October 1, 2004

U-M researchers show cottonseed drug boosts cancer treatment in mice

ANN ARBOR, MI - A drug refined from cottonseed oil and previously tried and abandoned as a male contraceptive could boost the effectiveness of treatment for prostate cancer and possibly other common cancers as well, according to new research from the University of Michigan Comprehensive Cancer Center.

Results of the study will be reported Oct. 1 at the Symposium on Molecular Targets and Cancer Therapeutics in Geneva, Switzerland. The symposium is sponsored by the European Organization for Research and Treatment of Cancer, the National Cancer Institute and the American Association for Cancer Research.

The U-M team demonstrated that a potential small molecule inhibitor of Bcl-2/xL proteins can boost the effectiveness of radiation therapy and chemotherapy. The researchers showed that the molecule, (-)-gossypol (minus gossypol), inhibited the function of Bcl-2/xL and made the cancer more sensitive to radiation therapy in human prostate tumors in mice.

The study demonstrates for the first time that (-)-gossypol enhances the anti-tumor efficacy of radiation therapy both in vitro and in vivo with increased induction of apoptosis, or programmed cell death.

“The significance of this is that anti-apoptotic proteins Bcl-2 and Bcl-xL are over expressed in many cancers, making them resistant to drug and radiation treatment. So, it is not just prostate cancer that our findings are relevant to, but also other cancers with BcL-2/xL expression, such as those of the lung, breast, ovary, pancreas, skin, brain and head and neck, where (-)-gossypol may also sensitize cancer cells to chemotherapy or radiation,” says Liang Xu, M.D., Ph.D., research assistant professor in hematology and oncology at the U-M Medical School, who will present the study in Geneva.

Based on the cell and animal data, the (-)-gossypol form of the drug was likely to be more active than the same doses of natural gossypol used in previous studies. Furthermore, their cell and animal data show that (-)-gossypol would make radiation and chemotherapy more powerful and overcome the resistance to drug and radiation treatment caused by high levels of Bcl-2/xL.

Gossypol was researched as a male contraceptive in China as long ago as 1929, but after large scale studies in the 1970s it was abandoned because some men remained infertile after stopping treatment. There were plans in Brazil in the 1990s to market the drug but these were shelved. In 1998 the World Health Organization said research on its use for contraception should be abandoned.

Gossypol is not the first drug investigated as a contraceptive to find a potential role in treating cancer. Tamoxifen was first developed as a female contraceptive and failed, only to become the world's most successful breast cancer drug.

Will gossypol follow in the footsteps of tamoxifen? “There is a lot of research still to do, but we certainly hope so,” Xu says. “The natural form of gossypol has been extensively tested in humans and is well tolerated for long-term use. If we use the more active form, (-)-gossypol, correctly and wisely – for example, in combination with radiation or chemotherapy – gossypol may soon find its new role in our fight against cancer.”

Xu says he hopes to see the findings clinically tested soon and a Phase I trial is planned.

The research team is led by Marc Lippman, M.D., John G. Searle Professor and chair of internal medicine, and Shaomeng Wang, Ph.D., associate professor of internal medicine and co-director of the U-M Comprehensive Cancer Center Experimental Therapeutics Program, in collaboration with Theodore Lawrence, M.D., Ph.D., Isadore Lampe Professor and chair of Radiation Oncology.

Funding for the study was from the U.S. Department of Defense and the National Cancer Institute.

Contact: Nicole Fawcett

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