Trypanosoma cruzi biochemical changes and cell death induced by an organometallic platinum‐based compound

Abstract

Chagas disease is an endemic illness in Latin America caused by the parasite Trypanosoma cruzi. Current chemotherapies are old and inadequate, and the emergence of drug-resistant strains underscores the need of new drugs. Platinum-based complexes have been shown to be a promising approach against parasitic diseases. In this work, the effect of 1,1'-bis(diphenylphosphino)ferrocene pyridine-2-thiolate-1-oxide Pt(II) hexafluorophosphate, Pt-dppf-mpo, was studied on T. cruzi. A promising antitrypanosomal activity was determined for the CL Brener strain with a low cytotoxicity determined using in vitro-cultured mammal cells. The compound uptake in parasites treated with concentrations of 1× and 10× the IC value reached ~75% and 19%, respectively. Pt-dppf-mpo induced necrosis after 24 hr of parasite incubation. This event was preceded by depolarization of mitochondrial membrane potential. Cell vitality assays showed high esterase activity in treated parasites. However, despite this increase in metabolic activity, treated epimastigotes showed rounded morphology and loss of flagellum with a reduction in mobility as compound concentration and/or time of incubation was increased. At last, we demonstrate that Pt-dppf-mpo incubation also affects the trypomastigote infection process as well as the infection persistence evaluated as the number of amastigotes per cell in a dose-dependent manner.

High Throughput Approaches to Unravel the Mechanism of Action of a New Vanadium-Based Compound against Trypanosoma cruzi

“…ough the percentage of the compound uptaken by the parasites (less than 2.4% of the total vanadium used for incubation) is similar to that obtained for other well-known metallic antiproliferative compounds such as cisplatin (3%), oxaliplatin (1%), or pyrodach-2 (0.1%) in three different human cell lines [39], it is notably lower than the ones obtained for other metal-based compounds (more than 20%) in T. cruzi epimastigotes [25,26]. Nonetheless, the low V IV O(5Brsal)(aminophen) uptake is enough to exert the antiparasitic effect.…”

“…e aim of this work was to evaluate the cellular and molecular mechanism of action of a new vanadium-based compound in T. cruzi. Proliferation assays revealed an IC 50 value of (3.76 ± 0.08) μM, similar to the one of the reference drug nifurtimox, (2.8 ± 0.2) μM [25,26]. us, V IV O(5Brsal)(aminophen) can be visualized as a promising antiproliferative compound.…”

“…Activity. Anti-T. cruzi activity was determined following a previously reported method [25][26][27]. Briefly, an 11.25 mM V IV O(5Brsal)(aminophen) solution was prepared in dimethyl sulfoxide (DMSO).…”

“…To find out if cell death mechanisms such as early apoptosis or necrosis/late apoptosis were involved, we performed flow cytometry analysis with the fluorescent hallmark probes AV and PI as described previously [25][26][27]. e absence of AV and/or PI positive cells after incubation with either 1x, 5x, or 10x IC 50 for 24 h suggests that neither apoptosis nor necrosis processes were triggered by the V IV O(5Brsal)(aminophen) treatment (Figure 3(a)).…”

Challenges in Chagas Disease Drug Development

“…Fexinidazole, an NTR-1-activated 5-nitroimidazole pro-drug [ 31 ], has been shown to outperform both benznidazole and nifurtimox as a curative treatment for experimental T. cruzi infections [ 34 ] ( Figure 2 A,B, as example), and a clinical trial to assess efficacy and tolerability against patients with asymptomatic chronic infections has been undertaken [ 35 ]. In addition, there have also been a number of recent studies reporting encouraging preliminary data on the antiparasite activities of other novel nitroaromatics [ 88 ], and of a new generation of diverse organometallic compounds [ 89 , 90 , 91 , 92 ].…”