ABSTRACT
Platelets are the critical target for preventing and treating pathological thrombus formation. However, despite current antiplatelet therapy, cardiovascular mortality remains high, and cardiovascular events continue in prescribed patients. In this study, first results were obtained with ortho-carbonyl hydroquinones as antiplatelet agents; we found that linking triphenylphosphonium cation to a bicyclic ortho-carbonyl hydroquinone moiety by a short alkyl chain significantly improved their antiplatelet effect by affecting the mitochondrial functioning. The mechanism of action involves uncoupling OXPHOS, which leads to an increase in mitochondrial ROS production and a decrease in the mitochondrial membrane potential and OCR. This alteration disrupts the energy production by mitochondrial function necessary for the platelet activation process. These effects are responsive to the complete structure of the compounds and not to isolated parts of the compounds tested. The results obtained in this research can be used as the basis for developing new antiplatelet agents that target mitochondria.
Subject(s)
Blood Platelets , Hydroquinones , Membrane Potential, Mitochondrial , Organophosphorus Compounds , Platelet Aggregation Inhibitors , Humans , Blood Platelets/metabolism , Blood Platelets/drug effects , Hydroquinones/pharmacology , Hydroquinones/chemistry , Membrane Potential, Mitochondrial/drug effects , Mitochondria/metabolism , Mitochondria/drug effects , Organophosphorus Compounds/pharmacology , Organophosphorus Compounds/chemistry , Oxidative Phosphorylation/drug effects , Platelet Activation/drug effects , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/chemistry , Reactive Oxygen Species/metabolismABSTRACT
Cancer is a complex pathology of great heterogeneity and difficulty that makes the constant search for new therapies necessary. A major advance on the subject has been made by focusing on the development of new drugs aimed to alter the metabolism of cancer cells, by generating a disruption of mitochondrial function. For this purpose, several new compounds with specific mitochondrial action have been tested, leading successfully to cell death. Recently, attention has centered on a group of natural compounds present in plants named polyphenols, among which is caffeic acid, a polyphenol that has proven to be a powerful antitumoral agent and a prominent compound for studies focused on the development of new therapies against cancer.In this review, we revised the antitumoral capacity and mechanisms of action of caffeic acid and its derivatives, with special emphasis in a new class of caffeic acid derivatives that target mitochondria by chemical binding to the lipophilic cation triphenylphosphonium.