17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice
| Autor: | Gaber El-Saber Batiha, Sambuu Gantuya, Ikuo Igarashi, Thillaiampalam Sivakumar, Azirwan Guswanto, Dickson Stuart Tayebwa, Bumduuren Tuvshintulga, Mohamed Abdo Rizk, Arifin Budiman Nugraha, Naoaki Yokoyama |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Hsp90 heat shock protein 90 Madin Darby Canine Kidney Cells Mice DA diminazene aceturate 0302 clinical medicine Theileria Drug Discovery Benzoquinones Pharmacology (medical) BW body weight RBC red blood cells 17-AAG 17-N-allylamino-17-demethoxygeldanamycin (tanespimycin) Infectious Diseases Toxicity Female Atovaquone medicine.drug CI combination index values Cell Survival Lactams Macrocyclic 17-DMAG 17-dimethylaminoethylamino-17-demethoxygeldanamycin 030231 tropical medicine Antiprotozoal Agents Babesia Biology Babesia microti Article Microbiology lcsh:Infectious and parasitic diseases 03 medical and health sciences Inhibitory Concentration 50 Dogs Heat shock protein Babesiosis 17-DMAG parasitic diseases medicine IC50 half maximum inhibition concentration Animals Humans lcsh:RC109-216 HSP90 Heat-Shock Proteins p.i post infection IC50 AV atovaquone Pharmacology Chemotherapeutic MDBK Madin-Darby Bovine Kidney cell line Hsp90 inhibitor biology.organism_classification In vitro Theileriasis 030104 developmental biology NIH/3T3 mouse embryonic fibroblast cell line Cell culture NIH 3T3 Cells Parasitology Diminazene |
| Zdroj: | International Journal for Parasitology: Drugs and Drug Resistance International Journal for Parasitology: Drugs and Drug Resistance, Vol 8, Iss 1, Pp 104-111 (2018) |
| ISSN: | 2211-3207 |
| Popis: | 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 (IC50) 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 IC50 of 15.5 ± 4 and 8.8 ± 2 μM, respectively. Since the IC50s 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. Graphical abstract Image 1 Highlights • 17-DMAG inhibits the in vitro multiplication of Babesia and Theileria parasites. • Combination of 17-DMAG with diminazene aceturate or atovaquone were also effective. • 17-DMAG also inhibits the multiplication of B. microti in mice. • 17-DMAG is a new treatment option for babesiosis in animal and human. |
| Databáze: | OpenAIRE |
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