BY KRISTIN WEIDENBACH

Researchers at the School of Medicine have discovered that a perennial herb used by the Chinese for hundreds of years to relieve rheumatoid arthritis symptoms has much more far-reaching medicinal qualities. The scientists found that the active component of the herb is a drug that is able to suppress an overactive immune system, prevent inflammation and kill cancer cells.

"This is a remarkable drug that could have a remarkable future," said Peter Kao, MD, PhD, assistant professor of pulmonary and critical care medicine and leader of one of two Stanford research studies on the drug. Kao's results and those of Glenn Rosen, MD, also an assistant professor in the department and lead researcher of the other study, were published in the May 7 issue of the Journal of Biological Chemistry.

People have known for 20 years that preparations from Tripterygium Wilfordii hook, a vine that grows in Southern China, have medicinal properties, but the way that the herb worked inside the body was not previously known, said both researchers. Using a pure preparation of triptolide, the active compound within the plant, the Stanford scientists have found that the drug exerts its effects by preventing activation of a DNA-binding protein, NF-KB, after it has partnered with its DNA target. This protein is a pivotal molecule that, once active, escalates an immune response by switching on other immunologically important genes. Figuring out exactly how the drug works on a molecular scale has assisted the two research teams in their efforts to determine the cause of the biological effects valued by Tripterygium users.

Dampening the immune system

Kao's group studied interactions between triptolide and other immunologically significant molecules and genes. His lab focuses on drugs known as immunosuppressants. These are drugs that rein in the cells of the immune system and prevent them from inappropriately attacking other cells of the body, as in the case of autoimmune diseases, or attacking cells that have been therapeutically introduced into the body, as in the case of organ transplants. Kao and his colleagues have found that the way triptolide tempers the immune system is completely different than the way traditional immunosuppressants, such as cyclosporin A and FK506, work. These drugs are prescribed to transplant patients to prevent their immune systems from rejecting a new kidney, heart or bone marrow.

Theoretically, these immunosuppressants can also be given to people suffering from autoimmune or inflammatory diseases where the immune system has gone awry. In practice, however, the severe adverse side effects of these drugs prevent their use in patients whose conditions are not life threatening. Because triptolide works in a different way, it may prove to be a useful alternative.

"Our work shows that [triptolide] is more potent than more traditional immunosuppressants such as cyclosporin and FK506," said Kao. He sees promise in using triptolide to temper the immune system and treat patients suffering from graft vs. host disease, inflammatory diseases like rheumatoid arthritis, and autoimmune diseases like multiple sclerosis.

An anti-cancer weapon

Rosen's determination of the tumor-killing properties of triptolide was more serendipitous. "We were trying to find ways to improve the ability to kill solid tumor cells like those found in the breast, lung and colon," said Rosen, who was primarily searching for agents that would augment killing of tumor cells by a class of compounds related to tumor necrosis factor (TNF). The new drug, triptolide, cooperates with TNF to cause cancerous cells to die. But Rosen and his colleagues soon discovered that triptolide is also capable of killing tumor cells on its own.

"Some tumor cells are susceptible on their own to triptolide or members of the TNF family but those that are resistant to one or the other can be made susceptible to the combination," said Rosen.

Triptolide and TNF-like compounds kill tumor cells by forcing them to commit suicide ­ a process known as apoptosis, according to Rosen. However, TNF and related molecules are themselves toxic to cells and can cause nasty side effects in patients. Because triptolide does not activate the NF-KB molecule, these side effects are expected to be greatly reduced in cancer patients treated with the herbal drug, he said.

Rosen's optimism about the drug is bolstered by the fact that triptolide, like the popular anti-cancer drug taxol, which comes from the bark of the Pacific Yew tree, kills cancer cells independent of the p53 gene. Chemotherapy to treat solid tumors is often hindered because cancer cells frequently become resistant to the drugs being used. A common cause of this drug resistance is changes to the p53 tumor suppressor gene. By causing tumor cells to die in a p53-independent way, drugs like taxol and triptolide are able to kill cells from cancers that are found to be resistant to other chemotherapy agents.

Rosen's research team includes Kao; Wen-teh Chang, PhD; Kye Young Lee, PhD; and Daoming Qiu, PhD. Scientists who collaborated on Kao's study include Qiu; Guohua Zhao, PhD; Yosuke Aoki, PhD; Lingfang Shi, PhD; and medical school graduate students Anne Uyei, Saman Nazarian and James Ng.

The pure preparations of triptolide used in both studies were provided by Pharmagenesis, Inc., of Palo Alto, Calif. Rosen's study was supported by a California Breast Cancer Research Grant and gifts from Pharmagenesis and Jan DiCarli. Funding for Kao's study was provided by grants from the National Institutes of Health and gifts from Pharmagenesis and the Donald E. and Delia B. Baxter Foundation. SR

