Indiana University Research & Creative Activity

Humanities, Then and Now

Volume XXIX Number 1
Fall 2006

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feverfew flowers
Photo by David Smith

Headache Herb May Boost Cancer Survival

Drug development has produced many tales of important pharmaceuticals that originate in plants. Now scientists at the Indiana University School of Medicine want to write another, hoping to turn an extract from feverfew--an herb traditionally used as a treatment for migraine headaches--into a new tool to fight cancer.

The compound, parthenolide, may be a key to reducing the spread (metastasis) or the recurrence of several types of cancer, including breast, prostate, lung, bladder, leukemia, and myeloma.

It's shown great promise in the lab in cell cultures and mice, and now, the first tests in humans are on the horizon. Those tests would be a big step along a path that started some seven years ago, when Harikrishna Nakshatri, associate professor of surgery, biochemistry, and molecular biology, and Marian J. Morrison, an investigator in breast cancer research, discovered that parthenolide could block the activity of a protein called NF-kB in breast cancer cells.

Scientists have been interested in NF-kB for a long time because it plays an important role in regulating cell growth. It's a transcription factor, meaning that its job is to regulate gene activity. In particular, NF-kB promotes the production of proteins that block cell death. In moderation, that's a good thing, but when NF-kB becomes overactive, cancer cells become resistant to chemotherapy drugs.

Nakshatri discovered that when he treated breast cancer cells in the laboratory with parthenolide, they were much more susceptible to a compound commonly used to fight breast cancer. Subsequent experiments in mice showed that neither parthenolide nor a chemotherapy drug alone provided any survival benefit. But when they were combined, there was a significant increase in survival, he says.

Nakshatri and Christopher J. Sweeney, associate professor of medicine and associate director of clinical research for the IU Cancer Center, are collaborating on the parthenolide testing, as well as working on various projects with IU faculty members including Rafat Abonour, associate professor of medicine in hematology/oncology and the school's associate dean for clinical research, and Attaya Suvannasankha, assistant professor of clinical medicine. Oral forms tested in mice produced increased activity of chemotherapy in breast cancer and prostate cancer and of hormonal therapy in prostate cancer.

While results in the lab have been promising, Nakshatri and Sweeney have had to overcome a delivery hurdle--parthenolide is not highly soluble in water. As a result, even though it showed promise in the mouse testing, the amount of drug entering the bloodstream was not at optimum levels.

They turned to Peter Crooks, a medicinal chemist, and Craig Jordan, a molecular biologist, at the University of Kentucky College of Pharmacy, who made and tested a version of parthenolide with a slight structural modification, resulting in a water-soluble form that maintains the same anti-cancer activity.

Sweeney says the final steps for sending a proposal for Phase 1 clinical trials to the U.S. Food and Drug Administration are being completed. This trial would test the analogue of parthenolide alone in patients who already have been treated for cancer, evaluating side effects and documenting how much of the drug gets into the bloodstream.

The next trial, which Sweeney dubs Phase 1B, would test the parthenolide analogue in combination with chemotherapy drugs to determine appropriate dosage levels. A later Phase 2 trial would begin to evaluate the effectiveness of the parthenolide analogue alone and in combination with chemotherapy in several types of cancer, probably prostate and breast cancer, myeloma, and leukemia, says Sweeney.

Sweeney is naturally cautious in predicting the possibilities for parthenolide, noting that new drugs have a one-in-ten chance of making it from a Phase 1 trial to the market.

But if Sweeney's team beats the odds, doctors will have a new tool to fight cancer because IU scientists saw potential in a simple flowering herb.

--Eric Schoch