Biochemical correlates of the antitumor and antimitochondrial properties of gossypol enantiomers

Christopher C. Benz, Max A. Keniry, James M. Ford, Alan J. Townsend, Fred W. Cox, Sanjeewani Palayoor, Stephen A. Matlin, William N. Hait, Kenneth H. Cowan

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117 Scopus citations


Racemic gossypol has been shown to have antitumor properties that may be due to its a bility to uncouple tumor mitochondria or to its inhibitory effects on a variety of nonmitochondrial enzymes. We have studied the antimitochondrial and enzyme-inhibiting properties of gossypol in human carcinoma cell lines of breast (MCF-7, T47-D), ovarian (OVCAR-3) colon (HCT-8), and pancreatic (MiaPaCa) origin by comparing the effects of its purified (+)- and (-)-enantiomers. (-)-Gossypol shows up to 10-fold greater antiproliferative activity than (+)-gossypol in the cancer cell lines and in normal hematopoietic stem cells grown in vitro, with IC50 values ranging from 1.5 to 4.0 μM for the cancer cells and from 10 to 20 μM for the human marrow stem cells. As well, multidrug-resistant MCF/Adr cells appear more resistant to (-)-gossypol than their parental cell line. Electron microscopy indicates that the earliest ultrastructural change in tumor cells exposed to a cytotoxic (10 μM) concentration of (-)-gossypol is the selective destruction of their mitochondria. Consistent with this observation, 31P magnetic resonance spectroscopy detects pronounced changes in tumor cell high energy phosphate metabolism within 24 hr of (-)-gossypol treatment, manifest by 1.6- to >50-fold differential reductions in the intracellular ratios of ATP/ Pi, relative to (+)-gossypol-treated cell lines; the magnitude of these antimitochondrial effects correlates with the antiproliferative activity of (-)-gossypol. Northern blot RNA analyses suggest that treatment with a 5-10 μM dose of (-)-gossypol induces a transient increase in the expression of heat shock gene products, particularly hsp-70 transcripts. The mean 5-fold increase in (-)-gossypol-induced hsp-70 mRNA appears coincident with a comparable heat-stimulated increase in transcript levels, as compared with control or (+)-gossypol-treated cells. The enzyme-inhibiting properties of gossypol enantiomers were compared in cell-free assays measuring glutathione-S-transferase-α, -μ, and n activities, calmodulin stimulation of cyclic nucleotide phosphodiesterase, and protein kinase C activity. Both enantiomers are near equivalent antagonists of calmodulin stimulation and protein kinase C activity, exceeding the potency of known inhibitors such as phenothiazines by as much as 50-fold. In contrast, (-)-gossypol is a 3-fold more potent inhibitor of glutathione-S-transferase-α and -π isozyme activity, resulting in IC50 values of 1.6 and 7.0 μM, respectively, for these two isozymes. Because of the enhanced resistance of MCF/Adr cells to (-)-gossypol, which may be related to their increased glutathione-S-transferase and protein kinase C content, (-)-gossypol should be evaluated for its potential to modify the cytotoxic resistance of human carcinoma cells to other chemotherapeutic agents. Furthermore, the above newly described (+)- and (-)-gossypol effects may be useful in directing structure-function studies using chiral-specific gossypol derivatives, in order to develop more selective and potent antimitochondrial chemotherapeutic agents.

Original languageEnglish (US)
Pages (from-to)840-847
Number of pages8
JournalMolecular pharmacology
Issue number6
StatePublished - Jun 1990
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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