Potential new drug target identified, as well
A study conducted at the San Francisco VA Medical Center (SFVAMC) has demonstrated that omega-6 fatty acids such as the fat found in corn oil promote the growth of prostate tumor cells in the laboratory. The study also identifies a potential new molecular target for anti-tumor drugs: an enzyme known as cPLA2, which plays a key role in the chain leading from omega-6 fatty acids to prostate tumor cell growth.
The study was led by Millie Hughes-Fulford, PhD, director of the Laboratory of Cell Growth at SFVAMC and scientific advisor to the U.S. Undersecretary of Health for the Department of Veterans Affairs. It is being published in the September 2005 issue of Carcinogenesis, and is currently available online.
Working with human prostate cancer cells in tissue culture, Hughes-Fulford and her fellow researchers identified for the first time a direct chain of causation: When introduced into prostate tumor cells in culture, omega-6 fatty acid causes the production of cPLA2, which then causes the production of the enzyme COX2. In turn, COX2 stimulates the release of PGE2, a hormone-like molecule that promotes cell growth.
"What's important about this is that omega-6 fatty acids are found in corn oil and most of the oils used in bakery goods," says Hughes-Fulford, who is also an adjunct professor of medicine at the University of California, San Francisco (UCSF). "Which means that if you're eating a diet high in omega-6 fatty acids, it's possible that you're turning on this cancer cascade, which has been shown to be a common denominator in the growth of prostate, colorectal, and some breast cancers."
The study points out that 60 years ago in the United States, the dietary ratio of omega-6 to omega-3, a beneficial fatty acid, was 1 to 2. Today, the ratio is 25 to 1. Over that same 60 years, the incidence of prostate cancer in the U.S. has increased steadily.
Hughes-Fulford also found that flurbiprofen, a non-steroidal anti-inflammatory drug commonly prescribed for arthritis, blocked the production of cPLA2 and broke the chain leading to cell growth. This means, she says, that new drugs might be developed that could specifically target cPLA2 and prevent COX2 from being released.
"COX2 has been implicated in the growth of many types of tumors," she notes. "So if you can find a way to block that cascade in the tumor, starting with cPLA2, you might have a new way of modifying or slowing tumor growth."
Hughes-Fulford points out that cPLA2 inhibitors would avoid the problems inherent in the class of drugs known as COX2 inhibitors. These drugs have been shown to be effective against tumor growth as well as in treating the pain associated with inflammatory conditions such as arthritis, but have been implicated in increased risk of cardiovascular problems in people who take them regularly. "COX2 inhibitors also inhibit prostacyclins, which are enzymes that are beneficial to the heart, and cPLA2 inhibitors would not affect those," she explains.
In future research, Hughes-Fulford will be looking at the overall effect of different types of fatty acids on different tumor types in cell lines as well as human biopsies. She plans a study that will correlate type of fatty acid with tumor stage and grade in order to obtain a clearer picture of specific effects of different fats on tumor progression.
Co-authors of the study were Raymond R. Tjandrawinata, PhD, of UCSF, Chai-Fei Li, BA, of SFVAMC, and Sina Sayyah, BA, of SFVAMC and UCSF.
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