Intrinsic and Chemotherapeutic Stressors Modulate ABCC-Like Transport in Trypanosoma cruzi

Autor:	Kelli Monteiro da Costa, Raphael C. Valente, Eduardo J. Salustiano, Lucia Mendonça-Previato, José O. Previato, Leonardo Freire-de-Lima
Jazyk:	angličtina
Rok vydání:	2021
Předmět:	Chagas disease Trypanosoma cruzi 030231 tropical medicine Cellular detoxification Pharmaceutical Science ATP-binding cassette transporter Pharmacology medicine.disease_cause Article Analytical Chemistry 03 medical and health sciences chemistry.chemical_compound QD241-441 0302 clinical medicine Drug Discovery medicine Animals oxidative stress Chagas Disease ceramide Physical and Theoretical Chemistry hemin 030304 developmental biology benznidazole 0303 health sciences drug resistance biology Organic Chemistry thiol Biological Transport Glutathione medicine.disease biology.organism_classification Trypanocidal Agents environmental stress chemistry Nitroimidazoles Chemistry (miscellaneous) Benznidazole Molecular Medicine ATP-Binding Cassette Transporters Efflux ABC transporter Oxidative stress medicine.drug
Zdroj:	Molecules Molecules, Vol 26, Iss 3510, p 3510 (2021) Volume 26 Issue 12
ISSN:	1420-3049
Popis:	Trypanosoma cruzi is the etiologic agent for Chagas disease, which affects 6–7 million people worldwide. The biological diversity of the parasite reflects on inefficiency of benznidazole, which is a first choice chemotherapy, on chronic patients. ABC transporters that extrude xenobiotics, metabolites, and mediators are overexpressed in resistant cells and contribute to chemotherapy failure. An ABCC-like transport was identified in the Y strain and extrudes thiol-conjugated compounds. As thiols represent a line of defense towards reactive species, we aimed to verify whether ABCC-like transport could participate in the regulation of responses to stressor stimuli. In order to achieve this, ABCC-like activity was measured by flow cytometry using fluorescent substrates. The present study reveals the participation of glutathione and ceramides on ABCC-like transport, which are both implicated in stress. Hemin modulated the ABCC-like efflux which suggests that this protein might be involved in cellular detoxification. Additionally, all strains evaluated exhibited ABCC-like activity, while no ABCB1-like activity was detected. Results suggest that ABCC-like efflux is not associated with natural resistance to benznidazole, since sensitive strains showed higher activity than the resistant ones. Although benznidazole is not a direct substrate, ABCC-like efflux increased after prolonged drug exposure and this indicates that the ABCC-like efflux mediated protection against cell stress depends on the glutathione biosynthesis pathway.
Databáze:	OpenAIRE
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