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Antitumor Quinol PMX464 Is a Cytocidal Anti-trypanosomal Inhibitor Targeting Trypanothione Metabolism
Better drugs are urgently needed for the treatment of African sleeping sickness. We tested a series of promising anticancer agents belonging to the 4-substituted 4-hydroxycyclohexa-2,5-dienones class (“quinols”) and identified several with potent trypanocidal activity (EC(50) < 100 nm). In mammal...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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American Society for Biochemistry and Molecular Biology
2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048735/ https://www.ncbi.nlm.nih.gov/pubmed/21212280 http://dx.doi.org/10.1074/jbc.M110.214833 |
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author | König, Janine Wyllie, Susan Wells, Geoffrey Stevens, Malcolm F. Wyatt, Paul G. Fairlamb, Alan H. |
author_facet | König, Janine Wyllie, Susan Wells, Geoffrey Stevens, Malcolm F. Wyatt, Paul G. Fairlamb, Alan H. |
author_sort | König, Janine |
collection | PubMed |
description | Better drugs are urgently needed for the treatment of African sleeping sickness. We tested a series of promising anticancer agents belonging to the 4-substituted 4-hydroxycyclohexa-2,5-dienones class (“quinols”) and identified several with potent trypanocidal activity (EC(50) < 100 nm). In mammalian cells, quinols are proposed to inhibit the thioredoxin/thioredoxin reductase system, which is absent from trypanosomes. Studies with the prototypical 4-benzothiazole-substituted quinol, PMX464, established that PMX464 is rapidly cytocidal, similar to the arsenical drug, melarsen oxide. Cell lysis by PMX464 was accelerated by addition of sublethal concentrations of glucose oxidase implicating oxidant defenses in the mechanism of action. Whole cells treated with PMX464 showed a loss of trypanothione (T(SH)(2)), a unique dithiol in trypanosomes, and tryparedoxin peroxidase (TryP), a 2-Cys peroxiredoxin similar to mammalian thioredoxin peroxidase. Enzyme assays revealed that T(SH)(2), TryP, and a glutathione peroxidase-like tryparedoxin-dependent peroxidase were inhibited in time- and concentration-dependent manners. The inhibitory activities of various quinol analogues against these targets showed a good correlation with growth inhibition of Trypanosoma brucei. The monothiols glutathione and l-cysteine bound in a 2:1 ratio with PMX464 with K(d) values of 6 and 27 μm, respectively, whereas T(SH)(2) bound more tightly in a 1:1 ratio with a K(d) value of 430 nm. Overexpression of trypanothione synthetase in T. brucei decreased sensitivity to PMX464 indicating that the key metabolite T(SH)(2) is a target for quinols. Thus, the quinol pharmacophore represents a novel lead structure for the development of a new drug against African sleeping sickness. |
format | Text |
id | pubmed-3048735 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-30487352011-03-08 Antitumor Quinol PMX464 Is a Cytocidal Anti-trypanosomal Inhibitor Targeting Trypanothione Metabolism König, Janine Wyllie, Susan Wells, Geoffrey Stevens, Malcolm F. Wyatt, Paul G. Fairlamb, Alan H. J Biol Chem Metabolism Better drugs are urgently needed for the treatment of African sleeping sickness. We tested a series of promising anticancer agents belonging to the 4-substituted 4-hydroxycyclohexa-2,5-dienones class (“quinols”) and identified several with potent trypanocidal activity (EC(50) < 100 nm). In mammalian cells, quinols are proposed to inhibit the thioredoxin/thioredoxin reductase system, which is absent from trypanosomes. Studies with the prototypical 4-benzothiazole-substituted quinol, PMX464, established that PMX464 is rapidly cytocidal, similar to the arsenical drug, melarsen oxide. Cell lysis by PMX464 was accelerated by addition of sublethal concentrations of glucose oxidase implicating oxidant defenses in the mechanism of action. Whole cells treated with PMX464 showed a loss of trypanothione (T(SH)(2)), a unique dithiol in trypanosomes, and tryparedoxin peroxidase (TryP), a 2-Cys peroxiredoxin similar to mammalian thioredoxin peroxidase. Enzyme assays revealed that T(SH)(2), TryP, and a glutathione peroxidase-like tryparedoxin-dependent peroxidase were inhibited in time- and concentration-dependent manners. The inhibitory activities of various quinol analogues against these targets showed a good correlation with growth inhibition of Trypanosoma brucei. The monothiols glutathione and l-cysteine bound in a 2:1 ratio with PMX464 with K(d) values of 6 and 27 μm, respectively, whereas T(SH)(2) bound more tightly in a 1:1 ratio with a K(d) value of 430 nm. Overexpression of trypanothione synthetase in T. brucei decreased sensitivity to PMX464 indicating that the key metabolite T(SH)(2) is a target for quinols. Thus, the quinol pharmacophore represents a novel lead structure for the development of a new drug against African sleeping sickness. American Society for Biochemistry and Molecular Biology 2011-03-11 2011-01-06 /pmc/articles/PMC3048735/ /pubmed/21212280 http://dx.doi.org/10.1074/jbc.M110.214833 Text en © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles |
spellingShingle | Metabolism König, Janine Wyllie, Susan Wells, Geoffrey Stevens, Malcolm F. Wyatt, Paul G. Fairlamb, Alan H. Antitumor Quinol PMX464 Is a Cytocidal Anti-trypanosomal Inhibitor Targeting Trypanothione Metabolism |
title | Antitumor Quinol PMX464 Is a Cytocidal Anti-trypanosomal Inhibitor Targeting Trypanothione Metabolism |
title_full | Antitumor Quinol PMX464 Is a Cytocidal Anti-trypanosomal Inhibitor Targeting Trypanothione Metabolism |
title_fullStr | Antitumor Quinol PMX464 Is a Cytocidal Anti-trypanosomal Inhibitor Targeting Trypanothione Metabolism |
title_full_unstemmed | Antitumor Quinol PMX464 Is a Cytocidal Anti-trypanosomal Inhibitor Targeting Trypanothione Metabolism |
title_short | Antitumor Quinol PMX464 Is a Cytocidal Anti-trypanosomal Inhibitor Targeting Trypanothione Metabolism |
title_sort | antitumor quinol pmx464 is a cytocidal anti-trypanosomal inhibitor targeting trypanothione metabolism |
topic | Metabolism |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048735/ https://www.ncbi.nlm.nih.gov/pubmed/21212280 http://dx.doi.org/10.1074/jbc.M110.214833 |
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