Abstract
Imiquimod is a TLR7/8 agonist that has anticancer therapeutic efficacy in the treatment of precancerous skin lesions and certain nonmelanoma skin cancers. To test our hypothesis that imiquimod enhances DNA repair as a mechanism for its anticancer activity, the nucleotide excision repair genes were studied in bone marrow-derived cells. Imiquimod enhanced the expression of xeroderma pigmentosum (XP) A and other DNA repair genes (quantitative real-time PCR analysis) and resulted in an increased nuclear localization of the DNA repair enzyme XPA. This was dependent on MyD88, as bone marrow-derived cells from MyD88(-/-) mice did not increase XPA gene expression and did not enhance the survival of MyD88(-/-)-derived bone marrow-derived cells after UV B exposure as was observed in bone marrow-derived cells from MyD88(+/+) mice. Imiquimod also enhanced DNA repair of UV light (UVL)-irradiated gene expression constructs and accelerated the resolution of cyclobutane pyrimidine dimers after UVL exposures in P388 and XS52. Lastly, topical treatment of mouse skin with 5% imiquimod cream prior to UVL irradiation resulted in a decrease in the number of cyclobutane pyridimine dimer-positive APC that were found in local lymph nodes 24 h after UVL irradiation in both wild-type and IL-12 gene-targeted mice. In total, these data support the idea that TLR7 agonists such as imiquimod enhance DNA repair in bone marrow-derived cells. This property is likely to be an important mechanism for its anticancer effects because it protects cutaneous APC from the deleterious effects of UVL.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminoquinolines / pharmacology*
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Animals
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Antineoplastic Agents / pharmacology*
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Bone Marrow Cells / immunology*
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Bone Marrow Cells / metabolism
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Cell Line
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DNA Damage* / drug effects
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DNA Damage* / immunology
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DNA Damage* / radiation effects
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DNA Repair / drug effects
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DNA Repair / genetics
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DNA Repair / immunology
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DNA Repair / radiation effects
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Gene Expression Regulation, Neoplastic / immunology
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Gene Expression Regulation, Neoplastic / radiation effects
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Imiquimod
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Membrane Glycoproteins / agonists*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology*
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Knockout
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / immunology
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Myeloid Differentiation Factor 88 / metabolism
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Pyrimidine Dimers / genetics
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Pyrimidine Dimers / immunology
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Pyrimidine Dimers / metabolism
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Signal Transduction* / drug effects
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Signal Transduction* / immunology
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Signal Transduction* / radiation effects
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Skin Neoplasms / drug therapy
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Skin Neoplasms / genetics
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Skin Neoplasms / immunology*
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Toll-Like Receptor 7 / agonists*
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Toll-Like Receptor 7 / genetics
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Toll-Like Receptor 7 / immunology*
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Toll-Like Receptor 7 / metabolism
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Ultraviolet Rays / adverse effects*
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Xeroderma Pigmentosum Group A Protein / biosynthesis
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Xeroderma Pigmentosum Group A Protein / genetics
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Xeroderma Pigmentosum Group A Protein / immunology
Substances
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Aminoquinolines
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Antineoplastic Agents
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Pyrimidine Dimers
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Tlr7 protein, mouse
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Toll-Like Receptor 7
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Xeroderma Pigmentosum Group A Protein
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Xpa protein, mouse
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Imiquimod