Hostname: page-component-8448b6f56d-t5pn6 Total loading time: 0 Render date: 2024-04-23T23:22:40.863Z Has data issue: false hasContentIssue false
  • English
  • Français

Trypanosoma cruzi: death phenotypes induced by ortho-naphthoquinone substrates of the aldo-keto reductase (TcAKR). Role of this enzyme in the mechanism of action of β-lapachone

Published online by Cambridge University Press:  05 February 2018

Patricia Andrea Garavaglia ,
María Fernanda Rubio ,
Marc Laverrière ,
Laura Mónica Tasso ,
Laura Edith Fichera ,
Joaquín J B Cannata  and
Gabriela Andrea García
Patricia Andrea Garavaglia
Affiliation:
Instituto Nacional de Parasitología ‘Dr. Mario Fatala Chaben’-A.N.L.I.S. ‘Dr. Carlos G. Malbrán’, Ciudad de Buenos Aires (1063), Argentina
María Fernanda Rubio
Affiliation:
Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari (IDIM-CONICET), Universidad de Buenos Aires, Ciudad de Buenos Aires (1427), Argentina
Marc Laverrière
Affiliation:
Instituto de Investigaciones Biotecnológicas (IIB–INTECH), Universidad Nacional de General San Martín-CONICET, San Martín (1650), Prov. Buenos Aires, Argentina
Laura Mónica Tasso
Affiliation:
Instituto Nacional de Parasitología ‘Dr. Mario Fatala Chaben’-A.N.L.I.S. ‘Dr. Carlos G. Malbrán’, Ciudad de Buenos Aires (1063), Argentina
Laura Edith Fichera
Affiliation:
Instituto Nacional de Parasitología ‘Dr. Mario Fatala Chaben’-A.N.L.I.S. ‘Dr. Carlos G. Malbrán’, Ciudad de Buenos Aires (1063), Argentina
Joaquín J B Cannata
Affiliation:
Instituto de Investigaciones Biotecnológicas (IIB–INTECH), Universidad Nacional de General San Martín-CONICET, San Martín (1650), Prov. Buenos Aires, Argentina
Gabriela Andrea García*
Affiliation:
Instituto Nacional de Parasitología ‘Dr. Mario Fatala Chaben’-A.N.L.I.S. ‘Dr. Carlos G. Malbrán’, Ciudad de Buenos Aires (1063), Argentina
*
Author for correspondence: Gabriela Andrea García, E-mail: gaandgarcia@yahoo.com
Get access Rights & Permissions [Opens in a new window]

Abstract

Several ortho-naphthoquinones (o-NQs) have trypanocidal activity against Trypanosoma cruzi, the aetiological agent of Chagas disease. Previously, we demonstrated that the aldo-keto reductase from this parasite (TcAKR) reduces o-NQs, such as β-lapachone (β-Lap) and 9,10-phenanthrenequinone (9,10-PQ), with concomitant reactive oxygen species (ROS) production. Recent characterization of TcAKR activity and expression in two T. cruzi strains, CL Brener and Nicaragua, showed that TcAKR expression is 2.2-fold higher in CL Brener than in Nicaragua. Here, we studied the trypanocidal effect and induction of several death phenotypes by β-Lap and 9,10-PQ in epimastigotes of these two strains. The CL Brener strain was more resistant to both o-NQs than Nicaragua, indicating that greater TcAKR activity is unlikely to be a major influence on o-NQ toxicity. Evaluation of changes in ROS production, mitochondrial membrane potential, phosphatidylserine exposure and monodansylcadaverine labelling evidenced that β-Lap and 9,10-PQ induce different death phenotypes depending on the combination of drug and T. cruzi strain analysed. To study whether TcAKR participates in o-NQ activation in intact parasites, β-Lap and 9,10-PQ trypanocidal effect was next evaluated in TcAKR-overexpressing parasites. Only β-Lap was more effective and induced greater ROS production in TcAKR-overexpressing epimastigotes than in controls, suggesting that TcAKR may participate in β-Lap activation.

Keywords

Chagas diseasechemotherapyoxido-reductaseregulated cell death
Type
Research Article
Information
Parasitology , Volume 145 , Issue 9 , August 2018 , pp. 1251 - 1259
Check for updates
Copyright
Copyright © Cambridge University Press 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ahn, KJ, Lee, HS, Bai, SK and Song, CW (2013) Enhancement of radiation effect using beta-lapachone and underlying mechanism. Radiation Oncology Journal 31, 57–65.Google Scholar
Beg, MS, Huang, X, Silvers, MA, Gerber, DE, Bolluyt, J, Sarode, V, Fattah, F, Deberardinis, RJ, Merritt, ME, Xie, XJ, Leff, R, Laheru, D and Boothman, DA (2017) Using a novel NQO1 bioactivatable drug, beta-lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer. Journal of Surgical Oncology 116, 83–88.Google Scholar
Biederbick, A, Kern, HF and Elsasser, HP (1995) Monodansylcadaverine (MDC) is a specific in vivo marker for autophagic vacuoles. European Journal of Cell Biology 66, 3–14.Google Scholar
de Castro, SL, Batista, DG, Batista, MM, Batista, W, Daliry, A, de Souza, EM, Menna-Barreto, RF, Oliveira, GM, Salomão, K, Silva, CF, Silva, PB and Soeiro, MN (2011) Experimental chemotherapy for Chagas disease: a morphological, biochemical, and proteomic overview of potential Trypanosoma cruzi targets of amidines derivatives and naphthoquinones. Molecular Biology International 2011, 306928.Google Scholar
Docampo, R, Lopes, JN, Cruz, FS and Souza, W (1977). Trypanosoma cruzi: ultrastructural and metabolic alterations of epimastigotes by beta-lapachone. Experimental Parasitology 42, 142–149.Google Scholar
Dos Anjos, DO, Sobral Alves, ES, Gonçalves, VT, Fontes, SS, Nogueira, ML, Suarez-Fontes, AM, Neves da Costa, JB, Rios-Santos, F and Vannier-Santos, MA (2016) Effects of a novel β-lapachone derivative on Trypanosoma cruzi: parasite death involving apoptosis, autophagy and necrosis. International Journal for Parasitology: Drugs and Drug Resistance 6, 207–219.Google Scholar
Fernandes, MC, Da Silva, EN, Pinto, AV, De Castro, SL and Menna-Barreto, RF (2012) A novel triazolic naphthofuranquinone induces autophagy in reservosomes and impairment of mitosis in Trypanosoma cruzi. Parasitology 139, 26–36.Google Scholar
Garavaglia, PA, Cannata, JJB, Ruiz, AM, Maugeri, D, Duran, R, Galleano, M and Garcia, GA (2010) Identification, cloning and characterization of an aldo-keto reductase from Trypanosoma cruzi with quinone oxidoreductase activity. Molecular and Biochemical Parasitology 173, 132–141.Google Scholar
Garavaglia, PA, Laverrière, M, Cannata, JJ and García, GA (2016) Putative role of the aldo-keto reductase from Trypanosoma cruzi (TcAKR) in benznidazole metabolism. Antimicrobial Agents and Chemotherapy 60, 2664–2670.Google Scholar
Gerber, D, Arriaga, Y, Beg, MS, Dowell, JE, Schiller, JH, Frankel, AE, Leff, R, Meek, C, Bolluyt, J, Fatunde, O, Martinez, RT, Vo, P, Fattah, F, Sarode, V, Zhou, Y, Xie, Y, McLeod, M, Schwartz, B and Boothman, DA (2014) Phase 1 correlative study of ARQ761, a β-lapachone analogue that promotes NQ01-mediated programmed cancer cell necrosis. European Journal of Cancer 50, 84–85.Google Scholar
Goijman, SG and Stoppani, AO (1985) Effects of beta-lapachone, a peroxide-generating quinone, on macromolecule synthesis and degradation in Trypanosoma cruzi. Archives of Biochemistry and Biophysics 240, 273–280.Google Scholar
González, L, García-Huertas, P, Triana-Chávez, O, García, GA, Murta, S and Mejía-Jaramillo, AM (2017) Aldo-keto reductase and alcohol dehydrogenase contribute to benznidazole natural resistance in Trypanosoma cruzi. Molecular Microbiology 106, 704–718.Google Scholar
Grosso, NL, Bua, J, Perrone, AE, González, MN, Bustos, PL, Postan, M and Fichera, LE (2010) Trypanosoma cruzi: biological characterization of an isolate from an endemic area and its susceptibility to conventional drugs. Experimental Parasitology 126, 239–244.Google Scholar
Jamison, JM, Gilloteaux, J, Taper, HS, Calderon, PB and Summers, JL (2002) Autoschizis: a novel cell death. Biochemical Pharmacology 63, 1773–1783.Google Scholar
Koyama, J (2006) Anti-infective quinone derivatives of recent patents. Recent Patents on Anti-Infective Drug Discovery 1, 113–125.Google Scholar
Kubata, BK, Kabututu, Z, Nozaki, T, Munday, CJ, Fukuzumi, S, Ohkubo, K, Lazarus, M, Maruyama, T, Martin, SK, Duszenko, M and Urade, Y (2002) A key role for old yellow enzyme in the metabolism of drugs by Trypanosoma cruzi. The Journal of Experimental Medicine 196, 1241–1251.Google Scholar
Lazarin-Bidóia, D, Desoti, VC, Ueda-Nakamura, T, Dias Filho, BP, Nakamura, CV and Silva, SO (2013) Further evidence of the trypanocidal action of eupomatenoid-5: confirmation of involvement of reactive oxygen species and mitochondria owing to a reduction in trypanothione reductase activity. Free Radical Biology and Medicine 60, 17–28.Google Scholar
Lopes, JN, Cruz, FS, Docampo, R, Vasconcellos, ME, Sampaio, MC, Pinto, AV and Gilbert, B (1978) In vitro and in vivo evaluation of the toxicity of 1,4-naphthoquinone and 1,2-naphthoquinone derivatives against Trypanosoma cruzi. Annals of Tropical Medicine and Parasitology 72, 523–531.Google Scholar
Matsunaga, T, Arakaki, M, Kamiya, T, Endo, S, El-Kabbani, O and Hara, A (2009) Involvement of an aldo-keto reductase (AKR1C3) in redox cycling of 9,10-phenanthrenequinone leading to apoptosis in human endothelial cells. Chemico-Biological Interactions 181, 52–60.Google Scholar
Menna-Barreto, RF, Salomão, K, Dantas, AP, Santa-Rita, RM, Soares, MJ, Barbosa, HS and de Castro, SL (2009) Different cell death pathways induced by drugs in Trypanosoma cruzi: an ultrastructural study. Micron 40, 157–168.Google Scholar
Molina Portela, MP, Fernandez Villamil, SH, Perissinotti, LJ and Stoppani, AO (1996) Redox cycling of o-naphthoquinones in trypanosomatids. Superoxide and hydrogen peroxide production. Biochemical Pharmacology 52, 1875–1882.Google Scholar
Ogindo, CO, Khraiwesh, MH, George, M Jr., Brandy, Y, Brandy, N, Gugssa, A, Ashraf, M, Abbas, M, Southerland, WM, Lee, CM, Bakare, O and Fang, Y (2016) Novel drug design for Chagas disease via targeting Trypanosoma cruzi tubulin: homology modeling and binding pocket prediction on Trypanosoma cruzi tubulin polymerization inhibition by naphthoquinone derivatives. Bioorganic & Medicinal Chemistry 24, 3849–3855.Google Scholar
Park, EJ, Min, KJ, Lee, TJ, Yoo, YH, Kim, YS and Kwon, TK (2014) β-Lapachone induces programmed necrosis through the RIP1-PARP-AIF-dependent pathway in human hepatocellular carcinoma SK-Hep1 cells. Cell Death & Disease 5, e1230.Google Scholar
Pieretti, S, Haanstra, JR, Mazet, M, Perozzo, R, Bergamini, C, Prati, F, Fato, R, Lenaz, G, Capranico, G, Brun, R, Bakker, BM, Michels, PA, Scapozza, L, Bolognesi, ML and Cavalli, A (2013) Naphthoquinone derivatives exert their antitrypanosomal activity via a multi-target mechanism. PLoS Neglected Tropical Diseases 7, 1e12.Google Scholar
Pink, JJ, Planchon, SM, Tagliarino, C, Varnes, ME, Siegel, D and Boothman, DA (2000) NAD(p)H:quinone oxidoreductase activity is the principal determinant of betalapachone cytotoxicity. The Journal of Biological Chemistry 275, 5416–5424.Google Scholar
Ramos, EI, Garza, KM, Krauth-Siegel, RL, Bader, J, Martinez, LE and Maldonado, RA (2009) 2,3-Diphenyl-1,4-naphthoquinone: a potential chemotherapeutic agent against Trypanosoma cruzi. The Journal of Parasitology 95, 461–466.Google Scholar
Salas, C, Tapia, RA, Ciudad, K, Armstrong, V, Orellana, M, Kemmerling, U, Ferreira, J, Maya, JD and Morello, A (2008) Trypanosoma cruzi: activities of lapachol and alpha- and beta-lapachone derivatives against epimastigote and trypomastigote forms. Bioorganic & Medicinal Chemistry 16, 668–674.Google Scholar
Salas, CO, Faúndez, M, Morello, A, Maya, JD and Tapia, RA (2011) Natural and synthetic naphthoquinones active against Trypanosoma cruzi: an initial step towards new drugs for Chagas disease. Current Medicinal Chemistry 18, 144–161.Google Scholar
Salmon-Chemin, L, Buisine, E, Yardley, V, Kohler, S, Debreu, MA, Landry, V, Sergheraert, C, Croft, SL, Krauth-Siegel, RL and Davioud-Charvet, E (2001) 2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity. Journal of Medicinal Chemistry 44, 548–565.Google Scholar
Salomao, K, De Santana, NA, Molina, MT, De Castro, SL and Menna-Barreto, RF (2013) Trypanosoma cruzi mitochondrial swelling and membrane potential collapse as primary evidence of the mode of action of naphthoquinone analogues. BMC Microbiology 3, 1e13.Google Scholar
Sengupta, S, Chowdhury, S, Bosedasgupta, S, Wright, CW and Majumder, HK (2011) Cryptolepine-induced cell death of Leishmania donovani promastigotes is augmented by inhibition of autophagy. Molecular Biology International 2011, 187850.Google Scholar
Silva, MT (2010) Secondary necrosis: the natural outcome of the complete apoptotic program. FEBS Letters 584, 4491–4499.Google Scholar
Silva, JS, Ferrioli-Filho, F, Kanesiro, MM, Ferreira, VF, Santos, SC, Pinto, CN, Fonseca, JL, Mizrahy, HE, Gilbert, B, Pinto, MC, Ribeiro, FW and Pinto, AV (1992) Evaluation of some organic compounds on bloodstream forms of Trypanosoma cruzi. Memórias do Instituto Oswaldo Cruz 87, 345–351.Google Scholar
Smirlis, D, Duszenko, M, Ruiz, AJ, Scoulica, E, Bastien, P, Fasel, N and Soteriadou, K (2010) Targeting essential pathways in trypanosomatids gives insights into protozoan mechanisms of cell death. Parasites & Vectors 3, 107–122.Google Scholar
Sosa-Estani, S, Viotti, R and Segura, EL (2009) Therapy, diagnosis and prognosis of chronic Chagas disease: insight gained in Argentina. Memórias do Instituto Oswaldo Cruz 104, 167–180.Google Scholar
Taguchi, K, Fujii, S, Yamano, S, Cho, AK, Kamisuki, S, Nakai, Y, Sugawara, F, Froines, JR and Kumagai, Y (2007) An approach to evaluate two-electron reduction of 9,10-phenanthraquinone and redox activity of the hydroquinone associated with oxidative stress. Free Radical Biology & Medicine 43, 789–799.Google Scholar
Taylor, MC and Kelly, JM (2006) pTcINDEX: a stable tetracycline-regulated expression vector for Trypanosoma cruzi. BioMed Central Biotechnology 6, 32–50.Google Scholar
Veiga-Santos, P, Barrias, ES, Santos, JF, de Barros Moreira, TL, de Carvalho, TM, Urbina, JA and de Souza, W (2012) Effects of amiodarone and posaconazole on the growth and ultrastructure of Trypanosoma cruzi. International Journal of Antimicrobial Agents 40, 61–71.Google Scholar
Zingales, B, Pereira, ME, Oliveira, RP, Almeida, KA, Umezawa, ES, Souto, RP, Vargas, N, Cano, MI, da Silveira, JF, Nehme, NS, Morel, CM, Brener, Z and Macedo, A (1997) Trypanosoma cruzi genome project: biological characteristics and molecular typing of clone CL Brener. Acta Tropica 68, 159–173.Google Scholar
Zong, WX and Thompson, CB (2006) Necrotic death as a cell fate. Genes and Development 20, 1–15.Google Scholar