisms involved in growth inhibition and apoptosis are not completely understood and cannot be completely explained by the inhibition of COX-2 activity. [5][6][7][8]11 To better understand the COX-independent mechanisms responsible for growth inhibition and apoptosis, the terminal phenyl ring and the benzenesulfonamide of celecoxib was modified to remove the COX-2 inhibitory activity and target growth inhibitory and apoptotic signaling pathway with much greater potency than celecoxib.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4] NSAIDs are potent inhibitors of cyclooxygenases (COX) prostaglandin synthesis and COX-2 is often over expressed in cancer cells. Thus NSAIDs which target COX-2 have been suggested as chemopreventive agents and celecoxib has been approved for adjuvant treatment of Familial Adenomatous Polyposis and in chemoprevention clinical trails of other types of cancers.…”

mentioning

confidence: 99%

Celecoxib derivatives induce apoptosis via the disruption of mitochondrial membrane potential and activation of caspase 9

Ding

Han

Zhu

et al. 2004

103

Celecoxib is a potent nonsteroid antiinflammatory drug (NSAID) that has shown great promise in cancer chemoprevention and treatment. The tumor suppression activity of celecoxib and other NSAIDs have been related to the induction of apoptosis in many cancer cell lines and animal models. While celecoxib is a specific inhibitor of cyclooxygenase (COX)-2, recent data indicate that its apoptotic properties may also be mediated through COX-independent pathways. In our study, we evaluated second generation celecoxib derivatives, lacking COX-2 inhibitory activity, in a premalignant and malignant human oral cell culture model to determine their potential anticancer effect and mechanisms responsible for the COX-independent apoptotic activity. Celecoxib and its derivatives delayed the progression of cells through the G 2 /M phase and induced apoptosis. The derivatives with apolar substituents at the terminal phenyl moiety of celecoxib greatly enhanced apoptosis and cell cycle delay. Apoptosis and cell cycle arrest appeared to be independent of derivative induced inhibition of PDK1 and phosphorylation of Akt and Erk1/2. Derivatives induced apoptosis was mediated by the cleavage and activation of caspase-9 and caspase-3, but not caspase 8, implicating the mitochondrial pathway for apoptosis induction. Inhibitors of caspase-3 and caspase-9 and cyclosporin A, a mitochondrial membrane potential stabilizer, attenuated derivative induced apoptosis. Inhibition of caspase-3 prevented the activation of caspase 8, while the inhibition of caspase-9 inhibitor blocked activation of both caspase 3 and 8 by the derivatives. Apoptosis was independent of Bcl-2. These results indicate that the second generation celecoxib derivatives induce apoptosis in human oral cancer lines by the disruption of mitochondrial membrane potential activating caspase 9 and downstream caspase 3 and 8. This suggests that the modification of the celecoxib structure can lead to highly effective COXindependent growth inhibitory and apoptotic agents in chemoprevention and therapy.

“…4). 49 Of 30 cases with biopsies from clinically normal mucosa, all had a normal (diploid) DNA content. COX-2 expression was observed in oral epithelial dysplastic lesions from 21 patients who had aneuploid lesions, and in none of 28 patients with diploid lesions.…”

Section: Cox-2 Expression In Oral Mucosamentioning

confidence: 99%

Retracted: The evolution of predictive oncology and molecular‐based therapy for oral cancer prevention

Sudbø

Reith

2005

Self Cite

More than 300,000 new cases worldwide are being diagnosed with oral squamous cell carcinoma annually. This aggressive epithelial malignancy is associated with a high mortality and severe morbidity among the long-term survivors. The ability to intervene prior to this advanced stage may improve treatment results. This requires the early identification of molecular events that represent early phases of malignant transition, which is possible through measurement of DNA ploidy in epithelial cells of oral leukoplakia. Recently, we showed that patients with aneuploid dysplastic oral lesions had a 96% rate of oral cancer (26 of the 27 patients received the diagnosis) with a 70% rate within three years, an 81% rate of subsequent cancer (22 of 27), a 74% rate of death from cancer (21 of 27) and virtually no help from complete resection-all hallmarks of biologically aggressive cancer. Standard treatment of oral leukoplakia-a precursor lesion of oral cancer-varies from watchful waiting to complete resection. We have recently demonstrated that complete resection of aneuploid oral leukoplakia does not prevent the occurrence of clinically aggressive and highly lethal oral cancer. Oral carcinogenesis is a complex multifocal process of multiclonal field carcinogenesis and intraepithelial clonal spread. The multifocal nature of early oral carcinogenesis may hinder local treatment modalities. Inhibitors of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR), either alone or in combination, may be used for reversing or stopping the oral carcinogenesis at an early stage of disease. The failure of standard treatment to control aneuploid oral leukoplakia justifies clinical trials with new treatment modalities, such as systemic therapy with molecular targeting agents, which in patients with aggressive leukoplakia is tantamount to cancer therapy. ' 2005 Wiley-Liss, Inc.Key words: leukoplakia; cancer prevention; molecular-based therapy; targeted therapy; predictive oncology; aneuploidy EpidemiologyMore than 300,000 new cases worldwide are being diagnosed with oral squamous cell carcinoma annually. This aggressive epithelial malignancy is associated with severe morbidity and less than 50% long-term survival despite advances in treatment with surgery, radiation and chemotherapy. The poor prognosis of oral cancer has not improved significantly over the last 4 decades.