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Deciphering the Molecular Mechanism and Function of Pore-Forming Toxins Using Leishmania major
Published on: October 28, 2022
Perifosine Mechanisms of Action in Leishmania Species
Atteneri López-Arencibia1,2, Carmen Martín-Navarro2, Ines Sifaoui3
1Centre for Integrative Physiology, Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom atlopez@ull.edu.es.
Abstract:
Here the mechanism by which perifosine induced cell death in Leishmania donovani and Leishmania amazonensis is described. The drug reduced Leishmania mitochondrial membrane potential and decreased cellular ATP levels while increasing phosphatidylserine externalization. Perifosine did not increase membrane permeabilization. We also found that the drug inhibited the phosphorylation of Akt in the parasites. These results highlight the potential use of perifosine as an alternative to miltefosine against Leishmania.
Insights
Perifosine induces cell death in Leishmania parasites by disrupting mitochondrial function and inhibiting Akt phosphorylation. This suggests perifosine as a potential alternative treatment for leishmaniasis.
Area of Science:
- Parasitology
- Molecular Biology
- Drug Discovery
Background:
- Leishmaniasis remains a significant global health concern, with limited treatment options.
- Miltefosine is a key drug for treating leishmaniasis, but resistance is a growing issue.
- Understanding new drug mechanisms is crucial for developing alternative therapies.
Purpose of the Study:
- To elucidate the mechanism of cell death induced by perifosine in *Leishmania donovani* and *Leishmania amazonensis*.
- To investigate the effects of perifosine on parasite mitochondrial function and key signaling pathways.
- To assess the potential of perifosine as an alternative to miltefosine.
Main Methods:
- Measurement of mitochondrial membrane potential in *Leishmania*.
- Quantification of cellular ATP levels.
- Assay for phosphatidylserine externalization.
- Analysis of Akt phosphorylation in response to perifosine treatment.
Main Results:
- Perifosine significantly reduced mitochondrial membrane potential in *Leishmania* species.
- A decrease in cellular ATP levels and an increase in phosphatidylserine externalization were observed.
- Perifosine did not induce membrane permeabilization.
- Inhibition of Akt phosphorylation was confirmed in the treated parasites.
Conclusions:
- Perifosine triggers cell death in *Leishmania* through mitochondrial dysfunction and inhibition of Akt signaling.
- The drug's mechanism differs from membrane permeabilization, suggesting a distinct mode of action.
- Perifosine shows promise as a potential alternative therapeutic agent for leishmaniasis, particularly against miltefosine-resistant strains.
