Drug Repurposing in Chagas Disease: Chloroquine Potentiates Benznidazole Activity against Trypanosoma cruzi In Vitro and In Vivo

Imagem de Miniatura
Arquivos
art_PANDEY_Drug_Repurposing_in_Chagas_Disease_Chloroquine_Potentiates_Benznidazole_2022.PDF (3.22 MB)
Citações na Scopus
5
Tipo de produção
article
Data de publicação
2022
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
AMER SOC MICROBIOLOGY
Autores
PANDEY, Ramendra P.
FRANCO, Caio Haddad
BORTOLUCI, Karina
SILVA, Marcelo Nunes
ZINGALES, Bianca
GIBALDI, Daniel
BARRIOS, Leda Castano
LANNES-VIEIRA, Joseli
CARISTE, Leonardo Moro
Citação
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, v.66, n.11, 2022
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Drug combinations and drug repurposing have emerged as promising strategies to develop novel treatments for infectious diseases, including Chagas disease. In this study, we aimed to investigate whether the repurposed drugs chloroquine (CQ) and colchicine (COL), known to inhibit Trypanosoma cruzi infection in host cells, could boost the anti-T. cruzi effect of the trypanocidal drug benznidazole (BZN), increasing its therapeutic efficacy while reducing the dose needed to eradicate the parasite. The combination of BZN and COL exhibited cytotoxicity to infected cells and low antiparasitic activity. Conversely, a combination of BZN and CQ significantly reduced T. cruzi infection in vitro, with no apparent cytotoxicity. This effect seemed to be consistent across different cell lines and against both the partially BZN-resistant Y and the highly BZN-resistant Colombiana strains. In vivo experiments in an acute murine model showed that the BZN+CQ combination was eight times more effective in reducing T. cruzi infection in the acute phase than BZN monotherapy. In summary, our results demonstrate that the concomitant administration of CQ and BZN potentiates the trypanocidal activity of BZN, leading to a reduction in the dose needed to achieve an effective response. In a translational context, it could represent a higher efficacy of treatment while also mitigating the adverse effects of high doses of BZN. Our study also reinforces the relevance of drug combination and repurposing approaches in the field of Chagas disease drug discovery.
Palavras-chave
Chagas disease drug discovery, drug combination, drug repurposing, chloroquine, benznidazole
URI
https://observatorio.fm.usp.br/handle/OPI/50378
Referências
  1. Alcantara LM, 2018, INT J PARASITOL-DRUG, V8, P430, DOI 10.1016/j.ijpddr.2018.09.006
  2. Barbosa AP, 2011, ARQ BRAS CARDIOL, V97, P517, DOI 10.1590/S0066-782X2011005000112
  3. Benvenuti LA, 2008, ANN TROP MED PARASIT, V102, P481, DOI 10.1179/136485908X311740
  4. Burleigh Barbara A, 2005, Sci STKE, V2005, ppe36, DOI 10.1126/stke.2932005pe36
  5. Bustamante JM, 2002, INT J PARASITOL, V32, P889, DOI 10.1016/S0020-7519(02)00023-1
  6. Cafferata ML, 2020, REPROD HEALTH, V17, DOI 10.1186/s12978-020-00972-1
  7. Cal M, 2016, INT J PARASITOL-DRUG, V6, P165, DOI 10.1016/j.ijpddr.2016.08.003
  8. Caldas S, 2012, ACTA TROP, V123, P170, DOI 10.1016/j.actatropica.2012.05.002
  9. Chatelain E, 2017, COMPUT STRUCT BIOTEC, V15, P98, DOI 10.1016/j.csbj.2016.12.002
  10. Circu M, 2017, PLOS ONE, V12, DOI 10.1371/journal.pone.0184922
  11. Coban C, 2020, CURR OPIN IMMUNOL, V66, P98, DOI 10.1016/j.coi.2020.07.005
  12. de Souza Wanderley, 2010, Int J Cell Biol, V2010, DOI 10.1155/2010/295394
  13. Diniz LD, 2018, ANTIMICROB AGENTS CH, V62, DOI [10.1128/AAC.00401-18, 10.1128/aac.00401-18]
  14. Engel JC, 2010, ANTIMICROB AGENTS CH, V54, P3326, DOI 10.1128/AAC.01777-09
  15. Field MC, 2017, NAT REV MICROBIOL, V15, DOI 10.1038/nrmicro.2016.193
  16. FILARDI LS, 1987, T ROY SOC TROP MED H, V81, P755, DOI 10.1016/0035-9203(87)90020-4
  17. Fivelman QL, 2004, ANTIMICROB AGENTS CH, V48, P4097, DOI 10.1128/AAC.48.11.4097-4102.2004
  18. Franco CH, 2019, TROP MED INFECT DIS, V4, DOI 10.3390/tropicalmed4020082
  19. Lidani KCF, 2019, FRONT PUBLIC HEALTH, V7, DOI 10.3389/fpubh.2019.00166
  20. Alvarez MG, 2020, ANTIMICROB AGENTS CH, V64, DOI 10.1128/AAC.00439-20
  21. Garcia S, 2005, ANTIMICROB AGENTS CH, V49, P1521, DOI 10.1128/AAC.49.4.1521-1528.2005
  22. Jang CH, 2006, RHEUMATOLOGY, V45, P703, DOI 10.1093/rheumatology/kei282
  23. Karres I, 1998, AM J PHYSIOL-REG I, V274, pR1058, DOI 10.1152/ajpregu.1998.274.4.R1058
  24. Kaufmann SHE, 2018, NAT REV DRUG DISCOV, V17, P35, DOI 10.1038/nrd.2017.162
  25. Kratz JM, 2018, EXPERT REV CLIN PHAR, V11, P943, DOI 10.1080/17512433.2018.1509704
  26. Kratz JM, 2019, ACTA TROP, V198, DOI 10.1016/j.actatropica.2019.105107
  27. Krishnan MN, 2014, VIRUSES-BASEL, V6, P683, DOI 10.3390/v6020683
  28. Kuznik A, 2011, J IMMUNOL, V186, P4794, DOI 10.4049/jimmunol.1000702
  29. Lee BY, 2013, LANCET INFECT DIS, V13, P342, DOI 10.1016/S1473-3099(13)70002-1
  30. Leung YY, 2015, SEMIN ARTHRITIS RHEU, V45, P341, DOI 10.1016/j.semarthrit.2015.06.013
  31. LEY V, 1990, J EXP MED, V171, P401, DOI 10.1084/jem.171.2.401
  32. Lo Presti MS, 2004, INT J ANTIMICROB AG, V23, P634, DOI 10.1016/j.ijantimicag.2003.10.006
  33. MacLean LM, 2018, PLOS NEGLECT TROP D, V12, DOI 10.1371/journal.pntd.0006612
  34. Manque PA, 2011, INFECT IMMUN, V79, P1855, DOI 10.1128/IAI.00643-10
  35. Mauthe M, 2018, AUTOPHAGY, V14, P1435, DOI 10.1080/15548627.2018.1474314
  36. Molina I, 2014, NEW ENGL J MED, V370, P1899, DOI 10.1056/NEJMoa1313122
  37. Molina-Morant D, 2020, TRIALS, V21, DOI 10.1186/s13063-020-4226-2
  38. Moore BR, 2011, ANTIMICROB AGENTS CH, V55, P3899, DOI 10.1128/AAC.00067-11
  39. Moraes CB, 2014, SCI REP-UK, V4, DOI 10.1038/srep04703
  40. Morillo CA, 2015, NEW ENGL J MED, V373, P1295, DOI 10.1056/NEJMoa1507574
  41. Morillo CA, 2017, J AM COLL CARDIOL, V69, P939, DOI 10.1016/j.jacc.2016.12.023
  42. MOSMANN T, 1983, J IMMUNOL METHODS, V65, P55, DOI 10.1016/0022-1759(83)90303-4
  43. Portella DCN, 2021, STEM CELLS INT, V2021, DOI 10.1155/2021/2642807
  44. Odds FC, 2003, J ANTIMICROB CHEMOTH, V52, P1, DOI 10.1093/jac/dkg301
  45. Parihar SP, 2014, J INFECT DIS, V209, P754, DOI 10.1093/infdis/jit550
  46. Perez-Molina JA, 2009, J ANTIMICROB CHEMOTH, V64, P1139, DOI 10.1093/jac/dkp357
  47. Ferreira LRP, 2017, SCI REP-UK, V7, DOI 10.1038/s41598-017-18080-9
  48. Reimao JQ, 2016, EVID-BASED COMPL ALT, V2016, DOI 10.1155/2016/1523691
  49. Rodriguez A, 1996, J CELL BIOL, V134, P349, DOI 10.1083/jcb.134.2.349
  50. Romanha AJ, 2010, MEM I OSWALDO CRUZ, V105, P233, DOI 10.1590/S0074-02762010000200022
  51. Sales PA, 2017, AM J TROP MED HYG, V97, P1289, DOI 10.4269/ajtmh.16-0761
  52. Sanchez-Valdez FJ, 2018, ELIFE, V7, DOI 10.7554/eLife.34039
  53. Schor S, 2018, ACS INFECT DIS, V4, P88, DOI 10.1021/acsinfecdis.7b00268
  54. Schrezenmeier E, 2020, NAT REV RHEUMATOL, V16, P155, DOI 10.1038/s41584-020-0372-x
  55. Sosa-Estani S, 2006, CURR OPIN INFECT DIS, V19, P583, DOI 10.1097/01.qco.0000247592.21295.a5
  56. Stecconi-Silva RB, 2003, MEM I OSWALDO CRUZ, V98, P953, DOI 10.1590/S0074-02762003000700016
  57. Torrico Faustino, 2021, Lancet Infect Dis, V21, P1129, DOI 10.1016/S1473-3099(20)30844-6
  58. Torrico F, 2018, LANCET INFECT DIS, V18, P419, DOI 10.1016/S1473-3099(17)30538-8
  59. Vilar-Pereira G, 2016, ANTIMICROB AGENTS CH, V60, P4297, DOI 10.1128/AAC.02123-15
  60. Wei L, 2021, CELL REP MED, V2, DOI 10.1016/j.xcrm.2021.100423
  61. World Health Organization, 2022, CHAG DIS ALSO KNOW A
  62. Yoshida N, 2006, AN ACAD BRAS CIENC, V78, P87, DOI 10.1590/S0001-37652006000100010
  63. Zingales B, 2014, MEM I OSWALDO CRUZ, V109, P828, DOI 10.1590/0074-0276140156

Coleções
Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - HC/InCor
Artigos e Materiais de Revistas Científicas - LIM/19
Artigos e Materiais de Revistas Científicas - LIM/49
Artigos e Materiais de Revistas Científicas - LIM/60