Inhibition of nucleic acid synthesis in P-388 lymphocytic leukemia tumor cells by helenalin and bis(helenalinyl)malonate in vivo

Article abstract of DOI:10.1002/jps.2600770217

Although the parent sesquiterpene lactone, helenalin, and its derivative, bis(helenalinyl)malonate, are structurally related chemically, they demonstrate differences in their antineoplastic activity, with bis(helenalinyl)malonate being much more active against P-388 lymphocytic leukemia cell growth (T/C%=261) compared with helenalin (T/C% = 162). Previous studies have shown that both agents strongly inhibit protein synthesis in vivo by >70% after 3 d of administration and in vitro by 50% at a 100 μM concentration of drug. This inhibition of protein synthesis of P-388 cells may be partially responsible for the cytotoxicity of the drug. These agents also inhibit nucleic acid synthesis in vivo, with DNA synthesis being suppressed by >90% after 2 d of administration of drugs at the therapeutic dose. Of the sulfhydryl-bearing enzymes involved in nucleic acid synthesis that were assayed, only the activities of inosine-5'-monophosphate (IMP) dehydrogenase and the ribonucleotide reductase complex were inhibited by >50% by these sulfhydryl-reactive drugs, which would account for the observed inhibition of nucleic acid synthesis in the P-388 cells. The inhibition of the activities of these enzymes lowered the deoxyribonucleotide levels in P-388 cells, which would explain the overall suppression of DNA synthesis by the sesquiterpene lactones.