Effect of helenalin and bis(helenalinyl)malonate on nucleic acid and protein synthesis in human KB carcinoma cells.
Helenalin and bis(helenalinyl)malonate were shown to be cytotoxic against the growth of human KB carcinoma cells. DNA synthesis was inhibited significantly. This inhibition was afforded because of the drugs' effects on a number of enzyme activities. The inhibition of IMP dehydrogenase and ribonucleotide reductase complex activities correlated positively with the inhibition of DNA synthesis of the KB cells. DNA polymerase activity was inhibited by the drugs to a lesser degree. The deoxyribonucleotide pools were markedly reduced in the presence of the drug, which would be consistent with a blockage of the enzyme ribonucleotide reductase as well as suppression of DNA synthesis. XMP levels were also reduced, which is consistent with suppression of IMP dehydrogenase activity by the drugs. Ribonucleoside phosphate pools, particularly CDP and GDP, were elevated after drug treatment, which would be expected with a blockage at ribonucleotide reductase. Thus DNA alkylation is not the mechanism of action of the antineoplastic sesquiterpene lactones; rather, the cell-killing effect is related to DNA synthesis inhibition by the drug.
Hall
I H
IH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27514.
Grippo
A A
AA
Lee
K H
KH
Chaney
S G
SG
Holbrook
D J
DJ
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D054477:Glutaredoxins; D006801:Humans; D007168:IMP Dehydrogenase / Q000378:metabolism; D007624:KB Cells / Q000187:drug effects* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010088:Oxidoreductases; D011506:Proteins / Q000378:metabolism; D011687:Purines / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis*; D012262:Ribonucleoside Diphosphate Reductase / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D045789:Sesquiterpenes, Guaiane; D013729:Terpenes / Q000494:pharmacology*; D013879:Thioredoxins / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D054477:Glutaredoxins; D009363:Neoplasm Proteins; D011506:Proteins; D011687:Purines; D012334:RNA, Neoplasm; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D013729:Terpenes; C001329:helenalin; D013879:Thioredoxins; C037387:bis(helenalinyl)malonate; D010088:Oxidoreductases; D007168:IMP Dehydrogenase; D012262:Ribonucleoside Diphosphate Reductase; D013940:Thymidylate Synthase