Cottonseed compound could help in prostate cancer
could find a new application as a cancer drug after failing to
prove itself as a male contraceptive.
Gossypol is being tested by researchers at the University of Michigan in the US as a potential treatment for prostate cancer.
The compound emerged as a possible male contraceptive in the 1970s, after it was found that people in China using raw cottonseed oil for cooking found it difficult to conceive children. This prompted the Chinese government to start a major trial of the compound as a male contraceptive that could help the country in its efforts to curb population growth.
Unfortunately, these studies found that gossypol acted all too well, with men taking the refined active ingredient experiencing irreversible declines in fertility. And adding to the problems were side effects, notably a decline in potassium levels among users that could lead to muscle weakness and even paralysis. The Chinese development effort was shelved in 1986, and in 1998 the World Health Organisation said that research on its use for contraception should be abandoned.
Liang Xu, a research assistant professor at UoM, told the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva last week that gossypol has been shown by many groups to have anti-tumour activities, but concern over side effects held back its development as a cancer drug.
His team, under the leadership of Marc Lippman and Shaomeng Wang at the University's Comprehensive Cancer Centre, has now demonstrated that a small molecule derived from gossypol that acts by the same mechanism of action - inhibiting a protein family called Bcl-2/xL - can boost the efficacy of radiotherapy and chemotherapy.
They showed that the molecule, (-)-gossypol, inhibited the ability of Bcl-2/xL to black the process of programmed cell death or apoptosis in cells. Apoptosis is the mechanism by which the body kills off unwanted cells, for example lymphocytes that have come to the end of their useful life, and is also a primary means of getting rid of cancerous cells. A mutation in Bcl/2-xL can prevent this protective mechanism from occurring.
In animal experiments, (-)- gosspypol increased apoptosis in human prostate tumours implanted into mice, and made them more sensitive to radiotherapy.
Dr Xu said that 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."
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.
Also, as a small molecule, the compound should be orally bioavailable and so relatively easy to develop and deliver to patients. Other Bcl-2-targetting treatments in development tend to rely on larger compounds, such as oligonucleotides, which present delivery difficulties.
Gossypol is not the first drug investigated as a contraceptive to find a potential role in treating cancer.
Tamoxifen - an anti-oestrogen compound - was first developed as a female contraceptive and failed, only to become the world's most successful breast cancer drug, sold by AstraZeneca (and Zeneca and ICU before that) as Nolvadex. It is now available as a generic and remains one of the most widely-used drugs in breast cancer.
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.
A Phase I trial of (-)-gossypol is at the planning stage, he added.
