Buthionine Sulfoximine Increases the Toxicity of Nifurtimox and Benznidazole to
            <i>Trypanosoma cruzi</i>

L-Buthionine (S,R)-sulfoximine (BSO) at a dose of 220 mg/kg of body weight/day showed an anti-Trypanosoma cruzi effect in infected mice, increasing their survival rate and decreasing the parasitemias and parasite burden in the hearts. Treatment with BSO plus nifurtimox caused an increase in the survival rate in comparison to the rates with treatment with each drug alone.Chagas' disease is a clinical condition caused by Trypanosoma cruzi. The limited success and side-effect liabilities of Chagas' disease therapy have led to a continued search for new antitrypanosomal treatments (16,17).The currently used drugs are nifurtimox (Nx) and benznidazole, which act through the formation of free radicals and electrophilic metabolites, respectively (12,14). Both drugs are trypanocidal against all forms of the parasite (16).Aerobic organisms, such as Trypanosoma cruzi, are exposed to reactive oxygen species generated by their metabolism. T. cruzi cells have to handle their endogenously produced reactive oxygen species and also cope with the oxidative burst delivered by the host's immune system and the free radicals and electrophilic metabolites generated by the antichagasic drugs (2, 12, 15).The redox metabolism of trypanosomatids is based on a bis-glutathionylspermidine conjugate, trypanothione, and on the flavoenzyme trypanothione reductase (1, 15).Trypanothione is synthesized by an ATP-dependent reaction catalyzed by trypanothione synthetase using the tripeptide glutathione (GSH) and the polyamine spermidine as substrates. GSH synthesis involves two ATP-requiring enzymes. The first is ␥-glutamylcysteine synthetase and is the rate-limiting step (10). The second is GSH synthetase. GSH synthesis is regulated primarily through ␥-glutamylcysteine synthetase by cysteine availability and GSH feedback inhibition (10).The glutamate analog L-buthionine (S,R)-sulfoximine (BSO) inhibits the synthesis of glutathionylcysteine and, thus, of GSH and trypanothione. The results of a previous report indicate that BSO increased the effects of Nx and benznidazole in an in vitro model of Chagas' disease (7).In agreement with the results of a previous report (9), a significant decrease in GSH content in liver, heart, blood, and kidney in BALB/c mice treated intraperitoneally with 220 mg/kg of body weight/day of BSO (Fig. 1) was observed after 20 days of treatment. The BSO treatment did not show toxic effect. The concentration of GSH was determined by high-pressure liquid chromatography separation and quantification of monobromobimane derivatives (6, 13). In the host, BSO can decrease GSH levels ( Fig. 1), but mammalian cells exert several efficient GSH-independent antioxidant mechanisms (3). Figure 2 shows the effect of BSO upon mice infected with 30,000 T. cruzi metacyclic trypomastigotes of clone Dm 28c. A dose of 220 mg/kg/day of BSO during 20 days significantly increased the survival rate of the mice, from 25% to 80% (Fig. 2A). The Kaplan-Meier nonparametric method was used to estimate the survival functions of the different experimental ...

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“…The results of a previous report indicate that BSO increased the effects of Nx and benznidazole in an in vitro model of Chagas' disease (7).…”

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confidence: 74%

Buthionine Sulfoximine Has Anti- Trypanosoma cruzi Activity in a Murine Model of Acute Chagas' Disease and Enhances the Efficacy of Nifurtimox

Faúndez

López‐Muñoz

Torres

et al. 2008

Antimicrob Agents Chemother

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“…GSH synthesis has not been extensively 259 studied in T. cruzi but BSO has been used as an experimental tool for 260 decreasing GSH and, to a lesser extent, T(SH) 2 and Gsp levels 261 [43,44,53].…”

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confidence: 99%

Insights into the redox biology of Trypanosoma cruzi: Trypanothione metabolism and oxidant detoxification

Irigoı́n

Cibils

Comini

et al. 2008

Free Radical Biology and Medicine

133

100

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“…Viability assays were performed using the formazan formation method, called 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, as previously described (Faundez et al, 2005;Mosmann, 1986). Briefl y, 1 · 10 7 trypomastigotes were incubated in RPMI 1640 culture medium at 37 °C for 24 h with and without addition of the extracts at fi nal concentrations of 10 -500 µg/mL.…”

Section: Trypomastigote Viability Assaymentioning

confidence: 99%

Medicinal Plants of Chile: Evaluation of their Anti-Trypanosoma cruzi Activity

Muñoz¹,

Maya²,

Ferreira³

et al. 2013

Z. Naturforsch. C

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The extracts of several plants of Central Chile exhibited anti-Trypanosoma cruzi trypomastigotes activity. Most active extracts were those obtained from Podanthus ovatifolius, Berberis microphylla, Kageneckia oblonga, and Drimys winteri. The active extract of Drimys winteri (IC 50 51.2 µg/mL) was purifi ed and three drimane sesquiterpenes were obtained: polygodial, drimenol, and isodrimenin. Isodrimenin and drimenol were found to be active against the trypomastigote form of T. cruzi with IC 50 values of 27.9 and 25.1 µM, respectively.

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Buthionine Sulfoximine Increases the Toxicity of Nifurtimox and Benznidazole to Trypanosoma cruzi

Cited by 88 publications

References 27 publications

Buthionine Sulfoximine Has Anti- Trypanosoma cruzi Activity in a Murine Model of Acute Chagas' Disease and Enhances the Efficacy of Nifurtimox

Buthionine Sulfoximine Has Anti- Trypanosoma cruzi Activity in a Murine Model of Acute Chagas' Disease and Enhances the Efficacy of Nifurtimox

Insights into the redox biology of Trypanosoma cruzi: Trypanothione metabolism and oxidant detoxification

Medicinal Plants of Chile: Evaluation of their Anti-Trypanosoma cruzi Activity

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