Abstract 1875: Dietary grape seed proanthocyanidins induce rapid repair of DNA damage via nucleotide excision repair genes in preventing UV-induced immunosuppression

Abstract

Abstract Ultraviolet (UV) radiation-induced immunosuppression has been implicated in the development of skin cancers, including melanoma and non-melanoma. UV-induced DNA damage, predominantly the formation of cyclobutane pyrimidine dimers (CPDs), has been recognized as an important molecular trigger for the initiation of UVB-induced immunosuppression and skin carcinogenesis. We have shown earlier that administration of dietary grape (Vitis vinifera) seed proanthocyanidins (GSPs) supplemented with AIN76A control diet inhibit photocarcinogenesis in mice; however, the molecular mechanism of chemopreventive effects of GSPs are not clearly understood. To investigate the possible mechanism of action of GSPs we used genetically modified human cells and animal model. We observed that administration of dietary GSPs (0.2 and 0.5%, w/w) with supplementation of AIN76A control diet inhibited (52-65%, P<0.001) UV-induced suppression of contact hypersensitivity response to a contact sensitizer, 2,4-dinitrofluorobenzene, in a contact hypersensitivity mouse (C3H/HeN) model. Dietary GSPs repaired UV-induced DNA damage (CPD-positive cells) faster in the skin of mice as demonstrated by reduced number of CPD-positive cells (59%, p<0.001), and reduced the migration of CPD-positive cells from the skin to draining lymph nodes compared to non-GSPs-fed control mice, which was associated with the elevated levels of nucleotide excision repair (NER) genes. GSPs did not prevent UV-induced immunosuppression in NER-deficient mice but significantly prevented in NER-proficient mice (p<0.001) concomitantly repaired UV-induced DNA damage in NER-proficient mice (p<0.01) but did not repair in NER-deficient mice as indicated by immunohistochemical analysis of CPD-positive cells. Further, southwestern dot-blot analysis revealed that GSPs repaired UV-induced CPDs in xeroderma pigmentosum complementation group A (XPA)-proficient cells obtained from healthy person but did not repair in XPA-deficient cells obtained from the patients suffering from xeroderma pigmentosum disease, indicating that NER mechanism is involved in DNA repair. Together, these data identify a novel mechanism by which dietary GSPs prevent UV-induced immunosuppression which is mediated through rapid repair of damaged DNA, and that these effects lead to the prevention of UV radiation-induced skin tumors in mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1875.