Intrinsic and Chemotherapeutic Stressors Modulate ABCC-Like Transport in Trypanosoma cruzi |
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Authors: | Kelli Monteiro da Costa Eduardo J Salustiano Raphael do Carmo Valente Leonardo Freire-de-Lima Lucia Mendona-Previato Jos Osvaldo Previato |
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Institution: | 1.Laboratory of Glycobiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, RJ, Brazil; (E.J.S.); (L.F.L.); (J.O.P.);2.Nucleus of Multidisciplinary Research in Biology (Numpex-Bio), UFRJ Duque de Caxias Campus—Professor Geraldo Cidade, Federal University of Rio de Janeiro (UFRJ), Duque de Caxias 25250-470, RJ, Brazil; |
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Abstract: | 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. |
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Keywords: | ABC transporter drug resistance benznidazole ceramide hemin thiol oxidative stress environmental stress |
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