Archive for the ‘Natural Products’ Category

Gossypol, 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.

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.

Laboratory of Reproductive and Molecular Endocrinology, College of Veterinary Medicine, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA.

BACKGROUND: Racemic gossypol [(+/-)-GP], a naturally occurring polyphenolic yellow pigment present in cottonseed products, inhibits in vitro proliferation of Dunning prostate cancer cells (MAT-LyLu), human prostate cancer cells derived from a bone marrow metastasis (PC3), MCF-7 and primary cultured human prostate cells. (+/-)-GP also has the ability to inhibit the metastasis of lung and lymph nodes of the androgen-independent rodent prostate cancer cell line, MAT-LyLu, after implantation into Copenhagen rats. MATERIALS AND METHODS: The effects of (+/-)-GP on the proliferation of human prostate cancer PC3 cells were determined by thymidine incorporation assay and doubling-time (DT) determination. The mechanisms of action of (+/-)-GP on the proliferation of PC3 cells were determined by RT-PCR analysis, ELISA assay and Western blot analysis. RESULTS: The results show that (+/-)-GP caused reductions in DNA synthesis and prolonged the DTs in PC3 cells. RT-PCR and ELISA results show that (+/-)-GP elevate the mRNA expression and protein secretion of transforming growth factor beta1 (TGFbeta1) in PC3 cells. Consistent with these findings, (+/-)-GP has been shown to decrease the cyclin D1 mRNA expression and protein expression in PC3 cells. Furthermore, the growth inhibition of PC3 cells by conditioned media collected from the (+/-)-GP-treated-PC3 cells was completely reversed by addition of 25 microg/ml of mouse monoclonal anti-TGFbeta1, -beta2, -beta3 antibody, suggesting the involvement of TGFbeta1 in (+/-)-GP-induced growth inhibition of PC3 cells. CONCLUSION: These results indicate that the inhibitory effects of (+/-)-GP on the proliferation of human prostate cancer PC3 cells are associated with induction of TGFbeta1, which in turn influences the expression of the cell cycle-regulatory protein, cyclin D1, in prostate cancer cells.

“We’re 80 percent of the way there, but that’s not enough. Our research is continuing in Texas, Oklahoma, and California.”

Cottonseed may one day offer increased returns as a result of research efforts by Cotton Incorporated, says Bill Lalor, vice president of research for the producer-funded research/promotion organization.

“Most growers and ginners don’t see the very extensive marketing program we conduct for cottonseed, because much of the trade show, print, radio, and Internet promotion and advertising is directed to the major dairy areas,” he told members of the Southern Cotton Ginners Association at their annual meeting at Biloxi, Miss.

Seeking ways to increase cottonseed use by the dairy industry, Cotton Incorporated researchers developed the Easiflo process, which removes lint tags and applies a starch coating to the seed, enabling it to flow smoothly through handling and feeding equipment.

“This eliminates the problems of clogging that can happen with untreated cottonseed and gives it handling qualities equivalent to shelled corn,” Lalor said.

The cost is about $15 per ton, and three commercial plants using the Easiflo process are now in operation in Alabama, Mississippi, and Virginia, with a total capacity of about 150,000 tons per year.

The coating process has helped to reduce energy costs related to handling, has improved railcar loading operations, and has resulted in increased efficiency “which is essential to expanding these markets,” Lalor said. Also being evaluated is a module tamper device that enables more cottonseed to be loaded into railcars.

A spinoff of the Easiflo coating process is a powered roll gin stand, which has a computer-controlled feeding mechanism, that has resulted in a 20 percent to 30 percent increase in ginning rate, improved fiber quality, reduced seed coat fragments, and from 25 pounds to 40 pounds more fiber per bale, he said.

The Easiflo coating is also being evaluated for use on cotton planting seed. “We’re quite a ways from marketing it, but it is showing potential and we’ll be doing field plots in the 2002 season.” But, he said, studies show the coating doesn’t interfere with normal generation and allows for other additives to be applied to the seed.

Cotton Incorporated research to eliminate gossypol from cottonseed is continuing, Lalor said. “If we could get rid of gossypol, we could increase by 30 percent the amount of cottonseed that could be fed to cows. It would also open the market for hogs and other animals, which can’t handle gossypol at all. The potential for gossypol-free cottonseed is huge.

“We’re 80 percent of the way there, but that’s not enough. Our research is continuing in Texas, Oklahoma, and California.”

Lalor said Cotton Incorporated is cooperating with the National Cottonseed Products Association in a promotional program to boost the use of cottonseed oil for the restaurant and food processing trade.

“Unfortunately, the price of cottonseed oil is less than that of soybean oil right now, when it had sold at a premium. Olestra, which was based on cottonseed oil and was used in food products to reduce fat absorption in the body, hasn’t been a success, and the GMO controversy has had an impact.”

Cottonseed prices have increased “quite a bit” since the “terrible seed prices” of 1990-91, which prompted growers and ginners to urge the creation of a promotion program, Lalor said. “We feel the program has been reasonably successful.

Complaints continue, he said, about small seed size for many of today’s varieties.

“We’ve been impressing on breeders the importance of keeping seed weight per bale up; it has been falling over the last 10 years, particularly for varieties in California. But small seed size goes with high lint yield, so we have to decide which way we want it until we can achieve some genetic breakthrough.”

Seedling vigor can also be a problem, Lalor said, “because smaller seed usually aren’t as vigorous.”

Source: Southwest Farm Press

Laboratory of Reproductive and Molecular Endocrinology, College of Veterinary Medicine, Ohio State University, Columbus 43210-1092, USA.

Gossypol (GP), an antifertility agent in males, is also capable of inhibiting the proliferation of a wide range of cancer cells in vivo and in vitro. Thus, in this study we investigated the effect of GP on the growth of human androgen-independent prostate cancer cell line (PC3). The results showed that GP acts as a potent inhibitor of PC3 cells as determined by thymidine incorporation assay and flow cytometric analysis. Flow cytometry revealed that treatment of PC3 cells with GP resulted in a dose- and time-dependent accumulation of cells in the GO/GI phase with a concomitant decrease in cells progressing to the S and G2/M phase. These data support our thymidine incorporation results which indicated that GP is a potent inhibitor of PC3 cells. By ribonuclease protection assay, we also investigated the effect of GP on transforming growth factor-beta 1 (TGF-beta 1) gene expression in PC3 cells. Interestingly, the stimulatory effect of GP on TGF-beta 1 gene expression correlates well with its inhibitory effect on PC3 cell DNA synthesis and its ability to arrest cells in GO/G1 phase. Based on these data, it can be concluded that GP is a potent inhibitor of prostate cancer cell growth that acts by arresting cells in GO/G1 phase and that this inhibitory effect may be mediated by TGF-beta 1.