New research has opened up the prospect that gossypol – a drug refined from cottonseed oil and previously tried and abandoned as a male contraceptive – could boost the effectiveness of treatment for prostate tumours and possibly other common cancers as well.
Dr. Liang Xu, a research assistant professor at the University of Michigan, reported today (Friday 1 October) to the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva that gossypol has been shown by many groups to have anti-tumour activities.
But his team, under the leadership of Dr Marc Lippman and Dr Shaomeng Wang at the University’s Comprehensive Cancer Center, has now demonstrated that a potential small molecule inhibitor of Bcl-2/xL proteins can boost the efficacy of radiotherapy and chemotherapy. They showed that the molecule, (-)-gossypol (minus gossypol), inhibited the anti-apoptotic function of Bcl-2/xL in cells, and increased induction of apoptosis (programmed cell death) and made the tumours more sensitive to radiotherapy in human prostate tumours in mice. The study demonstrates for the first time that(-)-gossypol enhances the anti-tumour efficacy of radiation therapy both in vitro and in vivo with increased induction of apoptosis.
Dr. Xu explained: "The significance of this is that Bcl-2 and Bcl-xL proteins 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 sensitise cancer cells to chemo/radiotherapy."
He said that based on their 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 radiotherapy 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 although the results were not published until 1957, 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 Organisation said that 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," said Dr. Xu. "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 and/or chemotherapy – gossypol may soon find its new role in our fight against cancer."
Dr. Xu wishes to see the findings clinically tested soon and a Phase I trial is planned.