Blocking COX-1 slows tumor growth in mice

Blocking the COX-1 enzyme – not COX-2 – might lead to a way to prevent and treat the most common and fatal form of ovarian cancer, researchers at Vanderbilt University Medical Center reported this week.

The finding, that COX-1 inhibition slowed the growth of epithelial ovarian tumors in a mouse model of the disease, is surprising, said Sudhansu K. Dey, Ph.D., senior author of the paper and director of the Division of Reproductive and Developmental Biology in the Vanderbilt Department of Pediatrics.

Previous studies have linked high levels of another cyclooxygenase enzyme, COX-2, to colorectal and other cancers. “But this is the exception,” said Dey, also professor of Cell & Developmental Biology and Pharmacology.

“These results establish the foundation for further studies and clinical trials using the novel approach of targeting COX-1 for the prevention and treatment of ovarian cancer,” the researchers concluded.

Dey said further studies should be conducted to determine whether aspirin and other non-steroidal anti-inflammatory drugs, which block both COX enzymes, might improve treatment of epithelial ovarian cancer.

The study, posted Sunday on the Web site of the journal Cancer Research, was led by Takiko Daikoku, Ph.D., research assistant professor of Pediatrics at Vanderbilt.

According to the American Cancer Society, more than 22,000 women in the United States will be diagnosed with ovarian cancer this year, and more than 16,000 will die from the disease. Ovarian cancer is the fourth leading cause of cancer death in American women after lung, breast and colorectal cancer.

Eighty-five percent of human ovarian tumors arise from the epithelium or surface layer of tissue that surrounds the ovaries. While the incidence of ovarian cancer has declined recently, the death rate has not, in part because it is difficult to diagnose the disease in the early stages.

Several previous studies have reported high COX-2 levels in ovarian tumors. Most of these, however, used antibodies to detect COX-2 expression. “We now know that many of the commercially available antibodies cross react with both COX-1 and COX-2,” Dey said.

The Vanderbilt researchers used multiple techniques, and in 2003 reported that COX-1 was over-expressed and promoted the growth of blood vessels in human epithelial ovarian tumors.

A year earlier, Sandra Orsulic, Ph.D., and her colleagues at the Memorial Sloan-Kettering Cancer Center in New York reported that they were able to induce ovarian cancer in a mouse model by using a virus to deliver two cancer-causing genes into ovarian surface epithelial cells that lacked a tumor suppressor gene.

In the current study, the Vanderbilt researchers used Orsulic’s model to test whether celecoxib (Celebrex), a selective COX-2 inhibitor, and SC-560, an experimental drug that selectively blocks COX-1, slowed tumor growth when these cells were transplanted into mice.

They found that while Celebrex had little effect, the COX-1 blocker dramatically reduced tumor growth. The drug also blocked production by COX-1 of prostacyclin, a member of a family of potent, hormone-like substances called prostaglandins that play a role in a wide variety of physiological functions including pain, inflammation and, presumably, cancer.

Whereas prostacyclin is the predominant prostaglandin found in mouse ovarian tumors, another prostaglandin, PGE2, seems to be generated in higher quantities in human ovarian cancers. This suggests that it’s not the particular enzyme – COX-1 or COX-2 – but downstream factors, including prostaglandins, that initiate tumor growth, Dey said.

Last fall, for example, the Vanderbilt researchers reported that silencing a cellular receptor called PPARä interfered with the ability of PGE2 to promote pre-cancerous colon polyps in mice.

Other researchers who contributed to the ovarian cancer study were Dingzhi Wang, Ph.D., research associate professor of Medicine; Susanne Tranguch, graduate student in Cell Biology; Jason D. Morrow, M.D., director of Clinical Pharmacology; Orsulic, now at Massachusetts General Hospital; and Raymond N. DuBois, M.D., Ph.D., director of the Vanderbilt-Ingram Cancer Center.