On the Clinical Pharmacology of Reactive Oxygen Species.

Casas AI; Nogales C; Mucke HAM; Petraina A; Cuadrado A; Rojo AI; Ghezzi P; Jaquet V; Augsburger F; Dufrasne F; Soubhye J; Deshwal S; Di Sante M; Kaludercic N; Di Lisa F; Schmidt HHHW

doi:10.1124/pr.120.019422

Back

Journal article

On the Clinical Pharmacology of Reactive Oxygen Species.

Casas AI Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy a.casasguijarro@maastrichtuniversity.nl.
Nogales C Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Mucke HAM Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Petraina A Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Cuadrado A Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Rojo AI Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Ghezzi P Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Jaquet V Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Augsburger F Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Dufrasne F Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Soubhye J Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Deshwal S Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Di Sante M Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Kaludercic N Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Di Lisa F Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy.
Schmidt HHHW Department of Pharmacology and Personalized Medicine, Maastricht University, School of Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands (A.I.C., C.N., A.P., H.H.H.W.S.); H. M. Pharma Consultancy, Wien, Austria (H.A.M.M.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., A.I.R.); Brighton and Sussex Medical School, Falmer, United Kingdom (P.G.); Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland (V.J., F.A.); Microbiology, Bioorganic and Macromolecular Chemistry, RD3, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Bruxelles, Belgium (F.D., J.S.); and Department of Biomedical Sciences (S.D., M.D.S., F.D.L.) and CNR Neuroscience Institute (N.K., F.D.L.), University of Padova, Padova, Italy h.schmidt@maastrichtuniversity.nl.

2020-08-30

Published in:

Pharmacological reviews. - 2020

English Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data-enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine. SIGNIFICANCE STATEMENT: Despite being correlated to almost every human disease, nearly no ROS modulator has been translated to the clinics yet. Here, we move far beyond the old-fashioned misconception of ROS as detrimental metabolic by-products and suggest 1) novel pharmacological targeting focused on selective modulation of ROS enzymatic sources, 2) mechanism-based redefinition of diseases, and 3) network pharmacology within the ROS field, altogether toward the new era of ROS pharmacology in precision medicine.

Language