Cyclooxygenase Inhibitors for Skin Cancer Prevention

Pentland, Alice P.

doi:10.1001/archderm.138.6.823

Cited by 18 publications

(13 citation statements)

References 12 publications

(9 reference statements)

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“…However, in recent years a great deal of evidence has emerged suggesting that UV light-induced inflammation also plays an important role in tumor promotion and progression (26, 90 -93). In murine models of skin carcinogenesis, it has been shown that administration of nonsteroidal anti-inflammatory drugs, especially selective COX-2 inhibitors, reduces the prevalence and multiplicity of UV light-induced neoplasms (74,(92)(93)(94)(95), strongly implying direct involvement of COX-2 in cutaneous carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFκB-dependent Repression of the COX-2 Promoter

Marwaha

Chen

Helms

et al. 2005

Journal of Biological Chemistry

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Chronically irradiated murine skin and UV light-induced squamous cell carcinomas overexpress the inducible isoform of cyclooxygenase (COX-2), and COX-2 inhibition reduces photocarcinogenesis in mice. We have reported previously that DNA oligonucleotides substantially homologous to the telomere 3-overhang (T-oligos) induce DNA repair capacity and multiple other cancer prevention responses, in part through up-regulation and activation of p53. To determine whether T-oligos affect COX-2 expression, human newborn keratinocytes and fibroblasts were pretreated with T-oligos or diluent alone for 24 h, UVirradiated, and processed for Western blotting. In both cell types, T-oligos transcriptionally down-regulated base-line and UV light-induced COX-2 expression, coincident with p53 activation. In fibroblasts with wild type versus dominant negative p53 (p53 WT versus p53 DN ), T-oligos decreased constitutive expression of a COX-2 reporter plasmid by >50%. We then examined NFB, a known positive regulator of COX-2 transcription. In p53 WT but not in p53 DN fibroblasts and in human keratinocytes, T-oligos decreased readout of an NFB promoter-driven reporter plasmid and decreased NFB binding to DNA. After T-oligo treatment and subsequent UV irradiation, binding of the transcriptional co-activator protein p300 to NFB was decreased, whereas binding of p300 to p53 was increased. Human skin explants provided with T-oligos had markedly decreased COX-2 immunostaining both at base-line and post-UV light, coincident with increased p53 immunostaining. We conclude that T-oligos transcriptionally down-regulate COX-2 expression in human skin via activation and up-regulation of p53, at least in part by inhibiting NFB transcriptional activation. Decreased COX-2 expression may contribute to the observed ability of T-oligos to reduce photocarcinogenesis.Nonmelanoma skin cancer accounts for well over 1 million cases of human malignancy annually in the United States, and the incidence continues to rise (1-3). The major initiator and promoter of skin cancer is UVB radiation (4, 5). Among the contributing effects of UVB radiation on skin are the formation of cyclobutane-pyrimidine dimers and pyrimidine (6-4) photoproducts (6, 7), which lead to mutations in key regulatory genes (8), epidermal hyperplasia (9, 10) allowing for expansion of mutated clones (11), immunosuppression (12, 13), and inflammation (14, 15).One way inflammation in particular is thought to affect carcinogenesis is by promoting epidermal hyperplasia and proliferation through production of cytokines and various second messengers such as prostaglandin E 2 (16). The major enzyme responsible for the UVB-induced prostaglandin synthesis is cyclooxygenase-2 (COX-2), 5 the inducible isoform of the cyclooxygenase enzyme (17) that carries out the ratelimiting step of prostaglandin and thromboxane production (18 -20). COX-2 has been shown to be overexpressed in numerous human malignancies, including colon, lung, and breast cancers (21-24). In relation to skin cancer, UVB irradiation increas...

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Section: Discussionmentioning

confidence: 99%

T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFκB-dependent Repression of the COX-2 Promoter

Marwaha

Chen

Helms

et al. 2005

Journal of Biological Chemistry

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“…This may also explain the difference in COX‐2 expression in AK and the clearance rate of AK that were treated with topical diclofenac 35 . Currently, the chemopreventive effect on skin cancer of oral celecoxib, which is a selective COX‐2 inhibitor, is evaluated in clinical trails 11 …”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 expression and angiogenesis in squamous cell carcinoma of the skin and its precursors: a paired immunohistochemical study of 35 cases

et al. 2004

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“…Moreover, several multicenter trials are in progress investigating the chemopreventive ef- fect of COX-2-selective inhibitors using actinic keratoses and BCC as endpoints [15] .…”

Section: Permanent Overexpression Of Cox-2 In Epithelial Tumors Of Thmentioning

confidence: 99%

Differential Protein Expression in the Epidermis of Wild-Type and COX-2 Transgenic Mice

Müller‐Decker

Fürstenberger²,

Neumann³

et al. 2006

Skin Pharmacol Physiol

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Cyclooxygenases (COX) 1 and 2 are the key enzymes of prostaglandin biosynthesis. Like in many tissues, in adult skin COX-1 is a constitutive ‘housekeeping’ enzyme, while COX-2 is induced transiently in stress situations such as tissue damage and regeneration. In human skin carcinomas and corresponding early-stage cancer lesions, permanent COX-2 expression and activation is a consistent feature. Knockout and various transgenic approaches and pharmacologic studies show strong evidence for a cause-and-effect relationship between the aberrant COX-2 activation and tumor formation. In skin epidermis, keratin 5 promoter-driven overexpression of COX-2 caused hyperplasia and dysplasia, and sensitized skin for carcinogenesis. Therefore, this model offers the unique possibility of identifying COX-2-dependent and prostaglandin-mediated molecular pathways leading to the formation and malignant progression of early-stage cancer lesions.

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Cyclooxygenase Inhibitors for Skin Cancer Prevention

Cited by 18 publications

References 12 publications

T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFκB-dependent Repression of the COX-2 Promoter

T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFκB-dependent Repression of the COX-2 Promoter

Cyclooxygenase-2 expression and angiogenesis in squamous cell carcinoma of the skin and its precursors: a paired immunohistochemical study of 35 cases

Differential Protein Expression in the Epidermis of Wild-Type and COX-2 Transgenic Mice

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