A milliliter of sea water can contain a million microorganisms. A deep sea sediment sample can harbor up to a billion organisms. Some may hold clues to preventing cancer, yet few are cataloged. So John Pezzuto and a small research team screen thousands of samples per year in a state-of-the-art laboratory at University of Hawaiʻi at Hilo College of Pharmacy.
Called chemoprevention, the concept is both old and new. Scientists have long known that certain natural substances seem to prevent or delay certain types of cancer in large populations, yet most medical treatment to date is reactive rather than preventive, with limited success in improving survival rates or longevity.
Pezzuto would like to see cancer care catch up with the dramatic strides made in treatment and prevention strategies for heart attacks, stroke and other leading killers over the past 30 years.
Pezzuto is dean of the pharmacy school and principal investigator on a $6.8 million grant from the National Cancer Institute that involves researchers at Purdue University, Scripps Institution of Oceanography, University of Illinois at Chicago and University of Alabama at Birmingham.
Team members divide the tasks—from sample collection to basic screening and isolation of bioactive compounds to testing against various cancer types for chemopreventive characteristics—an approach they call activity-guided fractionation. Collectively, they represent the largest chemopreventive program in the world.
The multi-step screening process utilizes in vitro tests—many developed by team members—designed to detect cancer prevention compounds. Researchers closely monitor a continuous purification process designed to isolate the most active agents. They then use mass spectrometry, x-ray crystallography and other molecular imaging techniques to visualize and study the structure of molecules in the compound, looking for those that are likely to be chemopreventive.
Chemical compounds that show strong anti-cancer activity in these assays may induce the synthesis of enzymes in the human body that could prevent the oxidative attack on normal cells and transformation of normal cells into cancer cells. Many different assays are used to monitor cancer fighting potential. Drawing on a decade of research and an 1880 logic tool called a Venn diagram, Pezzuto and his colleagues can ascertain the likelihood that an anti-cancer agent will be effective in animal models relatively quickly. Similar research programs in countries including Thailand, Korea, Brazil and Germany are using their approach.
Turning to Mother Nature for anti-cancer drugs is not novel. Of the 140 anti-cancer agents awarded U.S. Food and Drug Administration approval from 1940 through 2002, more than half were derived or made directly from natural sources. Taxol, perhaps the most successful anti-cancer agent in modern pharmaceutical history, is derived from the bark of the Pacific yew tree.
Epidemiological research has also identified a number of likely chemopreventative compounds found in common foods. Those include sulforaphane and phenethyl isothiocyanate (cruciferous vegetables), epigallocatechin-3-gallate (green tea) and curcumin (turmeric), among others.
Pezzuto and his team were the first to identify the anti-cancer potential of reservatrol, a compound found in red wine and other foods. A number of biotech startups are developing products around reservatrol.
Several years ago, Pezzuto’s group turned their focus to the marine environment. With much greater biodiversity, the seas provide a much greater pool of potential drug compounds. The group has yet to identify a clear winner from their marine organism samples, but Pezzuto remains optimistic.
Equally important, the research fills a gap where traditional pharmaceutical research fails to tread. Says Pezzuto, “It’s risky for drug companies to predict ultimate success and approval. So they are increasingly averse to this type of research. Our greatest hope is, working through the National Cancer Institute, some of our findings will be picked up by other labs or drug companies and they will carry our discoveries into the FDA approval process and then onto the shelves and into the hospitals.”
And the intellectual property potential isn’t limited to the molecular structures found in nature. Compounds that show initial promise can be tweaked for more powerful bioreactivity.
“The joy of natural product research is you can never predict from the beginning the chemical that comes out in the end,” says Pezzuto, who is listed as co-inventor on several patents. Even the assays developed by the team to gauge compounds’ potential can become licensed technologies.
This article adapted from the UH research magazine Kaunānā.
Other UH efforts explore natural products
The effort to identify beneficial compounds from nature isn’t limited to UH Hilo.
Three of the five organic chemists on UH Mānoa’s 11-member Department of Chemistry faculty focus on bioorganic and natural products chemistry, with emphasis on the isolation and identification of antitumor compounds that originate in algae, sponges and other marine organisms.
They are department Chair Thomas Hemscheidt, who specializes in biosynthesis and isolation of natural products from plants and fungi; organic group leader Marcus Tius, who works to improve organic synthesis methodologies; and Assistant Professor Philip Williams, who identifies and evaluates chemical compounds from marine sources as potential drug leads for the treatment of cancers and Alzheimer’s Disease.
Tius also leads the Natural Products and Cancer Biology Program at the UH Cancer Center. Formally organized in 1990, it brings together 25 faculty from the Mānoa and Hilo campuses in a multidisciplinary research/drug discovery group that works on acquisition of new, untested source material for screening; development and implementation of innovative mechanism-based, cancer-relevant in vitro and cell-based assays; isolation and identification of active compounds; and detailed pharmacological investigation, definitive in vivo evaluation and elucidation of relevant molecular mechanisms.
Researchers partner with private industry to translate laboratory research results into clinical trials. (An article on the work of group member André Bachmann appears in the April 2010 issue of Mālamalama.)
Even Windward Community College has gotten into the natural products act. Ethnobotanist Inge White established the Bioprocessing Medicinal Garden Complex in June 2007 to train students for biotech jobs and prime them for advanced scientific study.
Her students learn how to analyze plants for medicinal properties and create products to deliver the benefits. Their work on honohono grass is described in the July 2010 Mālamalama Online.