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.
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Authors | Rita Fishelevich, Yuming Zhao, Papapit Tuchinda, Hannah Liu, Ayako Nakazono, Antonella Tammaro, Tzu-Ching Meng, Jim Lee, Anthony A Gaspari |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 187
Issue 4
Pg. 1664-73
(Aug 15 2011)
ISSN: 1550-6606 [Electronic] United States |
PMID | 21765012
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Aminoquinolines
- Antineoplastic Agents
- Membrane Glycoproteins
- Myd88 protein, mouse
- Myeloid Differentiation Factor 88
- Pyrimidine Dimers
- Tlr7 protein, mouse
- Toll-Like Receptor 7
- Xeroderma Pigmentosum Group A Protein
- Xpa protein, mouse
- Imiquimod
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Topics |
- Aminoquinolines
(pharmacology)
- Animals
- Antineoplastic Agents
(pharmacology)
- Bone Marrow Cells
(immunology, metabolism)
- Cell Line
- DNA Damage
(drug effects, immunology, radiation effects)
- DNA Repair
(drug effects, genetics, immunology, radiation effects)
- Female
- Gene Expression Regulation, Neoplastic
(drug effects, genetics, immunology, radiation effects)
- Imiquimod
- Membrane Glycoproteins
(agonists, genetics, immunology, metabolism)
- Mice
- Mice, Knockout
- Myeloid Differentiation Factor 88
(genetics, immunology, metabolism)
- Pyrimidine Dimers
(genetics, immunology, metabolism)
- Signal Transduction
(drug effects, immunology, radiation effects)
- Skin Neoplasms
(drug therapy, genetics, immunology)
- Toll-Like Receptor 7
(agonists, genetics, immunology, metabolism)
- Ultraviolet Rays
(adverse effects)
- Xeroderma Pigmentosum Group A Protein
(biosynthesis, genetics, immunology)
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