Different pathways of cell killing by gossypol enantiomers.
Gossypol, a polyphenolic, aldehyde-containing constituent of cottonseed, produced partial responses (>50% reduction in tumor size) in some patients with advanced cancer and suppressed sperm as an antifertility agent for men. This action in vivo and its novel side effect profile suggest a specific mechanism of the action of gossypol. Using the random homozygous knockout approach of Li and Cohen (1), we developed a cell line resistant to killing by gossypol, but sensitive to methotrexate and doxorubicin. It showed stereospecific resistance to killing by (-) gossypol (ED(50) 4.9 microM) compared with wild type (ED(50) 2.0 microM). The resistant and wild-type cells were equally sensitive to (+) gossypol (ED(50) 8.8 and 8.4 microM, respectively), methotrexate, and doxyrubicin. We conclude that gossypol affects cells by a stereospecific pathway for (-) gossypol, possibly related to its selective effects, and a nonstereospecific pathway for (+) gossypol and higher concentrations of (-) gossypol. Further knowledge about the stereospecific pathway may lead to new therapeutic drugs.
Qiu
Jianping
J
Department of Pharmacology and Medicine, Weill Medical College, Cornell University, New York, New York 10021, USA.
Levin
Lonny R
LR
Buck
Jochen
J
Reidenberg
Marcus M
MM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death; D002460:Cell Line; D003369:Cottonseed Oil / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005821:Genetic Techniques; D006072:Gossypol / Q000494:pharmacology*; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic
D000970:Antineoplastic Agents; D003369:Cottonseed Oil; D019384:Nucleic Acid Synthesis Inhibitors; D016376:Oligonucleotides, Antisense; D004317:Doxorubicin; D006072:Gossypol; D008727:Methotrexate