In Vitro Effect of Mitochondria-Targeted Triphenylphosphonium-Based Compounds (Honokiol, Lonidamine, and Atovaquone) on the Platelet Function and Cytotoxic Activity

Introduction: Obtaining triphenylphosphonium salts derived from anticancer compounds to inhibit mitochondrial metabolism is of major interest due to their pivotal role in reactive oxygen species (ROS) production, calcium homeostasis, apoptosis, and cell proliferation. However, the use of this type o...

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Main Authors: Héctor Montecino-Garrido, Diego Méndez, Ramiro Araya-Maturana, Juan Pablo Millas-Vargas, Sergio Wehinger, Eduardo Fuentes
Format: Article
Language:English
Published: Frontiers Media S.A. 2022-05-01
Series:Frontiers in Pharmacology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fphar.2022.893873/full
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author Héctor Montecino-Garrido
Diego Méndez
Ramiro Araya-Maturana
Juan Pablo Millas-Vargas
Sergio Wehinger
Eduardo Fuentes
author_facet Héctor Montecino-Garrido
Diego Méndez
Ramiro Araya-Maturana
Juan Pablo Millas-Vargas
Sergio Wehinger
Eduardo Fuentes
author_sort Héctor Montecino-Garrido
collection DOAJ
description Introduction: Obtaining triphenylphosphonium salts derived from anticancer compounds to inhibit mitochondrial metabolism is of major interest due to their pivotal role in reactive oxygen species (ROS) production, calcium homeostasis, apoptosis, and cell proliferation. However, the use of this type of antitumor compound presents a risk of bleeding since the platelet activation is especially dependent on the mitochondrial function. In this study, we evaluated the in vitro effect of three triphenylphosphonium-based compounds, honokiol (HNK), lonidamine (LDN), and atovaquone (ATO), on the platelet function linked to the triphenylphosphonium cation by a lineal 10-carbon alkyl chain and also the decyltriphenylphosphonium salt (decylphos).Methods: Platelets obtained by phlebotomy from healthy donors were exposed in vitro to different concentrations (0.1–10 μM) of the three compounds; cellular viability, exposure of phosphatidylserine, the mitochondrial membrane potential (∆Ψm), intracellular calcium release, and intracellular ROS generation were measured. Platelet activation and aggregation were induced by agonists (adenosine diphosphate, thrombin receptor-activating peptide-6, convulxin, or phorbol-12-myristate-13-acetate) and were evaluated by flow cytometry and light transmission, respectively.Results: The three compounds showed a slight cytotoxic effect from 1 μM, and this was concomitant with a decrease in ∆Ψm and intracellular calcium increase. Only ATO produced a modest but significant increase in intra-platelet ROS. Also, the three compounds increased the exposure to phosphatidylserine in platelets expressed in platelets positive for annexin V. None of the compounds had an inhibitory effect on the aggregation or activation markers of platelets stimulated with three different agonists. Similar results were obtained with decylphos.Conclusion: Triphenylphosphonium derivatives showed slight platelet toxicity below 1 μM, probably associated with their effect on ∆Ψm and exposure to phosphatidylserine, but no significant effect on platelet activation and aggregation, making them an antitumoral alternative with a low risk of bleeding. However, future assays on animal models and human trials are required to evaluate if their effects with a low risk for hemostasis are replicated in vivo.
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spelling doaj.art-6930a693e5f94b82a975b141b79dc8892022-12-22T02:23:43ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-05-011310.3389/fphar.2022.893873893873In Vitro Effect of Mitochondria-Targeted Triphenylphosphonium-Based Compounds (Honokiol, Lonidamine, and Atovaquone) on the Platelet Function and Cytotoxic ActivityHéctor Montecino-Garrido0Diego Méndez1Ramiro Araya-Maturana2Juan Pablo Millas-Vargas3Sergio Wehinger4Eduardo Fuentes5Department of Clinical Biochemistry and Immunohematology, Thrombosis Research Center, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (ACT210097), Medical Technology School, Faculty of Health Sciences, Universidad de Talca, Talca, ChileDepartment of Clinical Biochemistry and Immunohematology, Thrombosis Research Center, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (ACT210097), Medical Technology School, Faculty of Health Sciences, Universidad de Talca, Talca, ChileInstituto de Química de Recursos Naturales, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (ACT210097), Universidad de Talca, Talca, ChileInstituto de Química de Recursos Naturales, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (ACT210097), Universidad de Talca, Talca, ChileDepartment of Clinical Biochemistry and Immunohematology, Thrombosis Research Center, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (ACT210097), Medical Technology School, Faculty of Health Sciences, Universidad de Talca, Talca, ChileDepartment of Clinical Biochemistry and Immunohematology, Thrombosis Research Center, MIBI: Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics (ACT210097), Medical Technology School, Faculty of Health Sciences, Universidad de Talca, Talca, ChileIntroduction: Obtaining triphenylphosphonium salts derived from anticancer compounds to inhibit mitochondrial metabolism is of major interest due to their pivotal role in reactive oxygen species (ROS) production, calcium homeostasis, apoptosis, and cell proliferation. However, the use of this type of antitumor compound presents a risk of bleeding since the platelet activation is especially dependent on the mitochondrial function. In this study, we evaluated the in vitro effect of three triphenylphosphonium-based compounds, honokiol (HNK), lonidamine (LDN), and atovaquone (ATO), on the platelet function linked to the triphenylphosphonium cation by a lineal 10-carbon alkyl chain and also the decyltriphenylphosphonium salt (decylphos).Methods: Platelets obtained by phlebotomy from healthy donors were exposed in vitro to different concentrations (0.1–10 μM) of the three compounds; cellular viability, exposure of phosphatidylserine, the mitochondrial membrane potential (∆Ψm), intracellular calcium release, and intracellular ROS generation were measured. Platelet activation and aggregation were induced by agonists (adenosine diphosphate, thrombin receptor-activating peptide-6, convulxin, or phorbol-12-myristate-13-acetate) and were evaluated by flow cytometry and light transmission, respectively.Results: The three compounds showed a slight cytotoxic effect from 1 μM, and this was concomitant with a decrease in ∆Ψm and intracellular calcium increase. Only ATO produced a modest but significant increase in intra-platelet ROS. Also, the three compounds increased the exposure to phosphatidylserine in platelets expressed in platelets positive for annexin V. None of the compounds had an inhibitory effect on the aggregation or activation markers of platelets stimulated with three different agonists. Similar results were obtained with decylphos.Conclusion: Triphenylphosphonium derivatives showed slight platelet toxicity below 1 μM, probably associated with their effect on ∆Ψm and exposure to phosphatidylserine, but no significant effect on platelet activation and aggregation, making them an antitumoral alternative with a low risk of bleeding. However, future assays on animal models and human trials are required to evaluate if their effects with a low risk for hemostasis are replicated in vivo.https://www.frontiersin.org/articles/10.3389/fphar.2022.893873/fullplateletcytotoxicityantiplatelettriphenylphosphoniummitochondria
spellingShingle Héctor Montecino-Garrido
Diego Méndez
Ramiro Araya-Maturana
Juan Pablo Millas-Vargas
Sergio Wehinger
Eduardo Fuentes
In Vitro Effect of Mitochondria-Targeted Triphenylphosphonium-Based Compounds (Honokiol, Lonidamine, and Atovaquone) on the Platelet Function and Cytotoxic Activity
Frontiers in Pharmacology
platelet
cytotoxicity
antiplatelet
triphenylphosphonium
mitochondria
title In Vitro Effect of Mitochondria-Targeted Triphenylphosphonium-Based Compounds (Honokiol, Lonidamine, and Atovaquone) on the Platelet Function and Cytotoxic Activity
title_full In Vitro Effect of Mitochondria-Targeted Triphenylphosphonium-Based Compounds (Honokiol, Lonidamine, and Atovaquone) on the Platelet Function and Cytotoxic Activity
title_fullStr In Vitro Effect of Mitochondria-Targeted Triphenylphosphonium-Based Compounds (Honokiol, Lonidamine, and Atovaquone) on the Platelet Function and Cytotoxic Activity
title_full_unstemmed In Vitro Effect of Mitochondria-Targeted Triphenylphosphonium-Based Compounds (Honokiol, Lonidamine, and Atovaquone) on the Platelet Function and Cytotoxic Activity
title_short In Vitro Effect of Mitochondria-Targeted Triphenylphosphonium-Based Compounds (Honokiol, Lonidamine, and Atovaquone) on the Platelet Function and Cytotoxic Activity
title_sort in vitro effect of mitochondria targeted triphenylphosphonium based compounds honokiol lonidamine and atovaquone on the platelet function and cytotoxic activity
topic platelet
cytotoxicity
antiplatelet
triphenylphosphonium
mitochondria
url https://www.frontiersin.org/articles/10.3389/fphar.2022.893873/full
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