Antitumor Agents XXIX: Effects of Eupahyssopin on Nucleic Acid, Protein, Anaerobic, and Aerobic Metabolism of Ehrlich Ascites Tumor Cells

Abstract

Evidence is presented that the antitumor agent eupahyssopin, a germacranolide, inhibits deoxyribonucleic acid, ribonucleic acid, protein, and cholesterol synthesis of Ehrlich ascites tumor cells in CF1 male mice. Eupahyssopin appears to bind to nucleotide bases of deoxyribonucleic acid. The drug also inhibits deoxyribonucleic acid and messenger ribonucleic acid polymerase activities and, marginally, thymidylate synthetase activity. Template activity, as regulated by phosphorylation of histones and nonhistones, and cyclic 3ʹ,5ʹ-adenosine monophosphate levels also were affected by drug therapy. Lysosomal enzymes, e.g., deoxyribonuclease and ribonuclease, and cathepsin activities were inhibited by eupahyssopin administration. A number of sulfhydryl-bearing enzymes of the glycolytic and Krebs cycles were inhibited by drug treatment, as were enzymes required for glycogen synthesis and breakdown and for phosphatase hydrolysis. Eupahyssopin also inhibited both basal respiration and coupled oxidative phosphorylation processes of the tumor cell. It was proposed that eupahyssopin, which contains the O=CC=CH2 as an α-methylene γ-lactone moiety within its allylic ester side chain, has the ability to undergo a rapid Michael-type addition with sulfhydryl groups of these enzymes and thus to inhibit their activities in a manner analogous to that described for other sesquiterpene antitumor agents containing the O=CC=CH2 moiety.