The binuclear cyclopalladated complex CP2 is targeting ubiquinol-cytochrome c reductase (complex III) of Leishmania amazonensis
Leishmaniasis is a neglected disease that remains with a limited number of drugs available for chemotherapy and has an increased drug resistance that affects treatment outcomes. Metal-based drugs such as cyclopalladated complex [Pd(dmba)(μ-N3)]2 (CP2), a Leishmania topoisomerase IB inhibitor involve...
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Elsevier
2025-04-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320724000551 |
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| author | Angela Maria Arenas Velásquez Irwin Alexander Patino Linares Lawrence D. Gaspers Paula J. Bartlett Jecika M. Velasques Adelino V.G. Netto Andrew P. Thomas Marcia A.S. Graminha |
| author_facet | Angela Maria Arenas Velásquez Irwin Alexander Patino Linares Lawrence D. Gaspers Paula J. Bartlett Jecika M. Velasques Adelino V.G. Netto Andrew P. Thomas Marcia A.S. Graminha |
| author_sort | Angela Maria Arenas Velásquez |
| collection | DOAJ |
| description | Leishmaniasis is a neglected disease that remains with a limited number of drugs available for chemotherapy and has an increased drug resistance that affects treatment outcomes. Metal-based drugs such as cyclopalladated complex [Pd(dmba)(μ-N3)]2 (CP2), a Leishmania topoisomerase IB inhibitor involved in calcium dysregulation and mitochondrial dysfunction of the parasite, had been an alternative to outline the appearance of chemoresistance. To identify new molecular targets and point out possible resistance mechanisms, a CP2-resistant Leishmania amazonensis (LaR) was selected by stepwise exposure to increasing drug pressure until a line capable of growth in 13.3 μM CP2. LaR IC50 value was 52.4 μM (4-fold higher than L. amazonensis–wild type, La). LaR promastigotes were cross-resistant to other DNA topoisomerase I inhibitors (camptothecin) and more susceptible to anti-leishmanial drugs pentamidine and miltefosine. A protective effect on cell viability was observed by pretreating the parasite with Ca2+ channel blockers followed by CP2 in La but not in LaR. Analyses of the cell viability of La and LaR using electron transport chain (ETC) inhibitors demonstrated that La is more sensitive than LaR. The studies of mitochondrial oxygen consumption demonstrated that LaR is less susceptible to complex III (ubiquinol-cytochrome c reductase – CcR) inhibitor, antimycin A (AA). CcR activities of La and LaR were equal for both strains in the absence of CP2 and significantly decreased, 69 % for La and 51 % for LaR, in the presence of CP2. This resistance is attributed to overexpression of CcR, confirmed by the RT-qPCR. CcR inhibition by CP2 leads the parasite to increase the reactive oxygen species (ROS) production, principally in La. Therefore, in this work, we suggested that CcR is the main target of CP2 in the mitochondria, acting to inhibit mitochondria respiratory, and the LaR mutant has increased activity of CcR, which reduces the formation of ROS. |
| format | Article |
| id | doaj-art-af3169d3b6d7449781e84c2c91ca4f9b |
| institution | DOAJ |
| issn | 2211-3207 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
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| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj-art-af3169d3b6d7449781e84c2c91ca4f9b2025-08-20T03:08:37ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072025-04-012710057410.1016/j.ijpddr.2024.100574The binuclear cyclopalladated complex CP2 is targeting ubiquinol-cytochrome c reductase (complex III) of Leishmania amazonensisAngela Maria Arenas Velásquez0Irwin Alexander Patino Linares1Lawrence D. Gaspers2Paula J. Bartlett3Jecika M. Velasques4Adelino V.G. Netto5Andrew P. Thomas6Marcia A.S. Graminha7São Paulo State University (Unesp), School of Pharmaceutical Sciences, Araraquara, São Paulo, Brazil; Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USADepartment of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USADepartment of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USADepartment of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USASão Paulo State University (Unesp), Institute of Chemistry, Araraquara, São Paulo, BrazilSão Paulo State University (Unesp), Institute of Chemistry, Araraquara, São Paulo, BrazilDepartment of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA; Corresponding author. Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Medical Science Building, 185 South Orange Avenue, Newark, NJ, 07103, USA.São Paulo State University (Unesp), School of Pharmaceutical Sciences, Araraquara, São Paulo, Brazil; Corresponding author. Laboratório de Parasitologia Clínica, Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas, UNESP- Araraquara, Rodovia Araraquara-Jaú Km 01, Campus Ville, Araraquara, SP, 14800, Brazil.Leishmaniasis is a neglected disease that remains with a limited number of drugs available for chemotherapy and has an increased drug resistance that affects treatment outcomes. Metal-based drugs such as cyclopalladated complex [Pd(dmba)(μ-N3)]2 (CP2), a Leishmania topoisomerase IB inhibitor involved in calcium dysregulation and mitochondrial dysfunction of the parasite, had been an alternative to outline the appearance of chemoresistance. To identify new molecular targets and point out possible resistance mechanisms, a CP2-resistant Leishmania amazonensis (LaR) was selected by stepwise exposure to increasing drug pressure until a line capable of growth in 13.3 μM CP2. LaR IC50 value was 52.4 μM (4-fold higher than L. amazonensis–wild type, La). LaR promastigotes were cross-resistant to other DNA topoisomerase I inhibitors (camptothecin) and more susceptible to anti-leishmanial drugs pentamidine and miltefosine. A protective effect on cell viability was observed by pretreating the parasite with Ca2+ channel blockers followed by CP2 in La but not in LaR. Analyses of the cell viability of La and LaR using electron transport chain (ETC) inhibitors demonstrated that La is more sensitive than LaR. The studies of mitochondrial oxygen consumption demonstrated that LaR is less susceptible to complex III (ubiquinol-cytochrome c reductase – CcR) inhibitor, antimycin A (AA). CcR activities of La and LaR were equal for both strains in the absence of CP2 and significantly decreased, 69 % for La and 51 % for LaR, in the presence of CP2. This resistance is attributed to overexpression of CcR, confirmed by the RT-qPCR. CcR inhibition by CP2 leads the parasite to increase the reactive oxygen species (ROS) production, principally in La. Therefore, in this work, we suggested that CcR is the main target of CP2 in the mitochondria, acting to inhibit mitochondria respiratory, and the LaR mutant has increased activity of CcR, which reduces the formation of ROS.http://www.sciencedirect.com/science/article/pii/S2211320724000551Leishmania amazonensisCyclopalladated complexUbiquinol-cytochrome c reductaseAnti-leishmanial drugMitochondrial oxygen consumptionMitochondrial calcium uniporter |
| spellingShingle | Angela Maria Arenas Velásquez Irwin Alexander Patino Linares Lawrence D. Gaspers Paula J. Bartlett Jecika M. Velasques Adelino V.G. Netto Andrew P. Thomas Marcia A.S. Graminha The binuclear cyclopalladated complex CP2 is targeting ubiquinol-cytochrome c reductase (complex III) of Leishmania amazonensis International Journal for Parasitology: Drugs and Drug Resistance Leishmania amazonensis Cyclopalladated complex Ubiquinol-cytochrome c reductase Anti-leishmanial drug Mitochondrial oxygen consumption Mitochondrial calcium uniporter |
| title | The binuclear cyclopalladated complex CP2 is targeting ubiquinol-cytochrome c reductase (complex III) of Leishmania amazonensis |
| title_full | The binuclear cyclopalladated complex CP2 is targeting ubiquinol-cytochrome c reductase (complex III) of Leishmania amazonensis |
| title_fullStr | The binuclear cyclopalladated complex CP2 is targeting ubiquinol-cytochrome c reductase (complex III) of Leishmania amazonensis |
| title_full_unstemmed | The binuclear cyclopalladated complex CP2 is targeting ubiquinol-cytochrome c reductase (complex III) of Leishmania amazonensis |
| title_short | The binuclear cyclopalladated complex CP2 is targeting ubiquinol-cytochrome c reductase (complex III) of Leishmania amazonensis |
| title_sort | binuclear cyclopalladated complex cp2 is targeting ubiquinol cytochrome c reductase complex iii of leishmania amazonensis |
| topic | Leishmania amazonensis Cyclopalladated complex Ubiquinol-cytochrome c reductase Anti-leishmanial drug Mitochondrial oxygen consumption Mitochondrial calcium uniporter |
| url | http://www.sciencedirect.com/science/article/pii/S2211320724000551 |
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