Abstract
Nifurtimox (Nfx) and benznidazole (Bz) are the current drugs used for the treatment of Chagas disease. The mechanisms of action and resistance to these drugs in this parasite are poorly known. Prostaglandin F2α synthase or old yellow enzyme (OYE), an NAD(P)H flavin oxidoreductase, has been involved in the activation pathway of other trypanocidal drugs such as Nfx; however, its role in the mechanism of action of Bz is uncertain. In this paper, we performed some experiments of functional genomics in the parasite Trypanosoma cruzi with the aim to test the role of this gene in the resistance to Bz. For this, we overexpressed this gene in sensitive parasites and evaluated the resistance level to the drug and other chemical compounds such as hydrogen peroxide, methyl methanesulfonate and gamma radiation. Interestingly, parasites overexpressing OYE showed alteration of enzymes associated with oxidative stress protection such as superoxide dismutase A and trypanothione reductase. Furthermore, transfected parasites were more sensitive to drugs, genetic damage and oxidative stress. Additionally, transfected parasites were less infective than wild-type parasites and they showed higher alteration in mitochondrial membrane potential and cell cycle after treatment with Bz. These results supply essential information to help further the understanding of the mechanism of action of Bz in T. cruzi.
Highlights
Nifurtimox (Nfx) and benznidazole (Bz) are the current drugs used for the treatment of Chagas disease
Other evidence is the resistance to hydrogen peroxide (H2O2), where it has been shown that H2O2-resistant parasites are resistant to Bz [3,10] indicating a close relationship between tolerance to oxidative stress and the effect of Bz
The scarce knowledge about the mechanisms of action of Nfx and Bz is an obstacle to the progress of controlling the resistance of T. cruzi and the identification of genes involved in this process, as well as the search for new therapeutic options for treating Chagas disease
Summary
Nifurtimox (Nfx) and benznidazole (Bz) are the current drugs used for the treatment of Chagas disease Their use is characterized by toxicity and low efficacy in the chronic stage of the disease, and cases refractory to the treatment are commonly reported; some of them are associated with the drug resistance of its causative agent, the protozoa Trypanosoma cruzi [1]. T. cruzi’s main defence mechanism against free radicals is trypanothione, characteristic of all trypanosomatids. This hypothesis is supported by recent studies where Bz induces 7,8-dihydro-8-oxoguanine (8-oxoG) formation in T. cruzi, which is the most common and best-characterized lesion created by ROS that in large proportion affects the DNA and induces the death of the parasite [3,10]. Only NTR I has been verified to participate in the activation of Bz by functional genomics, through overexpression in resistant parasites and knockdown in sensitive parasites [11]
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