July 21, 2003 ATLANTA - The beloved southern magnolia, state flower of Louisiana and Mississippi, could provide more to cancer patients than shade and pretty flowers. A team of scientists at Emory University School of Medicine has discovered that seed cones from magnolia trees contain substances that inhibit the growth of new blood vessels. The active ingredient in the magnolia cones inhibited the growth of blood vessel endothelial cells in the laboratory and cut tumor growth in half in experiments in mice. Researchers have been interested in this class of compounds, called angiogenesis inhibitors, for the last several years, and clinical trials are just now assessing their effectiveness against various kinds of cancer.
The team's research was published in the Journal of Biological Chemistry online on June 19. The research was performed in the laboratory of Jack Arbiser, MD, PhD, assistant professor of dermatology at Emory School of Medicine and a faculty member in the Winship Cancer Institute. Lead author was Xianhe Bai, PhD, Emory dermatology postdoctoral fellow. Collaborators include investigators from the University of North Carolina, Dana Farber Cancer Institute, Northwestern University, and Humboldt University in Berlin.
Tumors, once they begin growing, can't continue to grow past a certain size without the oxygen and nutrients that blood vessels provide. The most dangerous tumors secrete signals that tell the body to grow new blood vessels toward them. Angiogenesis inhibitors are designed to stop those signals from being received, and come in various forms. For example, the biotechnology firm Genentech's Avastin™, recently fast-tracked by the FDA for approval, is an antibody against a protein secreted by tumors –– vascular endothelial growth factor (VEGF). Recent clinical trials have demonstrated Avastin's effectiveness, in combination with chemotherapy, against colon cancer. Dr. Arbiser had previously developed a method for screening mixtures of compounds extracted from natural sources for their ability to inhibit blood vessel growth. The magnolia tree is one of many possible sources of anti-angiogenic compounds evaluated by his laboratory , including curcumin from the turmeric plant, and derivatives from mate tea.
The investigators separated the natural magnolia mixture chromatographically and tested the fractions for their ability to prevent the growth of an endothelial cell line in culture. Endothelial cells make up the walls of blood vessels. They identified honokiol, a compound previously studied by Japanese researchers in herbal medicines, as the active component of the magnolia extract. Honokiol reduced the growth of endothelial cells by driving them into apoptosis, a self-destruction program activated by cells when their growth signals are disrupted. Importantly for the specificity of its anti-tumor activity, honokiol inhibited the growth of endothelial cells more than other kinds of cells. In mice inoculated with tumor-promoting cells, honokial reduced tumor growth by 50 percent over a control group of mice. Now, Arbiser's laboratory is working to more precisely determine the mechanism by which honokiol affects endothelial cell growth. The Emory team found that honokiol acts within the cell to stop growth signals from VEGF being heard. Dr. Arbiser says: "We want to know the direct target in the cell –– what honokiol binds to." Honokiol may also act by activating a natural tumor defense, stimulating the production of a protein within the body that induces suicide by tumor cells.
"Most successful cancer drugs have more than one direct target," says Dr. Arbiser. "An example is Gleevec, Novartis's treatment for chronic myeloid leukemia, which was designed to target a growth-regulating enzyme critical for that form of cancer and later found also to inhibit similar emzymes as well. Honokiol could be the same way, in that it affects two aspects of tumorigenesis." Honokiol is the active ingredient in a Japanese herbal medicine, saiboku-to, and is traditionally consumed as a tea thought to have anti-anxiety effects. Although drinking the tea seems safe, more testing needs to be done on the higher doses needed for anti-tumor therapy, Dr. Arbiser says. Also, he points out, honokiol shows promise as a drug because in mice it appears not to be excreted or broken down by the liver too quickly. But it is too soon at this point for clinical trials. "We need to investigate the pharmacokinetics in larger animals first, in a collaboration." Dr. Arbiser says.
If further research on honokiol looks promising, a pharmaceutical firm probably wouldn't need to extract large quantities of magnolia cones. "Honokiol is easier to synthesize than other cancer drugs, and we've been looking into the best ways to synthesize honokiol and its derivatives in large quantities," Dr. Arbiser says. His team is collaborating with organic chemists at Emory and at the University of Georgia, and looking at the pharmacological properties of molecules related to honokiol.
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