Inhibition of the biosynthesis of deoxyribonucleic acid, ribonucleic acid and protein in HeLa S3 cells by cucurbitacins, glucocorticoid-like cytotoxic triterpenes.
Cucurbitacins were found to inhibit the incorporation of radioactive precursors into DNA, RNA and protein in intact and permeabilized HeLa S3 cells. The observed inhibition was rapid and irreversible although the maximal effect (almost complete inhibition) required several hours of cell exposition to the agent. The magnitude of the inhibition was, with some exceptions, nearly the same for all three precursors within the entire range of cucurbitacin concentrations examined. The ID50 values (concentrations required to produce half-maximal inhibition of the macromolecule biosynthesis) determined for several cucurbitacins were very close to their respective ED50 values (those for half-maximal inhibition of cell proliferation). Parallel with the inhibition of [3H]-labelled precursor incorporations into nucleic acids, cucurbitacin diminished the [3H]thymidine and [3H]uridine nucleotides' pool sizes of HeLa S3 cells. No effect of cucurbitacin on the [3H]leucine pool was observed. The studies presented prove that cucurbitacins inhibit the biosynthesis of DNA, RNA and protein in HeLa S3 cells, and that these inhibitory effects are closely related to the inhibition of HeLa S3 cell proliferation by cucurbitacins. The mechanism of the inhibition is unknown but the obtained results suggest that cucurbitacins act upon an unidentified target, which results in the inhibition of macromolecule biosynthesis. It was also found that these inhibitory effects of cucurbitacins are neither mediated by glucocorticoid receptors nor require replication, transcription or translation.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D054728:Cucurbitacins; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis*; D003609:Dactinomycin / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D007810:Lanosterol / Q000031:analogs & derivatives / Q000494:pharmacology; D014176:Protein Biosynthesis; D014315:Triterpenes / Q000494:pharmacology*; D014316:Tritium
D000970:Antineoplastic Agents; D005938:Glucocorticoids; D014315:Triterpenes; D014316:Tritium; D003609:Dactinomycin; D007810:Lanosterol; D054728:Cucurbitacins; D004247:DNA; D003513:Cycloheximide; C038106:cucurbitacin I