The (-)-enantiomer of gossypol possesses higher anticancer potency than racemic gossypol in human breast cancer.
Natural gossypol (GP), a polyphenolic pigment in cottonseed, is a racemic mixture of two enantiomers, (+)GP and (-)GP. Our aim was to compare the abilities of (+/-)GP, (+)GP and (-)GP to reduce proliferation of breast cancerous epithelial cells (cEC) and cancerous stromal cells (cSC). Proliferation was measured by 3H-thymidine uptake. Results showed that (+)GP had no effect on both cEC and cSC. In contrast, in both cell types, (+/-)GP and (-)GP significantly inhibited proliferation. (+/-)GP caused reductions of 15, 46 and 82% at 25, 5.0 and 7.5 microM, respectively, in cEC, and reductions of 17, 28, 39 and 56% at 2.0, 3.0, 4.0 and 5.0 microM, respectively, in cSC. (-)GP induced reductions of 33, 89 and 98% at 2.5, 5.0 and 7.5 microM, respectively, in cEC, and reductions of 29, 51, 64 and 72% at 2.0, 3.0, 4.0 and 5.0 microM, respectively, in cSC. By RT-PCR, we found that 3 microM of (+/-)GP and (-)GP decreased cyclin D1 mRNA expression in both cell types (52% and 71%, respectively, in cEC; and 47% and 71%, respectively, in cSC), and increased transforming growth factor beta (TGFbeta) mRNA expression in both cell types (93% and 130%, respectively, in cEC; and 45% and 89%, respectively, in cSC). Interestingly, (-)GP was significantly more potent than (+/-)GP. These results show that (-)GP is the major inhibitory component of (+/-)GP, (-)GP is the more potent inhibitor of cancerous breast cell growth, and the inhibitory activity of (-)GP and (+/-)GP is related to the reduction of the cell cycle regulator, cyclin D1, and the induction of the cell proliferation inhibitor, TGFbeta.
Liu
Suling
S
Laboratory of Reproductive and Molecular Endocrinology, College of Veterinary Medicine, The Ohio State University, Columbus 43210, USA.
Kulp
Samuel K
SK
Sugimoto
Yasuro
Y
Jiang
Jiahua
J
Chang
Hsiang-Lin
HL
Dowd
Michael K
MK
Wan
Peter
P
Lin
Young C
YC
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006072:Gossypol / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013237:Stereoisomerism; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D006072:Gossypol