cyclic-gmp and tiazofurin

When the human myeloid leukemia cell line, K562, was induced to differentiate along the erythroid lineage by a 4 day treatment with 10 microM tiazofurin, the cellular content of diacylglycerol decreased to 35% of the value in untreated control cells. Under the same conditions the content of cGMP decreased to 61% of the control value. Tiazofurin inhibits guanine nucleotide biosynthesis and lowers cellular GTP. When guanosine and adenine were added together with tiazofurin, the differentiation of K562 was prevented, the concentration of diacylglycerol was maintained at control values, and the reduction in the concentration of cGMP was partially prevented. Other inducers of differentiation which acted by different mechanisms, caused similar changes in the concentrations of diacylglycerol and cGMP.

Topics: Antimetabolites, Antineoplastic; Cell Differentiation; Chromatography, DEAE-Cellulose; Cyclic GMP; Diglycerides; Glycerides; Hemoglobins; Humans; Leukemia, Myeloid; Protein Kinase C; Ribavirin; Tumor Cells, Cultured

The synthetic nucleoside tiazofurin(2-beta-ribofuranosylthiazole-4-carboxyamide) and its selenium analog selenazofurin inhibited the growth of L1210 leukemia cell culture in a dose dependent manner with IC50 value of 2.0 and 0.2 Um respectively. The GTP/ATP ratio was diminished 4-6 fold as measured by HPLC, while IMP/ATP increased 6-8 fold. The decreased guanylate pools may explain the 30% reduction in cyclic GMP levels and GTPase activity measured after the treatment with the nucleosides. Inhibition of phospholipase C activity is suggested since diacylglycerol content, protein kinase C activity and phorbol ester binding of the membrane fraction were also reduced 20-40%. These results reveal a novel aspect in the action of these compounds which may play a role in their therapeutic action and selectivity.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Caenorhabditis elegans Proteins; Carrier Proteins; Cyclic GMP; Diglycerides; Guanosine Triphosphate; Inosine Monophosphate; Leukemia L1210; Mice; Organoselenium Compounds; Phorbol 12,13-Dibutyrate; Phosphates; Phosphatidylinositols; Protein Kinase C; Receptors, Drug; Ribavirin; Ribonucleosides; Selenium