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Stanford Report, January 16, 2002

Herb extract appears to trigger 'suicide' in cancer cells


People with cancer may find new hope in the form of an old Chinese herb. An extract of the herb, called triptolide, magnifies the effects of traditional chemotherapy — a discovery that earned a patent for Stanford researcher Glenn Rosen, MD. The drug is now in trials to test its safety in cancer patients.

"We are excited about the potential for [the extract] to help patients with solid tumors such as ovarian, breast, lung and colon cancer," said Rosen, who is an associate professor of pulmonary and critical care medicine.

Rosen said that the vine Tripterygium wilfordii has a long history in Chinese medicine. "In china they've been getting an extract of this herb for thousands of years to treat rheumatoid arthritis and other inflammatory diseases," Rosen said. In 1997, Rosen uncovered anti-cancer effects in addition to the herb's traditional use.

Since discovering triptolide's use in treating cancer, the question has been how the extract fights tumors. "We don't know exactly what it does, but we know some pathways that it affects," Rosen said. Those pathways turn out to be ones that are already of keen interest to cancer researchers.

One involves a protein called p53, which acts as a cellular inspector, examining the cell for mutations before allowing it to continue dividing. It works in part by activating another protein called p21, which halts cells before they divide in two.

Some chemotherapy drugs, such as doxorubicin used for treating breast cancer, take advantage of p53 and p21 to stop cancer cells from propagating, but Rosen points out one problem with this strategy. "If the cells stop dividing they can recover and then they can start to proliferate again," Rosen said.

It turns out that triptolide encourages a more permanent solution. When Ke Wei, MD, a postdoctoral fellow in Rosen's lab, exposed cancer cells to a combination of doxorubicin and triptolide, the cells entered a self-induced suicide rather than just pausing in their division. She discovered that cells treated with doxorubicin alone had high levels of p53 and p21, whereas cells treated with both drugs had dramatically lower levels of p21.

What's more, the doses Wei used of both drugs were so low as to be ineffective when she used either drug alone. "The ability for both compounds to work better than either alone at lower doses without increasing toxicity I think will be the major impact of this work," Rosen said. A low dose means fewer side effects such as nausea.

Palo Alto-based Pharmagenesis, where Rosen acts as a consultant, found similar results with a water-soluble form of triptolide. They had tested the compound in combination with low-dose chemotherapy on mice carrying tumors transplanted from humans. Based on the results in Rosen's lab and in mice, Rosen and Pharmagenesis received a patent for triptolide last November, and in December, Pharmagenesis began the first phase of testing the water-soluble form of the extract in humans. "This phase just examines safety and dosing," Rosen said. Within a year, Rosen hopes Stanford will be involved in testing the compound's usefulness in treating cancer patients.

The synergy between triptolide and chemotherapy relies on a functional p53. But many cancers develop mutations in the p53 gene, making them resistant to p53-dependant treatment. Rosen points out, however, that triptolide has potent cancer-killing properties of its own. "Triptolide uses the p53 pathway when it is present, but doesn't need it," he said.

It turns out triptolide interacts with a second pathway that researchers have been investigating for use in cancer treatment. This pathway involves a family of proteins called TNF (tumor necrosis factor). Although TNF can effectively kill cancer cells, it also activates an inflammation-inducing protein. The severe side effects associated with the protein make TNF a problematic treatment. However, when Rosen combines TNF with triptolide, inflammation from the protein all but disappears, and TNF becomes even more effective at driving cancer cells to, in effect, commit suicide. "Again, we see this at low doses," Rosen said. He is optimistic that triptolide may turn out to be a multi-use cancer-fighting agent, effective both in combination with traditional chemotherapy and in tumors that have become resistant to treatment.

The Tripterygium wilfordii vine has played a role in traditional Chinese medicine for thousands of years. Stanford cancer researchers believe it may enhance chemotherapy's positive effects.

Form of Chinese herb found to temper immune system and kill cancer cells (5/99)