Tiazofurin and selenazofurin induce depression of cGMP and phosphatidylinositol pathway in L1210 leukemia cells.
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.
Parandoosh
Z
Z
Department of Molecular Pharmacology, ICN-Nucleic Acid Research Institute, Costa Mesa, California.
Robins
R K
RK
Belei
M
M
Rubalcava
B
B
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D006152:Cyclic GMP / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D007291:Inosine Monophosphate / Q000378:metabolism; D007939:Leukemia L1210 / Q000378:metabolism*; D051379:Mice; D016566:Organoselenium Compounds; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D011493:Protein Kinase C; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D012254:Ribavirin / Q000494:pharmacology* / Q000031:analogs & derivatives; D012263:Ribonucleosides / Q000494:pharmacology*; D012643:Selenium / Q000494:pharmacology*
D000970:Antineoplastic Agents; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D004075:Diglycerides; D016566:Organoselenium Compounds; D010710:Phosphates; D010716:Phosphatidylinositols; D011955:Receptors, Drug; D012263:Ribonucleosides; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; D007291:Inosine Monophosphate; D015240:Phorbol 12,13-Dibutyrate; D012254:Ribavirin; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D006152:Cyclic GMP; D012643:Selenium; C039064:selenazofurin; C033706:tiazofurin