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Updated: 03/25/13

Researchers Study Whether Altering Cellular Fats Raises Cancer Risk

NCI CAM Annual Report-FY10

Oxygen, while necessary for life, can also damage molecules inside our bodies due to its highly reactive nature. Oxygen can “pull” electrons from many other molecules in the body through a process called oxidation, causing them to be reactive and unstable. If these reactive molecules interact with DNA, the result can be DNA damage, which is an early step in carcinogenesis (cancer formation). The fatty acids widespread in the body, including those found on the membranes of cells, are vulnerable to a type of oxidative damage called lipid peroxidation. Fung-Lung Chung, Ph.D., professor of oncology at Georgetown University Medical Center, is interested in how DNA damage, driven by lipid peroxidation, may contribute to cancer formation.


Previous research from his laboratory has shown* that the oxidation of polyunsaturated fatty acids found on cellular membranes can cause a type of DNA damage called a “cyclic adduct,” where a reactive compound formed by lipid peroxidation attaches itself to the double-helix structure of DNA. These cyclic adducts have been found in animals, in humans, and even in cultured cells. However, whether cyclic adducts contribute to cancer formation – and if so, how – remains unclear.


“There’s a lot of talk in the literature about cancer risk related to fat intake—for example, a fatty liver is a risk factor for liver cancer,” explained Dr. Chung. “And a high-fat diet is associated with colon cancer. So we thought there might be some sort of mechanistic role for this type of DNA modification caused by fatty acid peroxidation in those cancers.” In his current research funded by NCI**, Dr. Chung and his colleagues are using two animal models with spontaneous liver cancer to better under­stand this process. One model, the Long Evans Cinnamon rat, accumulates abnormal levels of copper in the liver and subsequently shows an increase in lipid peroxidation and liver cancer. The second model is a mouse strain that lacks the DNA-repair mechanism, called nucleotide excision repair, that the body normally uses to repair cyclic adducts caused by lipid peroxida­tion. These mice also have a high incidence of spontaneous liver cancer.


The researchers will look at the relationships between accumulation of cyclic adducts in the liver and progressive stages of liver carcino­genesis. Researchers will also closely examine cyclic adduct binding to the p53 gene and the relationship between adduct binding and other p53 mutations found in liver tumors from these animals. The p53 gene is a known tumor-suppressor gene that is inactivated (“turned off”) by mutations in many types of cancer that contributes to runaway tumor-cell growth.


In addition, Dr. Chung plans to test several antioxidants, including a mixture of green tea polyphenols (Polyphenon E) and dihydrolipoic acid (DHLA), to see if adding these compounds to the animals’ diets slows or prevents cyclic adduct formation. In a study published in 2010***, Dr. Chung and his colleagues found that epigallocatechin gallate E, a green tea polyphenol, and DHLA inhibited the forma­tion of cyclic DNA adducts in laboratory model systems.


* Chung FL, Chen HJ, Nath RG. Lipid peroxidation as a potential endogenous source for the formation of exocyclic DNA adducts. Carcinogenesis, October 1996;17(10):2105-11.

**Grant number: 5R01CA134892-02

*** Nath RG, Wu MY, Emami A, Chung FL. Effects of epigallocatechin gallate, L-ascorbic acid, alpha-tocopherol, and dihydrolipoic acid on the formation of deoxyguanosine adducts derived from lipid peroxidation. Nutrition and Cancer, 2010;62(5):622-9.