Sesquiterpene Antitumor Agents: Inhibitors of Cellular Metabolism

• Published in: Science (American Association for the Advancement of Science) Vol. 196; no. 4289; pp. 533 - 536
• Main Authors: Lee, Kuo-Hsiung, Hall, Iris H., Mar, Eng-Chun, Starnes, Charles O., ElGebaly, Salwa A., Waddell, Thomas G., Hadgraft, Robert I., Ruffner, Charles G., Weidner, Ivonne
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 29.04.1977
• Subjects: Adducts; Alkylation; Animals; Antimetabolites, Antineoplastic - pharmacology; Ascites; Carcinoma, Ehrlich Tumor - drug therapy; Carcinoma, Ehrlich Tumor - metabolism; Cellular metabolism; Cholesterol - biosynthesis; Cyclic AMP - metabolism; Cysteine; DNA; DNA, Neoplasm - biosynthesis; Enzymes; Glycolysis - drug effects; Ketones; Lactones; Lactones - pharmacology; Lactones - therapeutic use; Male; Nucleic Acid Synthesis Inhibitors; Oxygen Consumption - drug effects; Rats; Respiration; RNA; RNA, Neoplasm - biosynthesis; Sesquiterpenes; Sesquiterpenes - pharmacology; Sesquiterpenes - therapeutic use; Structure-Activity Relationship; Sulfhydryl Compounds
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.191909

Helenalin and tenulin injected into CF$_{1}$ male mice bearing Ehrlich ascites tumors inhibit DNA synthesis and DNA polymerase enzymatic activity in the tumor cells. Helenalin inhibited protein synthesis. Both drugs increased the concentration of adenosine 3′, 5′-monophosphate, and interfered with glycolytic and mitochondrial energy processes. Cholesterol synthesis was also inhibited, resulting in lower serum cholesterol levels in tumor-bearing animals. Data obtained in vitro indicate that the cyclopentenone-bearing sesquiterpene lactone and related compounds do not alkylate purine bases of nucleic acids but rather undergo a Michael-type addition reaction with the sulfhydryl groups of reduced glutathione and L-cysteine. Thus, the inhibition of cellular enzyme activities and metabolism that has been observed with these drugs might be explained by the occurrence of a Michael-type reaction.