Allicin Induces Calcium and Mitochondrial Dysregulation Causing Necrotic Death in Leishmania

• Published in: PLoS neglected tropical diseases Vol. 10; no. 3; p. e0004525
• Main Authors: Corral, María J, Benito-Peña, Elena, Jiménez-Antón, M Dolores, Cuevas, Laureano, Moreno-Bondi, María C, Alunda, José M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.03.2016; Public Library of Science (PLoS)
• Subjects: Adenosine Triphosphate - metabolism; Allium sativum; Apoptosis; Apoptosis - drug effects; Bioenergetics; Biology and Life Sciences; Calcium; Calcium - metabolism; Cancer; Cancer therapies; Care and treatment; Cell cycle; Chemotherapy; Deoxyribonucleic acid; Diagnosis; DNA; Dose-Response Relationship, Drug; Drugs; Experiments; Gangrene; Garlic; Health aspects; Homeostasis; Leishmania; Leishmania - drug effects; Mammals; Membrane Potential, Mitochondrial; Mitochondria - drug effects; Organic sulfur compounds; Oxidative stress; Parasites; Parasitic diseases; Physical Sciences; Protista; Reactive Oxygen Species; Sulfinic Acids - administration & dosage; Sulfinic Acids - pharmacology; Tropical diseases
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0004525

Allicin has shown antileishmanial activity in vitro and in vivo. However the mechanism of action underlying its antiproliferative effect against Leishmania has been virtually unexplored. In this paper, we present the results obtained in L.infantum and a mechanistic basis is proposed. Exposure of the parasites to allicin led to high Ca2+ levels and mitochondrial reactive oxygen species (ROS), collapse of the mitochondrial membrane potential, reduced production of ATP and elevation of cytosolic ROS. The incubation of the promastigotes with SYTOX Green revealed that decrease of ATP was not associated with plasma membrane permeabilization. Annexin V and propidium iodide (PI) staining indicated that allicin did not induce phospholipids exposure on the plasma membrane. Moreover, DNA agarose gel electrophoresis and TUNEL analysis demonstrated that allicin did not provoke DNA fragmentation. Analysis of the cell cycle with PI staining showed that allicin induced cell cycle arrest in the G2/M phase. We conclude that allicin induces dysregulation of calcium homeostasis and oxidative stress, uncontrolled by the antioxidant defense of the cell, which leads to mitochondrial dysfunction and a bioenergetic catastrophe leading to cell necrosis and cell cycle arrest in the premitotic phase.