ew Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Deat

Author(s):Show less -

Velasquez, Angela M. A. ^{[1, 2]} ; Bartlett, Paula J. ^[1] ; Linares, Irwin A. P. ^[3] ; Passalacqua, Thais G. ^[2] ; Teodoro, Daphne D. L. ^[2] ; Imamura, Kely B. ^[2] ; Virgilio, Stela ^[4] ; Tosi, Luiz R. O. ^[4] ; Leite, Aline de Lima ^[5] ; Buzalaf, Marilia A. R. ^[5] ; Velasques, Jecika M. ^[6] ; Netto, Adelino V. G. ^[6] ; Thomas, Andrew P. ^[1] ; Graminha, Marcia A. S. ^{[2, 7]}

Affiliation

^[1] Rutgers State Univ, New Jersey Med Sch, Dept Pharmacol Physiol & Neurosci, Newark, NJ - USA

^[2] Sao Paulo State Univ, Sch Pharmaceut Sci, UNESP, Araraquara, SP - Brazil

^[3] Univ Sao Paulo, Sao Carlos Inst Chem IQSC, Dept Chem, USP, Sao Carlos, SP - Brazil

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Cellular & Mol Biol & Pathogen Bioagents, Ribeirao Preto, SP - Brazil

^[5] Univ Sao Paulo, Bauru Sch Dent, Dept Biol Sci, Lab Biochem, USP, Bauru, SP - Brazil

^[6] Sao Paulo State Univ, Inst Chem, UNESP, Araraquara, SP - Brazil

^[7] UNESP, Dept Anal Clin, Araraquara, SP - Brazil

• Document type: Journal article
• Source: Antimicrobial Agents and Chemotherapy; v. 66, n. 1 JAN 2022.
• Web of Science Citations: 0

Abstract

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)(mu-N-3)](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. (AU)

• FAPESP's process: 16/18191-5 - Characterizing stress response of DNA replication in the protozoan Leishmania: the case of replication-transcription conflict
• Grantee: Stela Virgilio
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/05345-4 - Improving antimicrobial photodynamic therapy for infectious disease associating peptide aurein 1.2
• Grantee: Carla Raquel Fontana
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/23015-7 - Antimicrobial photodynamic therapy by continuous and switched mode irradiation against Enterococcus faecalis and Cutibacterium acnes
• Grantee: Carla Raquel Fontana
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/04415-4 - Therapeutics for leishmaniasis: from screening to the study of mechanisms of action, a contribution to the discovery of new antileishmanial molecules
• Grantee: Marcia Aparecida Silva Graminha
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/03552-5 - Leishmaniasis: from screening to the study of mechanisms of action, a contribution to the discovery of new bioactive molecules
• Grantee: Marcia Aparecida Silva Graminha
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/19289-9 - Characterization of Mechanism of cell death potentially induced by a binuclear antileishmanial cyclopalladated CP2: a contribution to the rational drug development
• Grantee: Angela Maria Arenas Velásquez
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/21661-1 - New insight into the mechanism of action of CP2 in Leishmania: analysis of calcium homeostasis and the respiratory chain
• Grantee: Angela Maria Arenas Velásquez
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor