Aims: Doxorubicin cardiomyopathy is a lethal pathology characterized by oxidative stress, mitochondrial dysfunction, and contractile impairment, leading to cell death. Although extensive research has been done to understand the pathophysiology of doxorubicin cardiomyopathy, no effective treatments are available. We investigated whether monoamine oxidases (MAOs) could be involved in doxorubicin-derived oxidative stress, and in the consequent mitochondrial, cardiomyocyte, and cardiac dysfunction. Results: We used neonatal rat ventricular myocytes (NRVMs) and adult mouse ventricular myocytes (AMVMs). Doxorubicin alone (i.e., 0.5 μM doxorubicin) or in combination with H2O2 induced an increase in mitochondrial formation of reactive oxygen species (ROS), which was prevented by the pharmacological inhibition of MAOs in both NRVMs and AMVMs. The pharmacological approach was supported by the genetic ablation of MAO-A in NRVMs. In addition, doxorubicin-derived ROS caused lipid peroxidation and alterations in mitochondrial function (i.e., mitochondrial membrane potential, permeability transition, redox potential), mitochondrial morphology (i.e., mitochondrial distribution and perimeter), sarcomere organization, intracellular [Ca2+] homeostasis, and eventually cell death. All these dysfunctions were abolished by MAO inhibition. Of note, in vivo MAO inhibition prevented chamber dilation and cardiac dysfunction in doxorubicin-treated mice. Innovation and Conclusion: This study demonstrates that the severe oxidative stress induced by doxorubicin requires the involvement of MAOs, which modulate mitochondrial ROS generation. MAO inhibition provides evidence that mitochondrial ROS formation is causally linked to all disorders caused by doxorubicin in vitro and in vivo. Based upon these results, MAO inhibition represents a novel therapeutic approach for doxorubicin cardiomyopathy.

Department of Biomedical Sciences University of Padova Padova Italy

European Institute of Oncology Milan Italy

Institute for Physiology Czech Academy of Sciences Prague Czech Republic

Neuroscience Institute National Research Council of Italy Padova Italy

Zobrazit více v PubMed

Ali MK, Ewer MS, Gibbs HR, Swafford J, and Graff KL. Late doxorubicin-associated cardiotoxicity in children. The possible role of intercurrent viral infection. Cancer 74: 182–188, 1994 PubMed

Antonucci S, Mulvey JF, Burger N, Di Sante M, Hall AR, Hinchy EC, Caldwell ST, Gruszczyk AV, Deshwal S, Hartley RC, Kaludercic N, Murphy MP, Di Lisa F, and Krieg T. Selective mitochondrial superoxide generation in vivo is cardioprotective through hormesis. Free Radic Biol Med 134: 678–687, 2019 PubMed PMC

Bassani JW, Bassani RA, and Bers DM. Twitch-dependent SR Ca accumulation and release in rabbit ventricular myocytes. Am J Physiol 265: C533–C540, 1993 PubMed

Belousov VV, Fradkov AF, Lukyanov KA, Staroverov DB, Shakhbazov KS, Terskikh AV, and Lukyanov S. Genetically encoded fluorescent indicator for intracellular hydrogen peroxide. Nat Methods 3: 281–286, 2006 PubMed

Benard G, Bellance N, James D, Parrone P, Fernandez H, Letellier T, and Rossignol R. Mitochondrial bioenergetics and structural network organization. J Cell Sci 120: 838–848, 2007 PubMed

Berthiaume JM and Wallace KB. Adriamycin-induced oxidative mitochondrial cardiotoxicity. Cell Biol Toxicol 23: 15–25, 2007 PubMed

Binda C, Newton-Vinson P, Hubalek F, Edmondson DE, and Mattevi A. Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nat Struct Biol 9: 22–26, 2002 PubMed

Cadeddu Dessalvi C, Pepe A, Penna C, Gimelli A, Madonna R, Mele D, Monte I, Novo G, Nugara C, Zito C, Moslehi JJ, de Boer RA, Lyon AR, Tocchetti CG, and Mercuro G. Sex differences in anthracycline-induced cardiotoxicity: the benefits of estrogens. Heart Fail Rev 24: 915–925, 2019 PubMed

Cappetta D, De Angelis A, Sapio L, Prezioso L, Illiano M, Quaini F, Rossi F, Berrino L, Naviglio S, and Urbanek K. Oxidative stress and cellular response to doxorubicin: a common factor in the complex milieu of anthracycline cardiotoxicity. Oxid Med Cell Longev 2017: 1521020, 2017 PubMed PMC

Cardinale D, Colombo A, Lamantia G, Colombo N, Civelli M, De Giacomi G, Rubino M, Veglia F, Fiorentini C, and Cipolla CM. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 55: 213–220, 2010 PubMed

Chandel NS. Mitochondria as signaling organelles. BMC Biol 12: 34, 2014 PubMed PMC

Chen MH, Colan SD, and Diller L. Cardiovascular disease: cause of morbidity and mortality in adult survivors of childhood cancers. Circ Res 108: 619–628, 2011 PubMed

Ciscato F, Filadi R, Masgras I, Pizzi M, Marin O, Damiano N, Pizzo P, Gori A, Frezzato F, Chiara F, Trentin L, Bernardi P, and Rasola A.. Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca(2+) -dependent death of cancer cells. EMBO Rep e49117, 2020. [Epub ahead of print]; DOI: 10.15252/embr.201949117 PubMed DOI PMC

Ciscato F, Sciacovelli M, Villano G, Turato C, Bernardi P, Rasola A, and Pontisso P. SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I. Oncotarget 5: 2418–2427, 2014 PubMed PMC

Deng S, Kruger A, Kleschyov AL, Kalinowski L, Daiber A, and Wojnowski L. Gp91phox-containing NAD(P)H oxidase increases superoxide formation by doxorubicin and NADPH. Free Radic Biol Med 42: 466–473, 2007 PubMed

Deshwal S, Antonucci S, Kaludercic N, and Di Lisa F. Measurement of mitochondrial ROS formation. Methods Mol Biol 1782: 403–418, 2018 PubMed

Deshwal S, Di Sante M, Di Lisa F, and Kaludercic N. Emerging role of monoamine oxidase as a therapeutic target for cardiovascular disease. Curr Opin Pharmacol 33: 64–69, 2017 PubMed

Deshwal S, Forkink M, Hu CH, Buonincontri G, Antonucci S, Di Sante M, Murphy MP, Paolocci N, Mochly-Rosen D, Krieg T, Di Lisa F, and Kaludercic N. Monoamine oxidase-dependent endoplasmic reticulum-mitochondria dysfunction and mast cell degranulation lead to adverse cardiac remodeling in diabetes. Cell Death Differ 25: 1671–1685, 2018 PubMed PMC

Di Lisa F, Menabo R, Canton M, Barile M, and Bernardi P. Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. J Biol Chem 276: 2571–2575, 2001 PubMed

Egea J, Fabregat I, Frapart YM, Ghezzi P, Gorlach A, Kietzmann T, Kubaichuk K, Knaus UG, Lopez MG, Olaso-Gonzalez G, Petry A, Schulz R, Vina J, Winyard P, Abbas K, Ademowo OS, Afonso CB, Andreadou I, Antelmann H, Antunes F, Aslan M, Bachschmid MM, Barbosa RM, Belousov V, Berndt C, Bernlohr D, Bertran E, Bindoli A, Bottari SP, Brito PM, Carrara G, Casas AI, Chatzi A, Chondrogianni N, Conrad M, Cooke MS, Costa JG, Cuadrado A, My-Chan Dang P, De Smet B, Debelec-Butuner B, Dias IHK, Dunn JD, Edson AJ, El Assar M, El-Benna J, Ferdinandy P, Fernandes AS, Fladmark KE, Forstermann U, Giniatullin R, Giricz Z, Gorbe A, Griffiths H, Hampl V, Hanf A, Herget J, Hernansanz-Agustin P, Hillion M, Huang J, Ilikay S, Jansen-Durr P, Jaquet V, Joles JA, Kalyanaraman B, Kaminskyy D, Karbaschi M, Kleanthous M, Klotz LO, Korac B, Korkmaz KS, Koziel R, Kracun D, Krause KH, Kren V, Krieg T, Laranjinha J, Lazou A, Li H, Martinez-Ruiz A, Matsui R, McBean GJ, Meredith SP, Messens J, Miguel V, Mikhed Y, Milisav I, Milkovic L, Miranda-Vizuete A, Mojovic M, Monsalve M, Mouthuy PA, Mulvey J, Munzel T, Muzykantov V, Nguyen ITN, Oelze M, Oliveira NG, Palmeira CM, Papaevgeniou N, Pavicevic A, Pedre B, Peyrot F, Phylactides M, Pircalabioru GG, Pitt AR, Poulsen HE, Prieto I, Rigobello MP, Robledinos-Anton N, Rodriguez-Manas L, Rolo AP, Rousset F, Ruskovska T, Saraiva N, Sasson S, Schroder K, Semen K, Seredenina T, Shakirzyanova A, Smith GL, Soldati T, Sousa BC, Spickett CM, Stancic A, Stasia MJ, Steinbrenner H, Stepanic V, Steven S, Tokatlidis K, Tuncay E, Turan B, Ursini F, Vacek J, Vajnerova O, Valentova K, Van Breusegem F, Varisli L, Veal EA, Yalcin AS, Yelisyeyeva O, Zarkovic N, Zatloukalova M, Zielonka J, Touyz RM, Papapetropoulos A, Grune T, Lamas S, Schmidt H, Di Lisa F, and Daiber A. European contribution to the study of ROS: a summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS). Redox Biol 13: 94–162, 2017 PubMed PMC

Eschenhagen T, Force T, Ewer MS, de Keulenaer GW, Suter TM, Anker SD, Avkiran M, de Azambuja E, Balligand JL, Brutsaert DL, Condorelli G, Hansen A, Heymans S, Hill JA, Hirsch E, Hilfiker-Kleiner D, Janssens S, de Jong S, Neubauer G, Pieske B, Ponikowski P, Pirmohamed M, Rauchhaus M, Sawyer D, Sugden PH, Wojta J, Zannad F, and Shah AM. Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 13: 1–10, 2011 PubMed

Fajardo G, Zhao M, Powers J, and Bernstein D. Differential cardiotoxic/cardioprotective effects of beta-adrenergic receptor subtypes in myocytes and fibroblasts in doxorubicin cardiomyopathy. J Mol Cell Cardiol 40: 375–383, 2006 PubMed PMC

Ferrans VJ, Clark JR, Zhang J, Yu ZX, and Herman EH. Pathogenesis and prevention of doxorubicin cardiomyopathy. Tsitologiia 39: 928–937, 1997 PubMed

Fortmann SP, Burda BU, Senger CA, Lin JS, and Whitlock EP. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: an updated systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 159: 824–834, 2013 PubMed

Geisberg CA and Sawyer DB. Mechanisms of anthracycline cardiotoxicity and strategies to decrease cardiac damage. Curr Hypertens Rep 12: 404–410, 2010 PubMed PMC

Glytsou C, Calvo E, Cogliati S, Mehrotra A, Anastasia I, Rigoni G, Raimondi A, Shintani N, Loureiro M, Vazquez J, Pellegrini L, Enriquez JA, Scorrano L, and Soriano ME. Optic atrophy 1 is epistatic to the core MICOS component MIC60 in mitochondrial cristae shape control. Cell Rep 17: 3024–3034, 2016 PubMed PMC

Gordon RR, Wu M, Huang CY, Harris WP, Sim HG, Lucas JM, Coleman I, Higano CS, Gulati R, True LD, Vessella R, Lange PH, Garzotto M, Beer TM, and Nelson PS. Chemotherapy-induced monoamine oxidase expression in prostate carcinoma functions as a cytoprotective resistance enzyme and associates with clinical outcomes. PLoS One 9: e104271, 2014 PubMed PMC

Gutscher M, Pauleau AL, Marty L, Brach T, Wabnitz GH, Samstag Y, Meyer AJ, and Dick TP. Real-time imaging of the intracellular glutathione redox potential. Nat Methods 5: 553–559, 2008 PubMed

Hao J, Li WW, Du H, Zhao ZF, Liu F, Lu JC, Yang XC, and Cui W. Role of vitamin C in cardioprotection of ischemia/reperfusion injury by activation of mitochondrial KATP channel. Chem Pharm Bull (Tokyo) 64: 548–557, 2016 PubMed

Hegstad AC, Antonsen OH, and Ytrehus K. Low concentrations of hydrogen peroxide improve post-ischaemic metabolic and functional recovery in isolated perfused rat hearts. J Mol Cell Cardiol 29: 2779–2787, 1997 PubMed

Hinchy EC, Gruszczyk AV, Willows R, Navaratnam N, Hall AR, Bates G, Bright TP, Krieg T, Carling D, and Murphy MP. Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly. J Biol Chem 293: 17208–17217, 2018 PubMed PMC

Ikeda S, Matsushima S, Okabe K, Ikeda M, Ishikita A, Tadokoro T, Enzan N, Yamamoto T, Sada M, Deguchi H, Morimoto S, Ide T, and Tsutsui H. Blockade of L-type Ca(2+) channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-kappaB pathway. Sci Rep 9: 9850, 2019 PubMed PMC

Jain D. Cardiotoxicity of doxorubicin and other anthracycline derivatives. J Nucl Cardiol 7: 53–62, 2000 PubMed

Kaludercic N, Carpi A, Nagayama T, Sivakumaran V, Zhu G, Lai EW, Bedja D, De Mario A, Chen K, Gabrielson KL, Lindsey ML, Pacak K, Takimoto E, Shih JC, Kass DA, Di Lisa F, and Paolocci N. Monoamine oxidase B prompts mitochondrial and cardiac dysfunction in pressure overloaded hearts. Antioxid Redox Signal 20: 267–280, 2014 PubMed PMC

Kaludercic N, Mialet-Perez J, Paolocci N, Parini A, and Di Lisa F. Monoamine oxidases as sources of oxidants in the heart. J Mol Cell Cardiol 73: 34–42, 2014 PubMed PMC

Kaludercic N, Takimoto E, Nagayama T, Feng N, Lai EW, Bedja D, Chen K, Gabrielson KL, Blakely RD, Shih JC, Pacak K, Kass DA, Di Lisa F, and Paolocci N. Monoamine oxidase A-mediated enhanced catabolism of norepinephrine contributes to adverse remodeling and pump failure in hearts with pressure overload. Circ Res 106: 193–202, 2010 PubMed PMC

Kokoszka JE, Coskun P, Esposito LA, and Wallace DC. Increased mitochondrial oxidative stress in the Sod2 (+/-) mouse results in the age-related decline of mitochondrial function culminating in increased apoptosis. Proc Natl Acad Sci U S A 98: 2278–2283, 2001 PubMed PMC

Li M, Sala V, De Santis MC, Cimino J, Cappello P, Pianca N, Di Bona A, Margaria JP, Martini M, Lazzarini E, Pirozzi F, Rossi L, Franco I, Bornbaum J, Heger J, Rohrbach S, Perino A, Tocchetti CG, Lima BHF, Teixeira MM, Porporato PE, Schulz R, Angelini A, Sandri M, Ameri P, Sciarretta S, Lima-Junior RCP, Mongillo M, Zaglia T, Morello F, Novelli F, Hirsch E, and Ghigo A. Phosphoinositide 3-kinase gamma inhibition protects from anthracycline cardiotoxicity and reduces tumor growth. Circulation 138: 696–711, 2018 PubMed

Li PC, Siddiqi IN, Mottok A, Loo EY, Wu CH, Cozen W, Steidl C, and Shih JC. Monoamine oxidase A is highly expressed in classical Hodgkin lymphoma. J Pathol 243: 220–229, 2017 PubMed PMC

Lim CC, Zuppinger C, Guo X, Kuster GM, Helmes M, Eppenberger HM, Suter TM, Liao R, and Sawyer DB. Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem 279: 8290–8299, 2004 PubMed

Lipshultz SE, Scully RE, Lipsitz SR, Sallan SE, Silverman LB, Miller TL, Barry EV, Asselin BL, Athale U, Clavell LA, Larsen E, Moghrabi A, Samson Y, Michon B, Schorin MA, Cohen HJ, Neuberg DS, Orav EJ, and Colan SD. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 11: 950–961, 2010 PubMed PMC

Meiners B, Shenoy C, and Zordoky BN. Clinical and preclinical evidence of sex-related differences in anthracycline-induced cardiotoxicity. Biol Sex Differ 9: 38, 2018 PubMed PMC

Milei J, Boveris A, Llesuy S, Molina HA, Storino R, Ortega D, and Milei SE. Amelioration of adriamycin-induced cardiotoxicity in rabbits by prenylamine and vitamins A and E. Am Heart J 111: 95–102, 1986 PubMed

Minotti G, Menna P, Salvatorelli E, Cairo G, and Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56: 185–229, 2004 PubMed

Moulin M, Piquereau J, Mateo P, Fortin D, Rucker-Martin C, Gressette M, Lefebvre F, Gresikova M, Solgadi A, Veksler V, Garnier A, and Ventura-Clapier R. Sexual dimorphism of doxorubicin-mediated cardiotoxicity: potential role of energy metabolism remodeling. Circ Heart Fail 8: 98–108, 2015 PubMed

Munoz-Castaneda JR, Montilla P, Munoz MC, Bujalance I, Muntane J, and Tunez I. Effect of 17-beta-estradiol administration during adriamycin-induced cardiomyopathy in ovariectomized rat. Eur J Pharmacol 523: 86–92, 2005 PubMed

Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 417: 1–13, 2009 PubMed PMC

Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, and Moens AL. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 52: 1213–1225, 2012 PubMed

Pal S, Ahir M, and Sil PC. Doxorubicin-induced neurotoxicity is attenuated by a 43-kD protein from the leaves of Cajanus indicus L. via NF-kappaB and mitochondria dependent pathways. Free Radic Res 46: 785–798, 2012 PubMed

Petronilli V, Miotto G, Canton M, Brini M, Colonna R, Bernardi P, and Di Lisa F. Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence. Biophys J 76: 725–734, 1999 PubMed PMC

Riccio G, Antonucci S, Coppola C, D'Avino C, Piscopo G, Fiore D, Maurea C, Russo M, Rea D, Arra C, Condorelli G, Di Lisa F, Tocchetti CG, De Lorenzo C, and Maurea N. Ranolazine attenuates trastuzumab-induced heart dysfunction by modulating ROS production. Front Physiol 9: 38, 2018 PubMed PMC

Ristow M. Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nat Med 20: 709–711, 2014 PubMed

Sag CM, Kohler AC, Anderson ME, Backs J, and Maier LS. CaMKII-dependent SR Ca leak contributes to doxorubicin-induced impaired Ca handling in isolated cardiac myocytes. J Mol Cell Cardiol 51: 749–759, 2011 PubMed PMC

Salvatorelli E, Guarnieri S, Menna P, Liberi G, Calafiore AM, Mariggio MA, Mordente A, Gianni L, and Minotti G. Defective one- or two-electron reduction of the anticancer anthracycline epirubicin in human heart. Relative importance of vesicular sequestration and impaired efficiency of electron addition. J Biol Chem 281: 10990–11001, 2006 PubMed

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, and Cardona A. Fiji: an open-source platform for biological-image analysis. Nat Methods 9: 676–682, 2012 PubMed PMC

Sena LA and Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48: 158–167, 2012 PubMed PMC

Son SY, Ma J, Kondou Y, Yoshimura M, Yamashita E, and Tsukihara T. Structure of human monoamine oxidase A at 2.2-A resolution: the control of opening the entry for substrates/inhibitors. Proc Natl Acad Sci U S A 105: 5739–5744, 2008 PubMed PMC

Sorato E, Menazza S, Zulian A, Sabatelli P, Gualandi F, Merlini L, Bonaldo P, Canton M, Bernardi P, and Di Lisa F. Monoamine oxidase inhibition prevents mitochondrial dysfunction and apoptosis in myoblasts from patients with collagen VI myopathies. Free Radic Biol Med 75: 40–47, 2014 PubMed PMC

Spinazzi M, Cazzola S, Bortolozzi M, Baracca A, Loro E, Casarin A, Solaini G, Sgarbi G, Casalena G, Cenacchi G, Malena A, Frezza C, Carrara F, Angelini C, Scorrano L, Salviati L, and Vergani L. A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function. Hum Mol Genet 17: 3291–3302, 2008 PubMed

Steinberg JS, Cohen AJ, Wasserman AG, Cohen P, and Ross AM. Acute arrhythmogenicity of doxorubicin administration. Cancer 60: 1213–1218, 1987 PubMed

Steinberg SF. Oxidative stress and sarcomeric proteins. Circ Res 112: 393–405, 2013 PubMed PMC

Sterba M, Popelova O, Vavrova A, Jirkovsky E, Kovarikova P, Gersl V, and Simunek T. Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid Redox Signal 18: 899–929, 2013 PubMed PMC

Sun A, Cheng Y, Zhang Y, Zhang Q, Wang S, Tian S, Zou Y, Hu K, Ren J, and Ge J. Aldehyde dehydrogenase 2 ameliorates doxorubicin-induced myocardial dysfunction through detoxification of 4-HNE and suppression of autophagy. J Mol Cell Cardiol 71: 92–104, 2014 PubMed

Tebbi CK, London WB, Friedman D, Villaluna D, De Alarcon PA, Constine LS, Mendenhall NP, Sposto R, Chauvenet A, and Schwartz CL. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 25: 493–500, 2007 PubMed

Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, and Altman RB. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics 21: 440–446, 2011 PubMed PMC

Timolati F, Ott D, Pentassuglia L, Giraud MN, Perriard JC, Suter TM, and Zuppinger C. Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation-contraction coupling and reduces oxidative stress in adult rat cardiomyocytes. J Mol Cell Cardiol 41: 845–854, 2006 PubMed

Tonolo F, Folda A, Cesaro L, Scalcon V, Marin O, Ferro S, Bindoli A, and Rigobello MP. Milk-derived bioactive peptides exhibit antioxidant activity through the Keap1-Nrf2 signaling pathway. J Funct Foods 64: 2020

Tonolo F, Sandre M, Ferro S, Folda A, Scalcon V, Scutari G, Feller E, Marin O, Bindoli A, and Rigobello MP. Milk-derived bioactive peptides protect against oxidative stress in a Caco-2 cell model. Food Funct 9: 1245–1253, 2018 PubMed

Wallace KB, Sardao VA, and Oliveira PJ. Mitochondrial determinants of doxorubicin-induced cardiomyopathy. Circ Res 126: 926–941, 2020 PubMed PMC

Wang F, He Q, Sun Y, Dai X, and Yang XP. Female adult mouse cardiomyocytes are protected against oxidative stress. Hypertension 55: 1172–1178, 2010 PubMed PMC

Wu JB, Shao C, Li X, Li Q, Hu P, Shi C, Li Y, Chen YT, Yin F, Liao CP, Stiles BL, Zhau HE, Shih JC, and Chung LW. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. J Clin Invest 124: 2891–2908, 2014 PubMed PMC

Yagi K. Assay for blood plasma or serum. Methods Enzymol 105: 328–331, 1984 PubMed

Zhou S, Starkov A, Froberg MK, Leino RL, and Wallace KB. Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 61: 771–777, 2001 PubMed

Zou Y, Yao A, Zhu W, Kudoh S, Hiroi Y, Shimoyama M, Uozumi H, Kohmoto O, Takahashi T, Shibasaki F, Nagai R, Yazaki Y, and Komuro I. Isoproterenol activates extracellular signal-regulated protein kinases in cardiomyocytes through calcineurin. Circulation 104: 102–108, 2001 PubMed