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17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice

Heat shock protein 90 (Hsp90) is a chaperone protein that stabilizes cells during stress or non-stress responses. Previous reports have shown that Hsp90 is a potential drug target to suppress the multiplication of several protozoan parasites. In this study, 17-dimethylaminoethylamino-17-demethoxygel...

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Autores principales: Guswanto, Azirwan, Nugraha, Arifin Budiman, Tuvshintulga, Bumduuren, Tayebwa, Dickson Stuart, Rizk, Mohamed Abdo, Batiha, Gaber El-Saber, Gantuya, Sambuu, Sivakumar, Thillaiampalam, Yokoyama, Naoaki, Igarashi, Ikuo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114103/
https://www.ncbi.nlm.nih.gov/pubmed/29499568
http://dx.doi.org/10.1016/j.ijpddr.2018.02.005
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author Guswanto, Azirwan
Nugraha, Arifin Budiman
Tuvshintulga, Bumduuren
Tayebwa, Dickson Stuart
Rizk, Mohamed Abdo
Batiha, Gaber El-Saber
Gantuya, Sambuu
Sivakumar, Thillaiampalam
Yokoyama, Naoaki
Igarashi, Ikuo
author_facet Guswanto, Azirwan
Nugraha, Arifin Budiman
Tuvshintulga, Bumduuren
Tayebwa, Dickson Stuart
Rizk, Mohamed Abdo
Batiha, Gaber El-Saber
Gantuya, Sambuu
Sivakumar, Thillaiampalam
Yokoyama, Naoaki
Igarashi, Ikuo
author_sort Guswanto, Azirwan
collection PubMed
description Heat shock protein 90 (Hsp90) is a chaperone protein that stabilizes cells during stress or non-stress responses. Previous reports have shown that Hsp90 is a potential drug target to suppress the multiplication of several protozoan parasites. In this study, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an Hsp90 inhibitor, was evaluated for its inhibitory effect on five in vitro cultures of Babesia and Theileria species, including B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi, and on the multiplication of a B. microti–infected mouse model. 17-DMAG showed the inhibitory effect in all of the species tested. The half maximum inhibition concentration (IC(50)) of 17-DMAG on B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi was 77.6 ± 2.9, 62.4 ± 1.9, 183.8 ± 3.2, 88.5 ± 9.6, and 307.7 ± 7.2 nM, respectively. The toxicity assay on MDBK and NIH/3T3 cell lines showed that 17-DMAG affected the viability of cells with an IC(50) of 15.5 ± 4 and 8.8 ± 2 μM, respectively. Since the IC(50)s were much lower on the parasites than on the host cell lines, the selectivity index were high for all tested species. Furthermore, the two-drug combination of 17-DMAG with diminazene aceturate (DA) and atovaquone (AV) showed synergism or addition on in vitro cultures of Babesia and Theileria parasites. In the mouse model, 17-DMAG at a concentration of 30 mg/kg BW effectively inhibited the multiplication of B. microti. Moreover, if combined with DA or AV, 17-DMAG showed a comparable inhibition at the half dose. Taken together, these results indicate that 17-DMAG is a potent drug for treating piroplamosis. The data warrant further evaluation of 17-DMAG as an antibabesial drug and as an option in combination with atovaquone for the treatment of human babesiosis.
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spelling pubmed-61141032018-08-31 17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice Guswanto, Azirwan Nugraha, Arifin Budiman Tuvshintulga, Bumduuren Tayebwa, Dickson Stuart Rizk, Mohamed Abdo Batiha, Gaber El-Saber Gantuya, Sambuu Sivakumar, Thillaiampalam Yokoyama, Naoaki Igarashi, Ikuo Int J Parasitol Drugs Drug Resist Article Heat shock protein 90 (Hsp90) is a chaperone protein that stabilizes cells during stress or non-stress responses. Previous reports have shown that Hsp90 is a potential drug target to suppress the multiplication of several protozoan parasites. In this study, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an Hsp90 inhibitor, was evaluated for its inhibitory effect on five in vitro cultures of Babesia and Theileria species, including B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi, and on the multiplication of a B. microti–infected mouse model. 17-DMAG showed the inhibitory effect in all of the species tested. The half maximum inhibition concentration (IC(50)) of 17-DMAG on B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi was 77.6 ± 2.9, 62.4 ± 1.9, 183.8 ± 3.2, 88.5 ± 9.6, and 307.7 ± 7.2 nM, respectively. The toxicity assay on MDBK and NIH/3T3 cell lines showed that 17-DMAG affected the viability of cells with an IC(50) of 15.5 ± 4 and 8.8 ± 2 μM, respectively. Since the IC(50)s were much lower on the parasites than on the host cell lines, the selectivity index were high for all tested species. Furthermore, the two-drug combination of 17-DMAG with diminazene aceturate (DA) and atovaquone (AV) showed synergism or addition on in vitro cultures of Babesia and Theileria parasites. In the mouse model, 17-DMAG at a concentration of 30 mg/kg BW effectively inhibited the multiplication of B. microti. Moreover, if combined with DA or AV, 17-DMAG showed a comparable inhibition at the half dose. Taken together, these results indicate that 17-DMAG is a potent drug for treating piroplamosis. The data warrant further evaluation of 17-DMAG as an antibabesial drug and as an option in combination with atovaquone for the treatment of human babesiosis. Elsevier 2018-03-01 /pmc/articles/PMC6114103/ /pubmed/29499568 http://dx.doi.org/10.1016/j.ijpddr.2018.02.005 Text en © 2018 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Guswanto, Azirwan
Nugraha, Arifin Budiman
Tuvshintulga, Bumduuren
Tayebwa, Dickson Stuart
Rizk, Mohamed Abdo
Batiha, Gaber El-Saber
Gantuya, Sambuu
Sivakumar, Thillaiampalam
Yokoyama, Naoaki
Igarashi, Ikuo
17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice
title 17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice
title_full 17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice
title_fullStr 17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice
title_full_unstemmed 17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice
title_short 17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice
title_sort 17-dmag inhibits the multiplication of several babesia species and theileria equi on in vitro cultures, and babesia microti in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114103/
https://www.ncbi.nlm.nih.gov/pubmed/29499568
http://dx.doi.org/10.1016/j.ijpddr.2018.02.005
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