Trypanosoma brucei: trypanocidal and cell swelling activities of lasalocid acid

Abstract

Chemotherapeutic treatment of human and animal trypanosomiasis is unsatisfactory because only a few drugs are available. As these drugs have poor efficacy and cause adverse reactions, more effective and tolerable medications are needed. As the polyether ionophore antibiotic lasalocid acid is used as medicated feed additive in cattle, the compound was tested for its trypanocidal and cytotoxic activity against bloodstream forms of Trypanosoma brucei and human myeloid HL-60 cells. The concentrations required of lasalocid acid to reduce the growth rate of trypanosomes by 50% and to kill the parasites were 1.75 and 10 μM, respectively. The ionophore displayed also cytotoxic activity against HL-60 cells but the human cells were about 10 to 14 times less sensitive indicating moderate selectivity. As the trypanocidal mechanism of action of polyether ionophore antibiotics is due to a sodium influx-induced cell swelling, the effect of lasalocid acid on cell volume change in bloodstream-form trypanosomes was investigated. Interestingly, lasalocid acid induced a much faster cell swelling in trypanosomes than the more trypanocidal related ionophore salinomycin. These results support further investigations of lasalocid acid and derivatives thereof as potential agents against African trypanosomiasis.Electronic supplementary materialThe online version of this article (10.1007/s00436-017-5624-6) contains supplementary material, which is available to authorized users.

Anti-parasitic activity of polyether ionophores

“…This mode of action differs from the mechanism of the anti-cancer activity of salinomycin reported to be the induction of apoptosis [53]. Interestingly, lasalocid acid has been found to induce a much faster cell swelling in trypanosomes than salinomycin and other polyether ionophores, and that the swelling was solely due to the influx of Na + cations [65]. Thus, it has been suggested that lasalocid acid may be directly applicable for the treatment of nagana disease, particularly as it is used in cattle as medicated feed additive ( Table 2)…”

“…As the few commonly used and outdated drugs available to treat sleeping sickness patients have limited efficacy as well as adverse side reactions, novel and better tolerated therapeutic strategies are highly desirable. The results from very recently published studies have clearly shown that three carboxylic polyether ionophores -lasalocid acid, monensin and salinomycin ( Figure 1) -are interesting lead compounds for rational anti-trypanosomal drug development in this context [65][66][67]. Importantly, it has been shown that monensin and salinomycin inhibit the growth of culture-adapted bloodstream forms of T. brucei (clone 427-221a) in vitro at sub-micromolar concentration [66,67].…”

“…Both these salinomycin derivatives(Figure haveenhanced selectivity (GI50 ratio of 288 and 363 for 1 and 2, respectively), proving undoubtedly the huge therapeutic potential of such analogues[66]. On the other hand, none Mannich base derivatives of lasalocid acid displayed better trypanocidal activity and selectivity than the unmodified lasalocid acid[65].…”

“…[65].An attractive approach to improve the activity of lead compounds is their chemical modification as the resulting derivatives may show better biological activity. In the case of salinomycin and monensin, most of the tested derivatives were less active against trypanosomes than their corresponding parent compounds[66].However, two salinomycin derivatives(Figure 4, compounds 12) obtained by chemical modification of its carboxyl group have been identified to display increased trypanocidal activity, with GI50 values in the mid nanomolar range and MIC values of < 1 μM.…”

Anti-trypanosomal activity of doubly modified salinomycin derivatives

“…All SAL precursors and their newly synthesized double-modified derivatives were evaluated for their in vitro activity against bloodstream forms of T. brucei and human myeloid HL-60 cell using the resazurin cell viability assay [28,29]. All compounds showed a dosedependent inhibitory effect on the growth of bloodstream-form trypanosomes ( Table 1).…”