@article {WOYNAROWSKI97, author = {JAN M. WOYNAROWSKI and JERZY KONOPA}, title = {Inhibition of DNA Biosynthesis in HeLa Cells by Cytotoxic and Antitumor Sesquiterpene Lactones}, volume = {19}, number = {1}, pages = {97--102}, year = {1981}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Parthenolide, a cytotoxic sesquiterpene lactone, was found to inhibit incorporation of radioactive thymidine, uridine, and leucine into macromolecules in HeLa cells. In the case of the two latter precursors, the inhibitory effects were predominantly due to decreased uptake of uridine and leucine into cells, which indicated a negligible effect of parthenolide on RNA and protein synthesis. In contrast, inhibition of thymidine incorporation into DNA was only partially caused by impaired uptake of the precursor into cells. This result was directly demonstrated in experiments with HeLa cells pulse-labeled with [3H]thymidine at 6{\textdegree} chased at 37{\textdegree} in the presence of parthenolide. The inhibition of thymidine incorporation into DNA, as observed under these conditions, seems to reflect the interference of parthenolide with DNA synthesis, since the metabolic conversion of thymidine to deoxythymidine triphosphate remained unaffected. Moreover, incubation of HeLa cells with parthenolide resulted in the inhibition of [3H]deoxythymidine triphosphate incorporation into DNA in nuclear systems ("lysates") derived from these cells. Hence, the inhibitory action of parthenolide probably occurs at the replication level as opposed to the effect on the biosynthesis of DNA precursors. Several other cytotoxic and antitumor sesquiterpene lactones were also found to inhibit DNA synthesis in HeLa cells. This inhibitory activity appeared to correlate with the cytotoxic activities of sesquiterpene lactones against HeLa cells in the case of eight compounds among nine studied. The results suggest that DNA is a target molecule in the mechanism of action of cytotoxic and antitumor sesquiterpene lactones. ACKNOWLEDGMENTS The authors thank Dr. Terry Beerman and Nina Ruth Wright for editoral help and also Christina Turley and Pat Dickens for typing the manuscript.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/19/1/97}, eprint = {https://molpharm.aspetjournals.org/content/19/1/97.full.pdf}, journal = {Molecular Pharmacology} }