**4. Oxidative stress as a source of chemotherapy targets**

Numerous therapeutic strategies exploit redox systems [124], including protozoal diseases [125], such as CD [126]. Therefore, antioxidant systems including SOD, trypanothione, and enzymes action on this glutathione-spermidine adduct (*N*1,*N*8 bis(glutathionyl)spermidine), such as trypanothione reductase, can comprise important chemotherapy targets [127]. Natural products such as the naphthoquinones -/β-lapachones [128–130] and their derivatives [131, 132] have microbicidal activity against *T. cruzi*, among other pathogens [132]. Interestingly, β-lapachone derivatives were shown to cause mitochondrial dysfunction [131], damage [133], and autophagy, including mitophagy as well as apoptosis and necrosis [134]. In this regard, mitochondria comprise important therapeutical targets for cancer [135], aging [136], cardiovascular diseases [137], and degenerative diseases such as rheumatoid arthritis [138], Alzheimer's disease [139], Parkinson's disease [140], etc. Mitochondria are also promising target for antiparasitic [141, 142] and particularly antiprotozoal [143–145] therapeutic agents, specifically approached in trypanosomatids [146–148].

Up to 2% of the O2 reaching the mitochondrial matrix is converted to O2 •− (superoxide anions) forming H2O2 via SOD [149]. Like mammalian cells, *T. cruzi* mitochondria are a source of ROS [150] producing superoxide. Therefore, the Mn-SOD is important for controlling oxidative stress in this redox organelle. Contrary to mammals, the trypanosomatid mitochondria present FeSOD [151] that can protect from O2 •− produced by macrophages [152].

Because of the prooxidant effects of antiparasitic drugs [126, 153–155], ROS detoxifying systems may comprise valuable scape mechanisms from pharmaceutical intervention [156] and programmed cell death triggered by mitochondrial O2 •− [157].

The prooxidant capacity of both NFX and BZ, particularly in the former, is due to redox cycling with the production of O2 •− [126, 158–160]. Superoxide may be not produced by BZ in the parasite, but in the host cell [161]. Therefore, FeSOD is linked to BZ resistance in *T. cruzi* [66, 162, 163]. Proteome of BZ-resistant *Trypanosoma cruzi* revealed enhanced FeSOD activity [164]. BZ resistance was associated to decreased cytosolic SOD but enhanced mitochondrial MnSOD and tryparedoxin-1 [165]. The deletion of the *sodb1* gene enhances *Trypanosoma brucei* susceptibility to BZ and NTX [166]. FeSOD is also implicated in drug resistance in *L.* (*Viannia*) *braziliensis* and *L.* (*Leishmania*) *infantum* [167, 168] *Entamoeba histolytica* [169]. Tryparedoxin peroxidase is also associated to antimony resistance in *L.* (*V.*) *braziliensis* [170]. In addition, SOD inhibition was reported to decrease parasitemia in *T. cruzi* murine infection [171].

Sirtuins are a highly conserved family of enzymes that deacetylate lysine residues on histone and non-histone proteins, using NAD+ as a cosubstrate, regulating cellular antioxidant/Redox mechanisms [172, 173]. It is noteworthy that SIRT3, 4, and 5 are found in the mitochondrial matrix [174]. As cardiomyocyte mitochondrial dysfunction plays a central role in chagasic myocarditis (*vide supra*), the activation of sirtuins such as SIRT1 by agonists including resveratrol may enhance antioxidant defenses [175], and SIRT3 activates MnSOD, scavenging ROS [176]. Nevertheless, the sirtuin TcSir2rp3 was shown to increase *T. cruzi* resistance to BZ and NTX for overexpressing TcFeSOD-A activities [177].

Selenium and selenium-containing compounds show beneficial effects both in murine [178–180] and human *T. cruzi* infection [181, 182], therefore comprise *Translational Research on Chagas Disease: Focusing on Drug Combination and Repositioning DOI: http://dx.doi.org/10.5772/intechopen.104231*

promising coadjuvant therapies for CD [183–185], although selenium was previously reported to increase tissue parasitism [186].

This activity maybe largely dependent on redox regulation as this inflammatory infection is associated with intense oxidative stress, and selenium may be antioxidant [187] and anti-inflammatory [188], as well as catalyze hydrogen peroxide (H2O2) reduction [189], therefore possibly diminishing the oxidative stress in infected cardiomyocytes, by impairing the Fenton reaction in the presence of iron.
