Scientists at the University of Pittsburgh have discovered how a novel form of vitamin K exerts its cancer-killing effects in primary liver cancers, which are notoriously resistant to chemotherapy. The research results, published in the May issue of the Journal of Biological Chemistry, describe an important new way to treat, and possibly prevent, cancer by triggering apoptosis.
"Our finding is extremely important if we are to maximize the use of vitamin K compounds against cancer," noted Brian Carr, MD, PhD, FRCP, professor of surgery in the Thomas E. Starzl Transplantation Institute and director of the Liver Cancer Center at the University of Pittsburgh Cancer Institute (UPCI). "Through our ongoing research, we now know that the vitamin K compounds not only can kill liver cancers, but also can destroy other types of cancer in tissue cultures, including breast cancer and melanoma. They do so by a quite novel growth-regulating mechanism."
"One of the attractive features of this unique compound is that it appears to stop cancer cell growth without producing toxicity. We now are testing this compound against cancers in rats, and given positive results, we hope to begin clinical trials of this agent within 2 years."
The research team found that a vitamin K analog, compound 5 (Cpd 5), causes an imbalance in the normal activity of enzymes that control the addition or removal of small molecules called phosphate groups from selected proteins inside cells. Specifically, Cpd 5 blocks the activity of protein-tyrosine phosphatases, which normally remove phosphate groups from selected proteins inside liver cancer cells.
Compoun 5 does not, however, interfere with protein tyrosine-kinases, which add phosphate groups to these same proteins. The result is an excess of tyrosine-phosphorylated proteins, which trigger a variety of activities within cells. They exert anticancer effects by inducing apoptosis.
Liver cancer is thought to be one of the three most common cancers worldwide. The disease caused about 13,000 deaths in the United States in 1998 alone. Major causes of this cancer include infection with either hepatitis B or C or chronic alcohol(Drug information on alcohol) consumption. In the United States and other developed countries, liver cancer may be treated by resection or transplantation. Liver transplantation is costly, however, and often unavailable due either to the scarcity of donated organs or the advanced nature of the cancer at diagnosis.
"By providing this modified vitamin K to individuals at known risk of developing liver cancer, we might be able to reduce the incidence of this devastating illness. By treating liver cancer with this agent, we possibly could remove some individuals with this disease from transplant waiting lists, if it is as effective in humans as it is experimentally," said Dr. Carr.
Dr. Carr and his colleagues recently reported that Cpd 5 can inhibit liver regeneration in rats that had part of their livers removed. The animals suffered no toxic side effects.
The new vitamin K is not in clinical testing at present. For more information about ongoing clinical trials, patients and physicians can, however, contact the UPCIs Cancer Information and Referral Service by calling 1(800) 237-4PCI (4724) or (412) 624-1115 or by visiting UPCIs web site at http://www.upci.upinc.edu.