γ-Hydroxy-1, N2-propanodeoxyguanosine (γ-OHPdG), a widely studied acrolein-derived cyclic adduct arisen from oxidized ω-3 and ω-6 polyunsaturated fatty acids (PUFAs), is a mutagenic lesion that is repaired by nucleotide excision repair (NER) pathway. C3H/HeN xeroderma pigmentosum group A (XPA) knockout mice which are deficient on NER pathway showed a significant elevation in liver tumors. We hypothesized that accumulation of γ-OHPdG is playing a role in liver tumorigenesis of XPA(-/-) mice; suppressing the formation of γ-OHPdG by dietary antioxidants should result in the prevention of liver cancer in this model. In this work, we investigated the chemoprotective efficacy of three antioxidants: α-lipoic acid, polyphenon E and vitamin E against liver tumorigenesis in XPA(-/-) mice. Autopsy at 19 months of age revealed that all the antioxidants exhibited significant inhibition effects on the development of liver tumors. Polyphenon E showed the most potent effects with 80% of the mice showing complete protection. The formation γ-OHPdG was measured in the livers of XPA(-/-) mice. An age-dependent increase of γ-OHPdG was found in the liver DNA of XPA(-/-) mice, but not in lungs (a non-target tissue). All the antioxidants decreased the formation of γ-OHPdG. Immunohistochemistry (IHC) for Ki-67 (proliferation index marker) was performed on all the liver samples, and the results showed that dietary antioxidants significantly decrease the proliferation in the liver tumors. α-Lipoic acid and vitamin E showed significant inhibitory effect, although to a lesser extent than Polyphenon E, against the spontaneous liver carcinogenesis in XPA gene-deficient mice model. A correlation between the cancer preventive efficacy and suppression of γ-OHPdG adduct level is observed, indicating a possible role of γ-OHPdG in the liver cancer development in this model. We also explored the feasibility of next-generation sequencing (NGS) to validate the mutation frequency changes as a result of feeding the antioxidant diets. This work was supported by the NCI grant: RO1-CA-134892. Y.F. thanks the Prevent Cancer Foundation for his fellowship (Marcia and Frank Carlucci Charitable Foundation Award in Cancer Prevention and Early Detection)
Note: This abstract was not presented at the meeting.
Citation Format: Ying Fu, Shana Silverstein, Marcin Dyba, Heidi Coia, Elizabeth Sinclair, Jishen Pan, Bhaskar Kallakury, Michael D. Johnson, Fung-Lung Chung. Cancer preventive effect of antioxidants for spontaneous liver cancer in XPA(-/-) mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4561. doi:10.1158/1538-7445.AM2015-4561