Effects of Some Antitumor Agents on Growth and Glycolytic Enzymes of the Flagellate Crithidia

Abstract

Some antitumor agents known to specifically inhibit certain tumor cell enzymes were examined for activity against glycolytic enzymes and growth of the insect trypanosomatid, Crithidia fasciculata. The cytoplasmic enzymes hexokinase, a-glycerophosphate dehydrogenase, malic dehydrogenase, and glucose-6-phosphate dehydrogenase were tested. Agaricic acid (2-hydroxy-1 ,2,3-nonadecane tricarboxylic acid) was highly inhibitory (50 to 100%) to malic and a-glycerophosphate dehydrogenases at 3 x 10-5 M; 2-(p-hydroxyphenyl)-2-phenylpropane (2 X 10-M), and 5,6-dichloro-2-benzoxazolinone (5 X 10-4 M) were less effective (50% inhibition) against them. The antiprotozoal agents primaquine (4 X 10-4 M) and Melarsoprol (8 X 10-4 M) were 30 to 40% inhibitory. Agaricic acid, 2-(p-hydroxyphenyl)-2-phenylpropane, and 5,6-dichloro-2-benzoxazolinone inhibited growth of Crithidia at less than 10-4 M. Eight other test compounds from the Cancer Chemotherapy National Service Center (CCNSC) were not toxic to cell growth, although two (4-biphenylcarboxylic acid and 1-[p-chlorobenzyl]-2-ethyl-5-methyl-indole-3acetic acid) inhibited Crithidia a-glycerophosphate dehydrogenase below 1 mM. All of the compounds used specifically inhibited cancer cell a-glycerophosphate dehydrogenase. The corresponding enzyme in pathogenic African trypanosomes is important in their terminal respiration. C. fasciculata may be useful in preliminary evaluation of chemotherapeutic agents as potential trypanocides. 11, 12) and arsenicals on glycolytic enzymes and cells of C. fasciculata. This trypanosomatid 23

Biology and physiology of the lower Trypanosomatidae.

“…The review by Wallace in 1966 (281) included a carefully worked out revision of the group but did not include a consideration of the genus Phytomonas. Since that review, there has been a renewed interest in the lower Trypanosomatidae stimulated not only by the review of Wallace, but also by the belief that these organisms might serve as models for the study of pathogens ofvertebrates and be suitable for testing effective chemotherapeutic agents (7,94,139). The pathogenic propensities of Phytomonas leptovasorum Stahel toward Coffea sp.…”

Strategies for Interfering With Bacterial Early Stage Biofilms

“…Agaric acid is a fatty acid naturally produced by certain fungi, such as Polyporus , and can be used as anhidrotic to treat tuberculosis patients with extreme sweating ( Bacchi et al, 1969 ). Studies on Salmonella showed that the formation of biofilms was significantly inhibited after the action of agaric acid because it significantly reduced the expression of flagellar rotation genes.…”

Antimicrobial activity and cytotoxicity of transition metal carboxylates derived from agaric acid

“…The mechanism of action is not fully understood but stems most likely from the analogy with citrate, for example, it inhibits citrate uptake in mitochondria (Chávez et al, 1978). Agaric acid is highly inhibitory against malic and α-glycerophosphate dehydrogenases at ~3.10 -5 M and it also inhibits the growth of the nonpathogenic trypanosomatid Crithidia fasciculata used as a model for the pathogenic representatives of the Trypanosoma genus (Bacchi et al, 1969). Furthermore, it inhibits ADPstimulated respiration.…”