Planting seeds for cancer research

Leslie Gunatilaka, PhD
Leslie Gunatilaka, PhD

Take a look outside. Where you may see a rocky landscape filled with prickly desert plants, one Arizona Cancer Center member sees a field of possibility.

Leslie Gunatilaka, PhD, looks at arid plants and the microorganisms that live in association with them for new cancer drugs and their drug targets.

As the director of the University of Arizona’s Southwest Center for Natural Products Research and Commercialization, known as the Natural Products Center, he and his team have discovered several compounds in desert organisms that can significantly inhibit the growth of tumors. They have also developed a new method to improve the production of natural products by using an innovative cultivation method.

“A lot of people think drugs come out of a test tube, but a little over 70 percent of cancer drugs come from natural sources,” said Dr. Gunatilaka, who visited traditional healers as a child in Sri Lanka and thus became interested in medicinal plant research.

Dr. Gunatilaka was involved in the National Cooperative Cancer Drug Discovery Group at Virginia Tech before coming to the UA in 1997. In 2002, he became the director of the Natural Products Center, which dedicates 90 percent of its efforts to cancerrelated research.

Arid-land plants are special because they have developed unusual adaptations to deal with extreme heat, sunlight and opportunistic pests, and they get a boost from some of the microorganisms living in them and around their roots. Natural Products Center scientists repeatedly extract and purify samples from desert organisms in search of the biological compounds, known as secondary metabolites, that help them survive and thrive in their harsh surroundings.

“We are starting with extracts containing hundreds of compounds and coming down to one or two compounds. It’s like looking for a needle in a haystack,” Dr. Gunatilaka said of finding a pure compound with cancer-fighting properties.

Recently his lab discovered something new about an old natural remedy. Withania somnifera, the winter cherry plant native to the deserts of India, Pakistan, the Middle East and Africa, has been used in traditional medicines for more than 3,000 years. A compound derived from the plant called withaferin A has been found to inhibit the formation and spread of tumors and increase healthy cell survival by inducing the heat-shock response.

Unfortunately, it has been difficult to produce the large quantities of withaferin A needed for biological research. When Dr. Gunatilaka first purchased the compound five years ago, he had to pay $195 for 10 milligrams.

“With natural products, the problem is quantity. If you want to do an animal study, you need gram quantities of the material,” he said. “That is why people like synthetic molecules, because when it’s synthesized, you can scale it up. But when you collect material from nature, it’s hard to obtain large quantities without ecological destruction.”

To solve this problem, he looked outside the field of cancer research – to agriculture. He began growing winter cherry plants using aeroponics, a successful food crop cultivation method that uses no soil but sprays plants’ roots with water and nutrients.

“With food plants, you are interested in biomass (the amount) and the quantity of secondary metabolite produced by a plant also depends on biomass, so I thought why not try?” he said.

The energy-efficient, water-efficient aeroponics technique resulted in plants that grew about five times larger and more than four times faster than if they had been grown in soil. They also produced a higher concentration of withaferin A. Now the Natural Products Center, the first to use aeroponics to grow plants for their potential cancer-fighting capacities, can easily produce more than 20 grams of withaferin A per harvest.

“The plants grow bigger and faster, and it’s not environmentally destructive,” Dr. Gunatilaka said of the new cultivation method.

The team also found that when grown aeroponically, the winter cherry plant produces large quantities of an entirely new watersoluble, sulfate form of withaferin A. The new compound is a prodrug — initial tests show it gets converted into the active form of withaferin A in cell cultures and animal models. Dr. Gunatilaka expects it will do the same thing when metabolized
in a human body.

“We found when we grow the plant aeroponically, it produces the prodrug,” he said. “It’s easier to administer because it’s water-soluble, and when it gets into the cell or culture medium, it converts into the drug.”

Natural Products Center scientists collaborated with researchers from the Whitehead Institute at the Massachusetts Institute of Technology on this project, so the patent application on the promising new prodrug is shared by the UA and MIT.

Dr. Gunatilaka continues to study withaferin A and its analogs with the hope that one of them will prove to be a novel anticancer drug. Because withaferin A targets heat shock proteins, the compound has many other potential applications. Thanks to his ability to produce large quantities of it, Dr. Gunatilaka has been able to provide withaferin A to Dartmouth College for a lung cancer chemoprevention study, Cornell University for Alzheimer’s and Parkinson’s studies and the University of Massachusetts for eye disease research.

As with all novel drugs, bringing a withaferin A analog to market could take 10 to 20 years and cost millions of dollars, said Dr. Gunatilaka. He now has three published patents and two patent applications under his belt, but none has made it to medicine cabinets yet.

“We are hoping that a withaferin A analog will be the one,” he said, “because there are a lot of people interested and involved.”