DNA oligonucleotide treatment corrects the age‐associated decline in DNA repair capacity

Goukassian, David A.; Bagheri, Sepideh; El-Keeb, Laila; Eller, Mark S.; Gilchrest, Barbara A.

doi:10.1096/fj.01-0829fje

Cited by 60 publications

(75 citation statements)

References 62 publications

(107 reference statements)

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“…S1, a and b). UV irradiation up-regulated p53 total and p53 Ser15 levels by 8 h and through 24 h and up-regulated COX-2 within 24 h, as reported previously (25,50,55), in diluent-treated cells (Fig. 1b and Fig.…”

Section: T-oligo Pretreatment Down-regulates Base-line and Uvb-inducesupporting

confidence: 88%

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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: T-oligo Pretreatment Down-regulates Base-line and Uvb-inducesupporting

confidence: 88%

“…Cell Culture-Primary human neonatal fibroblast and keratinocytes cultures were established as described (49,50). Cells were incubated at 37°C in 5% CO 2 .…”

Section: Methodsmentioning

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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“…The functional damage to the stratum corneum induced by ionizing radiation occurs with a delayed course, starting within a mean period of 11 days and reaching maximal values after a mean period of 27 days (range, 13-75 days) 12 . Moreover, Goukassian et al, 2002 reported that pTpT treated skin of all mice showed spongiosis and sunburn cells, which was prominent in Xeroderma pigmentosa diseased mice, consistent with compensatory hyperplasia 13 . The current study confirmed that presence of spongiosis, which increased the thickening of epidermis by 52.6% in the fourth day of irradiation when pTpT was previously applied with 0.5 Gy.…”

Section: Discussionmentioning

confidence: 67%

Comparative Study Between Topical Applications of Liposomally Entrapped Dna Repair Enzymes and Thymidine Dinucleotides as Radioprotectors

Shabon¹,

Bedewi²

2013

J Pharm Sci Innov

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The delivery of active agents to the skin by liposome carriers is of great interest during the last three decades, based on their potential to enclose various types of biological materials and to deliver them to diverse cell types. Purpose: is to compare between topical application of DNA repair enzymes and thymidine dinucleotide which is a photoprotective agent against non-ionizing radiation through induction of DNA repair. Materials and Methods: thirty six Albino rats were treated by either thymidine dinucleotides or liposomally entrapped DNA repair enzymes topically, 24 hours after they were irradiated with Cobalt-60(60Co) gamma radiation with different doses (0.5 and 3Gy), and they were evaluated with histolopathologically by H&E stain and computerized image analyzer using Masson's trichrome stain. Results: Gamma radiation produced epidermal thinning and dermal inflammatory cells together with collagen fragmentation and clumping in a dose-like manner. Thymidine dinucleotides gave a better response with both (0.5& 3 Gy) than liposomally entrapped DNA repair enzymes, the epidermis was preserved of with no inflammatory cells and also it maintained the normal architecture of collagen bundles. Conclusion: The effects of gamma radiation on the skin could be minimized by the use of certain dinucleotides.

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“…36 Reduction in DNA repair capacity appears to increase the risk of BCC development specifically because young individuals with a history of BCC have lower DNA repair capacity than age-matched controls. 36 Our group has previously shown that pTT treatment corrects the age-associated decline in DNA repair capacity 37 at least in part through p53 activation, known to play a key role in DNA damage repair, with up-regulation of multiple DNA repair proteins, some but not all of which are induced by p53. 38,39 Within 24 to 48 hours pTT treatment enhances DNA repair and induces other photoprotective responses in cultured cells, hairless mice, and human skin explants.…”

mentioning

confidence: 99%

“…42 In this article we demonstrate that 8-hydroxy-2Ј-diguanosine (8-oxo-dG), known to be generated by UV-induced oxidative DNA damage, 43 was reduced significantly in pTT-versus vehicle-treated UVirradiated murine skin. This suggests that in vivo pTT not only up-regulates nucleotide excision repair, 8,28,37 but may also up-regulate base excision repair and/or reduce reactive oxygen species by increasing superoxide dismutase levels. p53 mutation is an early event in skin carcinogenesis and occurs in 40 to 60% of BCCs.…”

mentioning

confidence: 99%

Topical Thymidine Dinucleotide Treatment Reduces Development of Ultraviolet-Induced Basal Cell Carcinoma in Ptch-1+/− Mice

Arad

Zattra

Hebert³

et al. 2008

The American Journal of Pathology

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Treatment with thymidine dinucleotide (pTT) has well documented DNA-protective effects and reduces development of squamous cell carcinoma in UV-irradiated mice. The preventive effect of pTT on basal cell carcinoma (BCC) was evaluated in UV-irradiated Ptch-1 ؉/؊ mice, a model of the human disease Gorlin syndrome. Topical pTT treatment significantly reduced the number and size (P < 0.001) of BCCs in murine skin after 7 months of chronic irradiation. Skin biopsies collected 24 hours after the final UV exposure showed that pTT reduced the number of nuclei positive for cyclobutane pyrimidine dimers by 40% (P < 0.0002) and for 8-hydroxy-2-deoxyguanosine by 61% (P < 0.01 compared with vehicle control). Immunostaining with an antibody specific for mutated p53 revealed 63% fewer positive patches in BCCs of pTTtreated mice compared with controls (P < 0.01), and the number of Ki-67-positive cells was decreased by 56% (P < 0.01) in pTT-treated tumor-free epidermis and by 76% (P < 0.001) in BCC tumor nests (P < 0.001). Terminal dUTP nick-end labeling staining revealed a 213% increase (P < 0.04) in the number of apoptotic cells in BCCs of pTT-treated mice. Cox-2 immunostaining was decreased by 80% in tumor-free epidermis of pTT-treated mice compared with controls (P < 0.01). We conclude that topical pTT treatment during a prolonged period of intermittent UV exposure decreases the number and size of UV-induced BCCs through several anti-cancer mechanisms. 1 Like squamous cell carcinomas (SCCs), BCCs are associated with fair skin and chronic sunlight exposure, 2,3 but the relationship is more complex and studies to date have failed to show that sun protection reduces development of BCCs, in contrast to SCCs.1 Moreover, BCCs and SCCs differ in their responsiveness to certain chemopreventive agents. For example, BCC development is inhibited strongly by topical retinoids but not by oral nonsteroidal anti-inflammatory drugs (NSAIDs) or green tea.4,5 By contrast, murine SCC photocarcinogenesis is inhibited poorly by topical retinoids and quite well by oral NSAIDs or green tea. 4,6 These differing effects of UV radiation and chemopreventive agents on BCC versus SCC, in combination with the large socioeconomic burden of BCCs, 7 stimulated us to test thymidine dinucleotide (pTT), an agent already demonstrated to prevent SCCs in UV-irradiated mice 8 for its ability to reduce BCC development.Studies during the past decade have tied BCC tumorigenesis quite firmly to activated hedgehog signaling, a Research involving processing tissue for evaluation of microscopic BCCs, routine histology, immunofluorostaining image, and statistical analyses, and manuscript preparation were performed at the

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DNA oligonucleotide treatment corrects the age‐associated decline in DNA repair capacity

Cited by 60 publications

References 62 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

Comparative Study Between Topical Applications of Liposomally Entrapped Dna Repair Enzymes and Thymidine Dinucleotides as Radioprotectors

Topical Thymidine Dinucleotide Treatment Reduces Development of Ultraviolet-Induced Basal Cell Carcinoma in Ptch-1+/− Mice

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