New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2022 |
| Outros Autores: | , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da UNESP |
| Texto Completo: | http://hdl.handle.net/11449/234761 |
Resumo: | Other grants supported: Programa de Apoio ao Desenvolvimento Científico da Faculdade de Ciências Farmacêuticas da UNESP (PADC); and funding from the Thomas P. Infusino Endowment at Rutgers University. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES)-finance code 001 (I.A.P.L., T.G.P., K.B.I., and J.M.V.). M.A.R.B., A.V.G.N., and M.A.S.G. are recipients of a Research Productivity Scholarship from the National Council for Research and Development (CNPq). |
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New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Deathbinuclear cyclopalladated complexcutaneous leishmaniasisnecrotic deathcalcium homeostasismitochondriaLeishmanialeishmanicidal activityOther grants supported: Programa de Apoio ao Desenvolvimento Científico da Faculdade de Ciências Farmacêuticas da UNESP (PADC); and funding from the Thomas P. Infusino Endowment at Rutgers University. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES)-finance code 001 (I.A.P.L., T.G.P., K.B.I., and J.M.V.). M.A.R.B., A.V.G.N., and M.A.S.G. are recipients of a Research Productivity Scholarship from the National Council for Research and Development (CNPq).The current treatment of leishmaniasis is based on a few drugs that present several drawbacks, such as high toxicity, difficult administration route, and low efficacy. These disadvantages raise the necessity to develop novel antileishmanial compounds allied with a comprehensive understanding of their mechanisms of action. Here, we elucidate the probable mechanism of action of the antileishmanial binuclear cyclopalladated complex [Pd(dmba)(m-N3)]2 (CP2) in Leishmania amazonensis. CP2 causes oxidative stress in the parasite, resulting in disruption of mitochondrial Ca2+ homeostasis, cell cycle arrest at the S-phase, increasing the reactive oxygen species (ROS) production and overexpression of stress-related and cell detoxification proteins, and collapsing the Leishmania mitochondrial membrane potential, and promotes apoptotic-like features in promastigotes, leading to necrosis, or directs programmed cell death (PCD)-committed cells toward necrotic-like destruction. Moreover, CP2 reduces the parasite load in both liver and spleen in Leishmania infantum-infected hamsters when treated for 15 days with 1.5 mg/kg body weight/day CP2, expanding its potential application in addition to the already known effectiveness on cutaneous leishmaniasis for the treatment of visceral leishmaniasis, showing the broad spectrum of action of this cyclopalladated complex. The data presented here bring new insights into the CP2 molecular mechanisms of action, assisting the promotion of its rational modification to improve both safety and efficacy.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)São Paulo State University (Unesp), School of Pharmaceutical Sciences, Araraquara, São Paulo, BrazilDepartment of Pharmacology, Physiology, and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USADepartment of Chemistry, São Carlos Institute of Chemistry–IQSC, University of São Paulo (USP), São Carlos, São Paulo, BrazilDepartment of Cellular and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, BrazilLaboratory of Biochemistry, Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo (USP), Bauru, São Paulo, BrazilSão Paulo State University (Unesp), Institute of Chemistry, Araraquara, São Paulo, Brazil2016/05345-42016/1771152017/03552-52018/23015-72016/19289-92016/18191-52019/21661-12020/04415-4American Society for MicrobiologyUniversidade Estadual Paulista (Unesp)Velásquez, Angela Maria ArenasBartlett, PaulaLinares, Irwin Alexander PatinoPassalacqua, Thais G.Teodoro, Daphne D. L.Imamura, Kely B.Virgilio, StelaTosi, Luiz R. O.Leite, Aline de LimaBuzalaf, Marilia A. R.Velasques, Jecika M.Netto, Adelino V. G.Thomas, Andrew P.Graminha, Marcia Aparecida Silva2022-05-17T22:52:55Z2022-05-17T22:52:55Z2022-01-18info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfVELÁSQUEZ, A. M. A.; BARTLETT, P. J.; LINARES, I. A. P.; PASSALACQUA, T. G.; TEODORO, D. D. L.; IMAMURA, K. B.; VIRGILIO, S.; TOSI, L. R. O.; DE, A.; LEITE, L.; BUZALAF, M. A. R.; VELASQUES, J. M.; NETTO, A. V. G.; THOMAS, A. P.; GRAMINHA, M. A. S. New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death. Antimicrobial Agents and Chemotherapy, v. 66, n. 1, e0076721, 2022.1098659600664804http://hdl.handle.net/11449/2347610000-0001-7280-37750000-0002-5985-39510000-0002-2112-13090000-0001-9932-54860000-0002-5277-24890000-0002-9026-74670000-0002-4660-51660000-0002-5655-54490000-0002-4089-12880000-0001-8120-48970000-0001-5195-99650000-0002-0086-93420000-0002-0057-7964enghttps://journals.asm.org/doi/10.1128/AAC.00767-21Antimicrobial Agents and Chemotherapyinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESP2024-06-21T15:19:43Zoai:repositorio.unesp.br:11449/234761Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T23:57:54.285611Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
| dc.title.none.fl_str_mv |
New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death |
| title |
New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death |
| spellingShingle |
New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death Velásquez, Angela Maria Arenas binuclear cyclopalladated complex cutaneous leishmaniasis necrotic death calcium homeostasis mitochondria Leishmania leishmanicidal activity |
| title_short |
New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death |
| title_full |
New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death |
| title_fullStr |
New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death |
| title_full_unstemmed |
New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death |
| title_sort |
New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death |
| author |
Velásquez, Angela Maria Arenas |
| author_facet |
Velásquez, Angela Maria Arenas Bartlett, Paula Linares, Irwin Alexander Patino Passalacqua, Thais G. Teodoro, Daphne D. L. Imamura, Kely B. Virgilio, Stela Tosi, Luiz R. O. Leite, Aline de Lima Buzalaf, Marilia A. R. Velasques, Jecika M. Netto, Adelino V. G. Thomas, Andrew P. Graminha, Marcia Aparecida Silva |
| author_role |
author |
| author2 |
Bartlett, Paula Linares, Irwin Alexander Patino Passalacqua, Thais G. Teodoro, Daphne D. L. Imamura, Kely B. Virgilio, Stela Tosi, Luiz R. O. Leite, Aline de Lima Buzalaf, Marilia A. R. Velasques, Jecika M. Netto, Adelino V. G. Thomas, Andrew P. Graminha, Marcia Aparecida Silva |
| author2_role |
author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) |
| dc.contributor.author.fl_str_mv |
Velásquez, Angela Maria Arenas Bartlett, Paula Linares, Irwin Alexander Patino Passalacqua, Thais G. Teodoro, Daphne D. L. Imamura, Kely B. Virgilio, Stela Tosi, Luiz R. O. Leite, Aline de Lima Buzalaf, Marilia A. R. Velasques, Jecika M. Netto, Adelino V. G. Thomas, Andrew P. Graminha, Marcia Aparecida Silva |
| dc.subject.por.fl_str_mv |
binuclear cyclopalladated complex cutaneous leishmaniasis necrotic death calcium homeostasis mitochondria Leishmania leishmanicidal activity |
| topic |
binuclear cyclopalladated complex cutaneous leishmaniasis necrotic death calcium homeostasis mitochondria Leishmania leishmanicidal activity |
| description |
Other grants supported: Programa de Apoio ao Desenvolvimento Científico da Faculdade de Ciências Farmacêuticas da UNESP (PADC); and funding from the Thomas P. Infusino Endowment at Rutgers University. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES)-finance code 001 (I.A.P.L., T.G.P., K.B.I., and J.M.V.). M.A.R.B., A.V.G.N., and M.A.S.G. are recipients of a Research Productivity Scholarship from the National Council for Research and Development (CNPq). |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022-05-17T22:52:55Z 2022-05-17T22:52:55Z 2022-01-18 |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.uri.fl_str_mv |
VELÁSQUEZ, A. M. A.; BARTLETT, P. J.; LINARES, I. A. P.; PASSALACQUA, T. G.; TEODORO, D. D. L.; IMAMURA, K. B.; VIRGILIO, S.; TOSI, L. R. O.; DE, A.; LEITE, L.; BUZALAF, M. A. R.; VELASQUES, J. M.; NETTO, A. V. G.; THOMAS, A. P.; GRAMINHA, M. A. S. New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death. Antimicrobial Agents and Chemotherapy, v. 66, n. 1, e0076721, 2022. 10986596 00664804 http://hdl.handle.net/11449/234761 0000-0001-7280-3775 0000-0002-5985-3951 0000-0002-2112-1309 0000-0001-9932-5486 0000-0002-5277-2489 0000-0002-9026-7467 0000-0002-4660-5166 0000-0002-5655-5449 0000-0002-4089-1288 0000-0001-8120-4897 0000-0001-5195-9965 0000-0002-0086-9342 0000-0002-0057-7964 |
| identifier_str_mv |
VELÁSQUEZ, A. M. A.; BARTLETT, P. J.; LINARES, I. A. P.; PASSALACQUA, T. G.; TEODORO, D. D. L.; IMAMURA, K. B.; VIRGILIO, S.; TOSI, L. R. O.; DE, A.; LEITE, L.; BUZALAF, M. A. R.; VELASQUES, J. M.; NETTO, A. V. G.; THOMAS, A. P.; GRAMINHA, M. A. S. New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death. Antimicrobial Agents and Chemotherapy, v. 66, n. 1, e0076721, 2022. 10986596 00664804 0000-0001-7280-3775 0000-0002-5985-3951 0000-0002-2112-1309 0000-0001-9932-5486 0000-0002-5277-2489 0000-0002-9026-7467 0000-0002-4660-5166 0000-0002-5655-5449 0000-0002-4089-1288 0000-0001-8120-4897 0000-0001-5195-9965 0000-0002-0086-9342 0000-0002-0057-7964 |
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http://hdl.handle.net/11449/234761 |
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eng |
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eng |
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https://journals.asm.org/doi/10.1128/AAC.00767-21 Antimicrobial Agents and Chemotherapy |
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American Society for Microbiology |
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American Society for Microbiology |
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reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
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Universidade Estadual Paulista (UNESP) |
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