The ultimate fate determinants of drug induced cell-death mechanisms in Trypanosomatids

Abstract

Chemotherapy constitutes a major part of modern-day therapy for infectious and chronic diseases. A drug is said to be effective if it can inhibit its target, induce stress, and thereby trigger an array of cell death pathways in the form of programmed cell death, autophagy, necrosis, etc. Chemotherapy is the only treatment choice against trypanosomatid diseases like Leishmaniasis, Chagas disease, and sleeping sickness. Anti-trypanosomatid drugs can induce various cell death phenotypes depending upon the drug dose and growth stage of the parasites. The mechanisms and pathways triggering cell death in Trypanosomatids serve to help identify potential targets for the development of effective anti-trypanosomatids. Studies show that the key proteins involved in cell death of trypanosomatids are metacaspases, Endonuclease G, Apoptosis-Inducing Factor, cysteine proteases, serine proteases, antioxidant systems, etc. Unlike higher eukaryotes, these organisms either lack the complete set of effectors involved in cell death pathways, or are yet to be deciphered. A detailed summary of the existing knowledge of different drug-induced cell death pathways would help identify the lacuna in each of these pathways and therefore open new avenues for research and thereby new therapeutic targets to explore. The cell death pathway associated complexities in metazoans are absent in trypanosomatids; hence this summary can also help understand the trigger points as well as cross-talk between these pathways. Here we provide an in-depth overview of the existing knowledge of these drug-induced trypanosomatid cell death pathways, describe their associated physiological changes, and suggest potential interconnections amongst them.

Antiprotozoal Activity of Benzoylthiourea Derivatives against Trypanosoma cruzi: Insights into Mechanism of Action

“…In the life cycle of T. cruzi , autophagy is induced during metacyclogenesis (the differentiation of epimastigotes to non-replicative and infective trypomastigote forms) [ 64 ] and amastigogenesis (the differentiation of trypomastigotes to intracellular replicative amastigote forms) [ 65 ]. However, trypanocidal compounds can also induce autophagy [ 66 , 67 ]. For instance, dibenzylideneacetone derivates inhibited the proliferation of epimastigotes and amastigotes, and the viability of trypomastigotes of T. cruzi Y strain.…”

Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum

“… 55 The triggered cell death mechanisms depend not only on the type of stimuli but also on the treatment dose and the exposure time. 56 Also, the mechanistic boundaries between the different types of cell death are currently not well determined in Leishmania sp., and cross-talks between the pathways exist. 56 Finally, despite the advances in our understanding of Leishmania cell death, 55 such an in situ evaluation on intracellular parasites is currently challenging at the technical level.…”

Targeting matrix metallopeptidase 2 by hydroxyurea selectively kills acute myeloid mixed-lineage leukemia

“…S5a, b ). Distinct cell death phenotypes depend on the different drug doses [ 50 , 51 ], and this might be owing to drug off-target effects.…”