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Mitochondria and lipid raft-located FOF1-ATP synthase as major therapeutic targets in the antileishmanial and anticancer activities of ether lipid edelfosine
- Source :
- Digital.CSIC. Repositorio Institucional del CSIC, instname, PLoS Neglected Tropical Diseases, GREDOS. Repositorio Institucional de la Universidad de Salamanca, PLoS Neglected Tropical Diseases, Vol 11, Iss 8, p e0005805 (2017)
- Publication Year :
- 2017
- Publisher :
- Public Library of Science, 2017.
-
Abstract
- [Background]:Leishmaniasis is the world's second deadliest parasitic disease after malaria, and current treatment of the different forms of this disease is far from satisfactory. Alkylphospholipid analogs (APLs) are a family of anticancer drugs that show antileishmanial activity, including the first oral drug (miltefosine) for leishmaniasis and drugs in preclinical/clinical oncology trials, but their precise mechanism of action remains to be elucidated.<br />[Methodology/Principal Findings]:Here we show that the tumor cell apoptosis-inducer edelfosine was the most effective APL, as compared to miltefosine, perifosine and erucylphosphocholine, in killing Leishmania spp. promastigotes and amastigotes as well as tumor cells, as assessed by DNA breakdown determined by flow cytometry. In studies using animal models, we found that orally-administered edelfosine showed a potent in vivo antileishmanial activity and diminished macrophage pro-inflammatory responses. Edelfosine was also able to kill Leishmania axenic amastigotes. Edelfosine was taken up by host macrophages and killed intracellular Leishmania amastigotes in infected macrophages. Edelfosine accumulated in tumor cell mitochondria and Leishmania kinetoplast-mitochondrion, and led to mitochondrial transmembrane potential disruption, and to the successive breakdown of parasite mitochondrial and nuclear DNA. Ectopic expression of Bcl-XL inhibited edelfosine-induced cell death in both Leishmania parasites and tumor cells. We found that the cytotoxic activity of edelfosine against Leishmania parasites and tumor cells was associated with a dramatic recruitment of FOF1-ATP synthase into lipid rafts following edelfosine treatment in both parasites and cancer cells. Raft disruption and specific FOF1-ATP synthase inhibition hindered edelfosine-induced cell death in both Leishmania parasites and tumor cells. Genetic deletion of FOF1-ATP synthase led to edelfosine drug resistance in Saccharomyces cerevisiae yeast.<br />[Conclusions/Significance]:The present study shows that the antileishmanial and anticancer actions of edelfosine share some common signaling processes, with mitochondria and raft-located FOF1-ATP synthase being critical in the killing process, thus identifying novel druggable targets for the treatment of leishmaniasis.<br />This work was supported by grants from the Spanish Ministerio de Economia y Competitividad (SAF2014-59716-R and BIO2014-56930-P), Instituto de Salud Carlos III (RD12/0036/0065 from Red TemaÂtica de Investigación Cooperativa en Cáncer, cofunded by the EU's European Regional Development Fund ± FEDER),European Community's Seventh Framework Programme FP7-2007-2013 (grant HEALTH-F2-2011-256986, PANACREAS), and Spain-UK International Joint Project grant from The Royal Society-CSIC (2004GB0032). CG was supported by the RamoÂn y Cajal Program from the Spanish Ministerio de Ciencia e Innovación.AÂCM was recipient of Formación de Profesorado Universitario predoctoral fellowship from the Spanish Ministerio de Ciencia e Innovación.
- Subjects :
- 0301 basic medicine
Life Cycles
Molecular biology
Apoptosis
Pharmacology
Protozoology
Biochemistry
chemistry.chemical_compound
Mice
White Blood Cells
0302 clinical medicine
MItocondrias
Animal Cells
Zoonoses
Medicine and Health Sciences
Macrophage
Tratamiento
Leishmaniosis
Leishmaniasis
Cells, Cultured
Energy-Producing Organelles
Leishmania
Membrane Potential, Mitochondrial
Protozoans
Cell Death
lcsh:Public aspects of medicine
Phospholipid Ethers
Perifosine
Lipids
3. Good health
Mitochondria
Proton-Translocating ATPases
Treatment Outcome
Infectious Diseases
Cell Processes
030220 oncology & carcinogenesis
Protozoan Life Cycles
Cellular Structures and Organelles
Cellular Types
medicine.drug
Edelfosine
Research Article
Neglected Tropical Diseases
lcsh:Arctic medicine. Tropical medicine
lcsh:RC955-962
Cell Survival
Immune Cells
Immunology
Antiprotozoal Agents
Antineoplastic Agents
Saccharomyces cerevisiae
Biology
Bioenergetics
Microbiology
03 medical and health sciences
Membrane Microdomains
medicine
Parasitic Diseases
Animals
Humans
Amastigote
Miltefosine
Blood Cells
Protozoan Infections
Macrophages
Promastigotes
Public Health, Environmental and Occupational Health
Organisms
Biology and Life Sciences
lcsh:RA1-1270
Cell Biology
biology.organism_classification
Tropical Diseases
Parasitic Protozoans
Disease Models, Animal
030104 developmental biology
chemistry
Cancer cell
Gene Deletion
Developmental Biology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Digital.CSIC. Repositorio Institucional del CSIC, instname, PLoS Neglected Tropical Diseases, GREDOS. Repositorio Institucional de la Universidad de Salamanca, PLoS Neglected Tropical Diseases, Vol 11, Iss 8, p e0005805 (2017)
- Accession number :
- edsair.doi.dedup.....0963ae4f75034eca5f68698ee7724a39