Arid Land Crop Plants with Anticancer Activity

Research Year: 
2010
Issue: 

The powdered roots and/or extracts derived from roots of the winter cherry plant—Withania somnifera (L.) Dunal—have been used for more than 3,000 years in India as a general tonic to build stamina, improve mental concentration, relieve stress and enhance health. Commonly known as “ashwagandha” in Ayurvedic medicine, scientific tests on the preparation have shown that it has anti-inflammatory, cardio-protective, antioxidant and antitumor properties, among others. Withania is widely cultivated for commercial use in its native India, and also in the Middle East and in North America. Ashwagandha is sold as a dietary supplement in the United States and Europe. The compound withaferin A, scientifically studied since the 1960s, seems to play the largest role in the plant’s anticancer effects by reducing tumor mass and preventing the growth of blood vessels that make a tumor malignant. It also shows promise in treating Alzheimer’s and Parkinson’s diseases.

Description of Action: 

University of Arizona scientists at the Southwest Center for Natural Products Research and Commercialization (or Natural Products Center), in collaboration with the Whitehead Institute at the Massachusetts Institute of Technology, have discovered a second form of withaferin that has identical functions in a less potent, slower-acting form that might be used as a “prodrug,” or drug precursor in the pharmaceutical industry. The UA team used an entirely nontraditional method—aeroponics—to produce bulk amounts of withaferin A needed for biological evaluation. In aeroponics, plants are set over enclosed chambers where their suspended roots are misted with water and nutrients, instead of growing in soil. The UA College of Agriculture and Life Sciences provided funding for the project, along with the USDA.

Similarly, in a collaborative project with Nuvogen Research, a small Tucson-based company, a lead compound isolated from the Natural Products Center’s library of extracts from Sonoran Desert plants has shown activity against prostate cancer. A provisional patent application has been filed for this discovery and the compound, called PCa (prostate cancer a), is currently being tested in animal models. The arid land plant containing this compound is rare and difficult to cultivate, however Natural Products Center scientists have been able to grow this plant in the greenhouse using the same innovative aeroponic technology as described for winter cherry. They are obtaining the promising compound in large quantities, toward the goal of yielding enough of the compound required for preclinical and clinical evaluation.

Withaferin A and PCa are just two of hundreds of such compounds the Natural Products Center has isolated, characterized and evaluated since its inception in 1996. The center searches for compounds in desert plants and their associated microorganisms that can improve human health and also be developed as potential industrial products in Arizona. The work focuses on economical methods for producing and structurally diversifying natural products from plants; natural products make up 60 percent of the anticancer agents that are commercially available or are in late stage clinical development.

Impact: 

Using the aeroponic system for cultivation yielded Withania plants with five times the biomass produced in soil-grown plants. The nontraditional method produced more than 20 grams of the active ingredient withaferin A in a single greenhouse operation in Tucson. Withaferin A normally costs about $195 for just 10 milligrams, thus the potential value of the test crop was about $390,000. And although Withania usually takes two to three years to mature to sizeable roots to be commercially viable, it took just six to nine months in this study.

Not only did the aeroponic method yield bigger plants faster, with more withaferin A than usual, it also unexpectedly stimulated the plants to produce large amounts of a new natural product—a water soluble sulfate form of withaferin A. Upon testing, this new form demonstrated the same bioactivity as withaferin A. The researchers found it was able to inhibit the proliferation and survival of tumor cells, disrupt tumor formation and induce the healthy cells’ heat-shock response to reduce stress and increase survival. The difference is that the sulfate form of withaferin A is slower acting and water soluble, and can be converted to withaferin A in cell culture media. The researchers, expecting that this withaferin A analog will convert to its active form when metabolized in the body, are pursuing further testing in animal models. The patent will be held by the UA and MIT.

The work on the compound active against prostate cancer focuses on late stage Hormone Refractory Disease (HRD), for which no effective therapies currently exist. This stage kills more than 20,000 men per year in the United States alone. In addition to the potential for saving and/or prolonging thousands of lives, the direct target, a substance called PCa (prostate cancer a), represents a large market—greater than $3 billion—that remains focused on hormone ablation therapy. Many companies are active in this area and will be potential partners for commercial development.

Conact Name: 
Leslie Gunatilaka
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