Gossypol

Scientific Name(s): Gossypium spp. Family: Malvaceae (mallow)

Common Name(s): Gossypol , AT-101 , ApoG2

Uses

According to Chinese studies, gossypol is effective as a nonhormonal male contraceptive; however, it has been documented to have irreversible effects on male fertility. It is being studied for clinical applications in cancer therapy.

Dosing

Antifertility : Trials have used 5 to 10 mg daily for 2 to 3 months to achieve azoospermia, with a lower maintenance dose for up to 2 years. Cancer : Maximum tolerated dosages appear to be 40 mg of gossypol (as AT-101) per day.

Contraindications

None well documented.

Pregnancy/Lactation

Documented abortifacient effects. Avoid use.

Interactions

None well documented.

Adverse Reactions

Nausea, emesis, anorexia, diarrhea, altered taste sensation, small intestine obstruction, and fatigue have been recorded in clinical trials. The irreversible effects of gossypol on male fertility have been well documented, as has the incidence of hypokalemia.

Toxicology

Gossypol is potentially toxic.

Botany

Gossypol is derived from members of the family Malvaceae. The stem, seed, and root of the cotton plant Gossypium hirsutum represent the most common source of gossypol. Gossypium are shrubs that grow to a height of 3 m, have broad lobed leaves, and contain seeds in a capsule or “boll” of fibers. These fibers are harvested and woven in the textile industry. The seeds of Gossypium species vary widely in gossypol content, with levels ranging from 0.13% to 6.6%. 1 , 2

History

Gossypol was first identified as an antifertility agent as a result of epidemiologic studies conducted in China during the 1950s. Investigators had been puzzled by the extremely low birth rates in a particular geographic region. The men had very low sperm counts and many women had amenorrhea. Eventually the phenomenon was attributed to the use of crude cottonseed oil for cooking and the consumption of cotton cake left over after the extraction of oil and fiber from the cotton plant. Further investigation revealed that the antifertility component was gossypol, and crystalline extracts were supplied to Chinese doctors for widespread use in the 1970s as the principle contraceptive method in China. Because gossypol's use had irreversible effects on fertility and caused hypokalemia in some people, this led to a reduced scientific interest in gossypol. 3

Chemistry

Gossypol is a polyphenolic compound that can be made synthetically or produced inexpensively on a very large scale by the extraction of cottonseed. In more recent years, different versions of the compound have been developed to improve efficacy and reduce the toxicity of the original chemical. Apogossypolone (ApoG2) and R-(-)-gossypol (AT-101) have been used in clinical trials. 2 , 4 , 5 , 6

Uses and Pharmacology

Antifertility/Contraceptive

Gossypol is a nonsteroidal compound that inhibits sperm production and motility in a variety of male animals and in humans, but it does not affect sex hormone levels or libido. Gossypol exerts its contraceptive action by inhibiting enzyme systems that play a crucial role in energy metabolism in sperm and spermatogenic cells. 2 , 3

Animal data

Gossypol is used as an active antifertility agent in a variety of male animals, including mice, rats, hamsters, monkeys, rabbits, and bulls. 2

Clinical data

Large-scale clinical trials in men, conducted by Chinese investigators, have found gossypol to be orally active and relatively safe and effective. The clinical testing of gossypol began in the early 1970s in China, and to date the drug has been studied extensively in thousands of men. Reviews of the clinical trials of gossypol have been published. 7 , 8

Clinical trials focus on establishing lower dosages in an attempt to reduce the potential for hypokalemia and irreversibility. Trials have used 10, 12.5, and 15 mg daily for 2 to 3 months to achieve azoospermia, with maintenance dosages of 35 to 43.75 mg weekly and 7.5 to 10 mg daily tested for up to 2 years. 3 , 9

Sperm counts usually return to normal within 3 months after termination of therapy, and men treated with gossypol have fathered normal children. However, long-term follow-up studies indicate that inhibition of spermatogenesis may continue following discontinuation in up to 50% of men after 2 years. Spermatogenesis does not return to normal in some men. Concerns regarding the lack of predictable, reversible effects have delayed the further clinical development of gossypol in Western countries. 3 The use of gossypol as a nonhormonal alternative to high-dose estrogen in transsexual patients has been suggested. 10

Cancer

Gossypol inhibits the growth of various cancer cell lines in vitro, including breast, colon, prostate, and leukemia. Inhibition of cytoplasmic and mitochondrial enzymes (including key enzymes for DNA replication and repair), uncoupling of oxidative phosphorylation, and depletion of cellular ATP are proposed mechanisms of action. 2 , 4 , 6 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18

Animal data

Gossypol inhibited tumor growth in mice within 7 days in 1 experiment and reduced the tumor size by 65% in another at dosages of 30 mg/kg/day. 11 , 14 , 16

Clinical data

Phase 1 and 2 clinical trials are being conducted using gossypol enantiomer AT-101 in non-Hodgkin lymphomas and breast and prostate cancer. 4 , 15 , 17 Limited efficacy has been demonstrated, with effects on surrogate outcomes such as Rb protein and cyclin D1 expression in the breast cancer study and decreased prostate-specific antigen in the prostate cancer study. Maximum tolerated dosages appear to be 40 mg/day. 15

Other uses
Female contraception

Although gossypol is generally considered to be a male antifertility agent, it is also effective when given to female animals. In addition, gossypol has been evaluated as a topical spermicide; however, this line of study appears to have not been pursued. 19 , 20

Gossypol and its derivatives have demonstrated antiviral, antibacterial, and antiprotozoal activity. An effect on plasma cholesterol has also been demonstrated in animals. 2

Dosage

Antifertility

Trials have used 10, 12.5, and 15 mg daily for 2 to 3 months to achieve azoospermia, with maintenance dosages of 35 to 43.75 mg weekly and 7.5 to 10 mg daily used for up to 2 years. 3 , 9

Cancer

Maximum tolerated dosages appear to be 40 mg of gossypol (as AT-101) per day. 15

Pregnancy/Lactation

Documented abortifacient effects. Avoid use.

The intramuscular injection of gossypol into female rats inhibited implantation and the maintenance of normal pregnancy, most likely by affecting luteinizing hormone levels. 21

Interactions

None well documented.

Adverse Reactions

The irreversible effects of gossypol on male fertility have been well documented, as has the incidence of hypokalemia. 2

Clinical trials evaluating AT-101 in cancer have recorded nausea, emesis, anorexia, diarrhea, altered taste sensation, small intestine obstruction, and fatigue as adverse reactions. 15 , 17

Toxicology

Dose-dependent acute, subchronic, and chronic toxicity has been demonstrated in animals.

Circulatory failure and pulmonary edema are consequent to the cardiotoxicity of gossypol, thought to be due to the prevention of oxygen release from oxyhemoglobin and interference in enzymatic processes. Hepatotoxicity has been observed in some animal studies. 2 , 22 , 23 , 24

Cottonseed oil was nontoxic in short-term oral studies in rats because the gossypol content is generally low and extraction processes may influence the amount of gossypol obtained. However, an increase in the incidence of mammary tumors was observed in some studies. Apogossypol is suggested to have a lower toxicity profile. 2 , 22

The compound was not mutagenic when tested in the Ames Salmonella microsome test, but questions remain about its genotoxic characteristics. 22 Teratogenicity studies found no adverse effect on the fetus or pregnancy in rats at 40 mg/kg body weight. 3

Bibliography

1. USDA, NRCS. 2010. The PLANTS Database ( http://plants.usda.gov , August 2010). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
2. Wang X, Howell CP, Chen F, Yin J, Jiang Y. Gossypol—a polyphenolic compound from cotton plant. Adv Food Nutr Res . 2009;58:215-263.
3. Coutinho EM. Gossypol: a contraceptive for men. Contraception . 2002;65(4):259-263.
4. Cheson BD. Novel therapies for peripheral T-cell non-Hodgkin's lymphomas. Curr Opin Hematol . 2009;16(4):299-305.
5. Zhan Y, Jia G, Wu D, Xu Y, Xu L. Design and synthesis of a gossypol derivative with improved antitumor activities. Arch Pharm (Weinheim) . 2009;342(4):223-229.
6. Azmi AS, Mohammad RM. Non-peptidic small molecule inhibitors against Bcl-2 for cancer therapy. J Cell Physiol . 2009;218(1):13-21.
7. Wu D. An overview of the clinical pharmacology and therapeutic potential of gossypol as a male contraceptive agent and in gynaecological disease. Drugs . 1989;38(3):333-341.
8. Lopez LM, Grimes DA, Schulz KF. Nonhormonal drugs for contraception in men: a systematic review. Obstet Gynecol Surv . 2005;60(11):746-752.
9. Gu ZP, Mao BY, Wang YX, et al. Low dose gossypol for male contraception. Asian J Androl . 2000;2(4):283-287.
10. Yurekli B, Karaca B, Cetinkalp S, Saygili F, Uslu R. Can gossypol be a hope for transsexual patients (male to female) before sex reassignment surgery? Just for adjusting the body to mind. Med Hypotheses . 2009;73(4):625-626.
11. Rodríguez-Enríquez S, Marín-Hernández A, Gallardo-Pérez JC, Carreño-Fuentes L, Moreno-Sánchez R. Targeting of cancer energy metabolism. Mol Nutr Food Res . 2009;53(1):29-48.
12. Reddish JM, Ye W, Lin YC, Wick M. (-)-Gossypol containing hen sera and a myosin (-)-gossypol conjugate reduces the proliferation of MCF-7 cells. Anticancer Res . 2010;30(2):439-444.
13. Xu P, Ye W, Jen R, Lin SH, Kuo CT, Lin YC. Mitogenic activity of zeranol in human breast cancer cells is enhanced by leptin and suppressed by gossypol. Anticancer Res . 2009;29(11):4621-4628.
14. Zhang XQ, Huang XF, Mu SJ, et al. Inhibition of proliferation of prostate cancer cell line, PC-3, in vitro and in vivo using (-)-gossypol. Asian J Androl . 2010;12(3):390-399.
15. Van Poznak C, Seidman AD, Reidenberg MM, et al. Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial. Breast Cancer Res Treat . 2001;66(3):239-248.
16. Yan F, Cao XX, Jiang HX, et al. A novel water-soluble gossypol derivative increases chemotherapeutic sensitivity and promotes growth inhibition in colon cancer. J Med Chem . 2010;53(15):5502-5510.
17. Liu G, Kelly WK, Wilding G, Leopold L, Brill K, Somer B. An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin Cancer Res . 2009;15(9):3172-3176.
18. Banerjee S, Choi M, Aboukameel A, et al. Preclinical studies of apogossypolone, a novel pan inhibitor of bcl-2 and mcl-1, synergistically potentiates cytotoxic effect of gemcitabine in pancreatic cancer cells. Pancreas . 2010;39(3):323-331.
19. Cameron SM, Waller DP, Zaneveld LJ. Vaginal spermicidal activity of gossypol in the Macaca arctoides . Fertil Steril . 1982;37(2):273-274.
20. Ratsula K, Haukkamaa M, Wichmann K, Luukkainen T. Vaginal contraception with gossypol: a clinical study. Contraception . 1983;27(6):571-576.
21. Lin YC, Fukaya T, Rikihisa Y, Walton A. Gossypol in female fertility control: ovum implantation and early pregnancy inhibited in rats. Life Sci . 1985;37(1):39-47.
22. de Peyster A, Wang YY. Gossypol—proposed contraceptive for men passes the Ames test. N Engl J Med . 1979;301(5):275-276.
23. Kovacic P. Mechanism of drug and toxic actions of gossypol: focus on reactive oxygen species and electron transfer. Curr Med Chem . 2003;10(24):2711-2718.
24. Final report on the safety assessment of hydrogenated cottonseed oil, cottonseed ( Gossypium ) oil, cottonseed acid, cottonseed glyceride, and hydrogenated cottonseed glyceride. Int J Toxicol . 2001;(20)(suppl 2):21-29.

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