A Randomized Double-Blind Placebo-Controlled Phase II Trial of the Cyclooxygenase-2 Inhibitor Celecoxib in the Treatment of Cervical Dysplasia

Farley, John H.; Truong, Vu; Goo, Elwin D.H.; Uyehara, Catherine F. T.; Belnap, Christina; Larsen, Wilma

doi:10.1097/01.lgt.0000245056.92621.ce

Cited by 2 publications

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“…HPV16 causes a number of epithelial cancers and precancers, including cervical cancer and cervical dysplasia, and an earlier clinical study showed that celecoxib treatment induced a clinical response in 75% of the women with severe cervical dysplasia (31). Although HPV transcription was not investigated in that study, our current data suggest that this response may have been due in part to the effects of celecoxib on viral transcription.…”

Section: Discussioncontrasting

confidence: 37%

Constitutive Overexpression of the Oncogene Racl in the Airway of Recurrent Respiratory Papillomatosis Patients Is a Targetable Host-Susceptibility Factor

Lucs

Mullooly

et al. 2011

Mol Med

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Recurrent respiratory papillomatosis (RRP) is caused by human papillomaviruses (HPVs), primarily types 6 and 11. The disease is characterized by multiple recurrences of airway papillomas, resulting in high levels of morbidity and significant mortality. The prevalence of latent HPV in the larynx of the general population is much greater than the prevalence of RRP, suggesting a host-susceptibility factor for disease. We report that the oncogene Rac1 and its downstream product cyclooxygenase-2 (COX-2) are both constitutively expressed at high levels throughout the airway of these patients, independent of active HPV infection. Use of the COX-2 inhibitor celecoxib in primary papilloma cell culture resulted in the downregulation of HPV transcription. Furthermore, a proof-of-principle study treating three patients with severe RRP with celecoxib resulted in remission of disease in all cases. Therefore, we have identified the first pharmacologically targetable host-susceptibility pathway that contributes to RRP recurrence.

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Section: Discussioncontrasting

confidence: 37%

Constitutive Overexpression of the Oncogene Racl in the Airway of Recurrent Respiratory Papillomatosis Patients Is a Targetable Host-Susceptibility Factor

Lucs

Mullooly

et al. 2011

Mol Med

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“…Treatment with celecoxib, a selective COX-2 inhibitor, has proven efficacy in the treatment of colorectal polyps in humans (30,31). Recently, celecoxib was also found to be active in the treatment of women with high-grade cervical dysplasia (32). Several different mechanisms can potentially explain the link between COX-2 and malignancy.…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase-2 Transcription Is Regulated by Human Papillomavirus 16 E6 and E7 Oncoproteins: Evidence of a Corepressor/Coactivator Exchange

2007

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Cyclooxygenase (COX-2) is overexpressed in human papillomavirus (HPV)-induced diseases, including cervical cancer. Although HPV E6 and E7 oncoproteins have been causally linked to cervical carcinogenesis, their effects on COX-2 gene expression are unknown. Increased levels of COX-2 mRNA, protein, and prostaglandin E 2 synthesis were detected in HPV16 E6-and E7-expressing cervical cancer cells (CaSki and SiHa) compared with an uninfected cervical cancer cell line (C33A). HPV16 E6 and E7 oncoproteins induced COX-2 transcription by activating the epidermal growth factor receptor (EGFR)!Ras!mitogen-activated protein kinase pathway. Interestingly, HPV16 oncoproteins stimulated EGFR signaling, in part, by inducing the release of amphiregulin, an EGFR ligand. The inductive effects of HPV16 E6 and E7 were mediated by enhanced binding of activator protein-1 to the cyclic AMP (cAMP)-responsive element (À59/À53) of the COX-2 promoter. The potential contribution of coactivators and corepressors to HPV16 E6-and E7-mediated induction of COX-2 was also investigated. Chromatin immunoprecipitation assays indicated that E6 and E7 oncoproteins induced the recruitment of phosphorylated c-Jun, c-Fos, UbcH5, and cAMP-responsive element binding protein-binding protein/ p300 to the COX-2 promoter. In contrast, E6 and E7 inhibited the binding of the histone deacetylase 3-nuclear receptor corepressor (NCoR) complex to the COX-2 promoter. Moreover, overexpression of NCoR blocked E6-and E7-mediated stimulation of the COX-2 promoter. Taken together, these results indicate that HPV16 E6 and E7 oncoproteins stimulated COX-2 transcription by inducing a corepressor/coactivator exchange. To our knowledge, this study also provides the first evidence that NCoR can function as a repressor of COX-2 gene expression. [Cancer Res 2007;67(8):3976-85]

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A Randomized Double-Blind Placebo-Controlled Phase II Trial of the Cyclooxygenase-2 Inhibitor Celecoxib in the Treatment of Cervical Dysplasia

Cited by 2 publications

References 0 publications

Constitutive Overexpression of the Oncogene Racl in the Airway of Recurrent Respiratory Papillomatosis Patients Is a Targetable Host-Susceptibility Factor

Constitutive Overexpression of the Oncogene Racl in the Airway of Recurrent Respiratory Papillomatosis Patients Is a Targetable Host-Susceptibility Factor

Cyclooxygenase-2 Transcription Is Regulated by Human Papillomavirus 16 E6 and E7 Oncoproteins: Evidence of a Corepressor/Coactivator Exchange

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