(-)-Gossypol inhibits zeranol and leptin-induced mcf-7 adr cell proliferation

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Breast cancer is a world-wide disease and it is the second cause of death in cancers in postmenopausal women. One of known risk factors of breast cancer is obesity which has become a major public health concern. The morbidity is increased by 30-50% in obese cancer patients comparing to normal weight cancer patients. Leptin, mainly secreted by adipocytes, is a product of obese (ob) gene and plays an important role in breast cancer development. Leptin expression is upregulated in obesity and it can promote breast cancer cell growth by signaling through its receptors and by direct effects on estrogen receptor (ER) pathway. Zeranol (Z) is a mycotoxin produced by fusarium fungus existed in wetted cereals. Z is a non-estrogenic anabolic growth promoter used in the U. S. beef industry. The (-)-Gossypol {(-)-GP} enantiomer, a potent natural polyphenolic agent contained in cottonseed products possesses anticancer and chemopreventive activities. We investigate whether (-)-GP interferes with Z- or leptin-induced MCF-7 Adr cell proliferation. After 24 hours treatment, cell proliferation and mRNA expression levels were analyzed from controls and treated cell samples. Exposure of Z at 30 nM and leptin at 100 ng/ml for 24 hrs significantly increased MCF-7 Adr cell growth. The combined treatment of 30 nM Z and 100 ng/ml of leptin further stimulated the cell proliferation compared to treatment of Z or leptin alone. (-)-GP at 5 µM significantly suppressed the Z- and leptin-induced cell proliferation. Leptin or Z treatment is capable of suppressing the PTP γ, enhancing the cyclin D1 mRNA expression levels. However, (-)-GP treatment reversed the stimulatory effect of Z and leptin’s regulation on PTP γ and cyclin D1 expressions. Z and leptin are capable of stimulating human breast cancer cell growth and (-)-GP suppresses both actions of Z and leptin on human breast cancer cell growth.
 Our report is the first to reveal that (-)-GP as a food component in cottonseed products may serve as a potential chemopreventive agent to suppress the stimulatory effect of Z and leptin on human breast cancer cells. (Supported by Grants from NIH R01 ES 015212 and Cotton Inc. Project No. 06-864).