Genistein inhibits nonoxidative ribose synthesis in MIA pancreatic adenocarcinoma cells: A new mechanism of controlling tumor growth

Genistein is a plant isoflavonoid bearing potent turner growth-regulating c haracteristics. This effect of genistein has been attributed partially to i ts tyrosine kinase-regulating properties, resulting in cell-cycle arrear an d limited angiogenesis. Genistein has been used in chemotherapy-resistant c ases of advanced leukemia with promising results. Here we demonstrate that genistein primarily affects nucleic acid synthesis and glucose oxidation in tumor cells using the [1,2-C-'13(2)]glucose isotope as the single tracer a nd gas chromatography/mass spectrometry to follow various intracellular glu cose metabolites. The ribose fraction of RNA demonstrated a rapid 4.6%, 16. 4%, and 46.3% decrease in isotope uptake through the nonoxidative branch of the pentose cycle and a sharp 4.8%, 24.6%, and 48% decrease in (CO2)-C-13 release from glucose after 2, 20, and 200 mu mol/L genistein treatment, res pectively. Fatty acid synthesis and the C-13 enrichment of acetyl units wer e not significantly affected by genistein treatment. De novo glycogen synth esis from media glucose was not detected in cultured MIA cells. It can be c oncluded from these studies that genistein controls tumor growth primarily through the regulation of glucose metabolism, specifically targeting glucos e carbon incorporation into nucleic acid ribose through the nonoxidative st eps of the pentose cycle, which represents a new paradigm for the antiproli ferative action of a plant phytochemical.