New York /PSA Rising/ October 5, 2004 — Gossypol, a drug made from a toxic yellow pigment in cottonseed, for about a decade has been tested for use against prostate and other cancers.
Gossypol in cotton is a natural toxin present in the plant that protects it from insects. Its name is derived from the scientific name of cotton ( Gossypium spp.) and phenol, its main chemical structure.
Cottonseed can poison cattle yet gossypol is an old, abandoned male contraceptive used in China in the 1920s. After studies in the 1970s it was abandoned because some men remained infertile after stopping treatment and some developed hypokalemia (potassium shortage in the blood, which can lead to serious heart problems). Although in 1998 the World Health Organization said research on its use for contraception should be abandoned, Chinese researchers are still testing low-doses.
New interest has developed in gossypol as an anti-cancer drug. Gossypol is able to inhibit growth of a wide range of cancer cells both in a lab dish (in vitro) and in mice and other lab animals (in vitro). A study in Ohio in 1996 of the effect of gossypol on the growth of human androgen-independent prostate cancer cell line (PC3) found that gossypol "is a potent inhibitor of prostate cancer cell growth."
Natural gossypol (GP) is made up of two mirror image molecules (enantiomers) — (+)GP (plus gossypol) and (-)GP (minus gossypol). Tests on breast cancer cells have shown that (-)GP is the more potent inhibitor of cancerous breast cell growth (Anticancer Res. 2002 Jan-Feb).
Now researchers at the University of Michigan Comprehensive Cancer Center say that minus gossypol (-)GP inhibits the function of Bcl-2/xL in human prostate tumors implanted in mice and makes the cancer more sensitive to radiation therapy and chemotherapy. The drug increased 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.
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, 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 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.
Results of the Michigan study were reported Oct. 1 at the Symposium on Molecular Targets and Cancer Therapeutics in Geneva, Switzerland. The symposium is sponsored by three major cancer organizations: European Organization for Research and Treatment of Cancer, the National Cancer Institute and the American Association for Cancer Research.
Funding for the study was from the U.S. Department of Defense and the National Cancer Institute.
The inhibitory effects of gossypol on human prostate cancer cells-PC3 are associated with transforming growth factor beta1 (TGFbeta1) signal transduction pathway.
Jiang J, et al. Laboratory of Reproductive and Molecular Endocrinology, College of Veterinary Medicine, The Ohio State University, USA.
Anticancer Res. 2004 Jan-Feb;24(1):91-100.
Inhibition of human prostate cancer cells growth by gossypol is associated with stimulation of transforming growth factor-beta. Shidaifat F, et al.
Cancer Lett. 1996 Oct 1;107(1):37-44.
Low dose gossypol for male contraception GU Z- P, et al, Asian J Androl 2000 Dec; 2: 283-287
This article edited by J. Strax, Oct 5 2004