Gossypol (棉酚) for cancer

This is an unusual one because Gossypol it is not yet approved for us in the US or Europe.  However, notwithstanding approvals or not, it is developed mainly as a male contraceptive.  As such its potential application as a cancer therapy is vastly interesting and can loosely be classified as “off-label”.

What is Gossypol?

Gossypol is a polyphenolic compound isolated from the seeds, stems, and roots of the cotton plant (genus Gossypium, family Malvaceae; pls feel free to search under these in our Asian Anti-cancer Herbs database for more research data). It was discovered during the late 1960s, when people in rural China complained of fatigue attributable to exposure to cotton seed oil.  Years later, many couples had fertility problems despite reduced exposure to the oil. The finding that exposure to cotton seed oil was related to lowered sperm counts in men exposed led to the hypothesis its active ingredient Gossypol could be used as a male fertility-control agent, which is gossypol’s main pharmacologic application now.   Of course, a natural line of thinking with an agent that may inhibit dividing or growing cells such as sperm would lead one to query if it may have chemotherapeutic properties that may be applicable in cancer, so this is where the idea of Gossypol for cancer arises.

And where is the evidence?

a) In Vitro (cellular evidence):

Russian scientist Vermel EM et al. reported on the anti-cancer activity of gossypol in animals as early as 1963 and Jolad SD et al reported in 1975 (J Pharm Sci 64:11, pp.1889-1890, 1975) that Gossypol extracted from Montezuma speciosissima Sesse and Moc. demonstrated tumor-inhibiting properties in the P-338 lympocytic leukemia test system (3PS).

Gossypol promotes apoptosis of breast, bladder, lymphoma, leukemia (CML and CLL), myeloma, prostate, colorectal, alveolar cell lung, glioma, pancreas, melanoma, nasopharyngeal, and head and neck squamous cell cancers.  A preponderance of the research reported on efficacy against hematologic cancers and prostate cancer.

Gossypol was known in the 1990s as a compound which depleted cellular energy by inhibition of intracellular dehydrogenases. More recently, (-)-Gossypol, now understood to be a natural BH3 mimetic, is found to be a small-molecule inhibitor of Bcl-2/Bcl-xL/Mcl-1, possibly exerts its antitumor activity through inhibition of the antiapoptotic protein Bcl-xL accompanied by an increase of proapoptotic Noxa and Puma (Meng Y, et al. Mol Cancer Ther, 7:7, pp. 2192-2202, 2008). A separate line of evidence suggests that Gossypol may exert its apoptotic effects via downregulated expression of NF-kappaB-regulated gene products, including inhibitor of apoptosis protein IAP-1, IAP-2, and X-linked IAP (Moon DO, et al. Cancer Lett 264:2, pp.192-200, 2008).

It is also known as a protein kinase C inhibitor.

Besides direct anticancer action, it enhances anti-tumor activity of chemotherapy against lymphoma, modulates multi-drug resistance gene expression in human breast cancer cells, and enhanced breast cancer sensitivity to Tamoxifen as well as Adriamycin.

In Vivo (animal evidence):

Testing of gossypol on tumor growth and the survival of 10- to 12-week-old BDF1 mice bearing injected mammary adenocarcinoma 755 (Ca 755) or P388 or L1210 leukemias was investigated and reported as early as 1985.

Gossypol enhances prostate cancer response to radiation therapy (mice), enhances chemotherapy against diffuse large cell lymphoma in WSU-DLCL2-SCID mouse model pre-clinical testing.

Many other reports of in vivo activity of Gossypol against transplanted tumors in rodents exists.

Clinical (human evidence):

Much clinical experience of Gossypol’s anticancer use and demonstration of its efficacy has been accumulating in the past 20 years.

One of the earliest trials was reported from the U.K. (Stein RC, et al. Cancer Chemother Pharmacol 30:6, pp. 480-2, 1992) where advanced cancer patients were given Gossypol, but benefit was not seen.

In 1993, the NIH published a trial of oral Gossypol using doses of 30-70 mg a day in metastatic adrenal cancer patients where 30% of eligible patients had some reponse to therapy (Flack MR et al., J Clin Endocrinol Metab 76:4, pp. 1019-24, 1993). A study was also carried out using low dose Gossypol of 10mg twice a day on adults with heavily pre-treated, poor prognosis recurrent malignant gliomas and found approximately 25% with some response including one patient who remained stable with improved quality of life for one and a half years. More importantly, toxicity was found to be mild.

Around the same time, a Phase I/II clinical trial of Gossypol against refractory metastatic breast cancer was carried out at Memorial Sloan-Kettering in New York  ( Van Poznak C, et al. Breast Cancer Res Treat, 66:3, pp. 239-248). Doses were in the 30-50mg per day range with 30% of patients experiencing fatigue, 15%, nausea/vomitting, and diarrhea in 10%.  Antitumor activity was seen with a 15% response/stability rate.

Significantly, long-term clinical remission of a patient with chronic lymphocytic leukemia using gossypol was reported. (Politzer, Phytomedicine 15:8, pp. 563-5, 2008)

So What’s new?

Gossypol is currently the only orally bioavailable pan-Bcl-2 inhibitor under clinical investigation.

In the US, phase I/II clinical trials are currently ongoing or planned with gossypol under the product code “AT-101” by Ascenta Therapeutics as an adjuvant therapy for human prostate cancer.  A small trial of the product in 23 men with prostate cancer who were chemo-naive but had rising PSA and who took 30mg of product for 21 out of 28 days over 20 to 24 weeks noted decreases in PSA parameters in some.  5 out of the 23 patients had to discontinue the drug because of gastrointestinal side-effects (ileus).  Last summer, Ascenta also presented preliminary data indicating that AT-101 has activity in combination with taxol and prednisone in advanced prostate cancer.

The biotech firm Bioenvision (now owned by Genzyme) was in collaboration with Bowman Research to develop a process to separate and purify more efficacious but less toxic iso-forms of gossypol, but the isoforms are not currently in the company’s development pipeline.

My Take

This is a fairly low toxicity and inexpensive natural derivative that can be used in combination with chemotherapy or other anti-apoptotic agents for a wide-range of cancers but appear especially promising for prostate, breast and B-cell hematologic malignancies.   The main concern here is side-effects which include fatigue, nausea/vomitting, diarrhea, and ileus.  Side-effects can be managed by individualized dosing and schedule adjustments. The long-term concern of infertility in males should be considered in young male patients.  The lack of bone marrow suppression makes it a good agent to combine with with chemotherapies.  The potential usefulness of an agent like this points the way to screen other anti-fertility herbs in traditional pharmacopoeias for other potentially useful anti-cancers.  Additionally, this interesting natural derivative has been demonstrating promise as an anti-HIV, as well as anti-malarial .  (More on the very interesting off-label potential of a whole range of anti-malarials against cancer in this blog in the near future, when I get to it) .  Your comments please !