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Oxidative Medicine and Cellular Longevity
Volume 2018, Article ID 7582730, 15 pages
https://doi.org/10.1155/2018/7582730
Review Article

Chemotherapeutic Drugs and Mitochondrial Dysfunction: Focus on Doxorubicin, Trastuzumab, and Sunitinib

1Laboratory of Pathophysiology of Cachexia and Metabolism of Skeletal Muscle, IRCCS San Raffaele Pisana, 00166 Rome, Italy
2Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
3Bionem Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
4Cardiovascular and Cell Sciences Institute, St George’s, University of London, Cranmer Terrace, London, UK

Correspondence should be addressed to Elisabetta Ferraro; ti.eleaffarnas@orarref.attebasile

Received 3 November 2017; Revised 23 January 2018; Accepted 6 February 2018; Published 18 March 2018

Academic Editor: Vladimir Jakovljevic

Copyright © 2018 Stefania Gorini et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. Waseem and S. Parvez, “Mitochondrial dysfunction mediated cisplatin induced toxicity: modulatory role of curcumin,” Food and Chemical Toxicology, vol. 53, pp. 334–342, 2013. View at Publisher · View at Google Scholar · View at Scopus
  2. J. Serrano, C. M. Palmeira, D. W. Kuehl, and K. B. Wallace, “Cardioselective and cumulative oxidation of mitochondrial DNA following subchronic doxorubicin administration,” Biochimica et Biophysica Acta (BBA) - Bioenergetics, vol. 1411, no. 1, pp. 201–205, 1999. View at Publisher · View at Google Scholar · View at Scopus
  3. K. H. Lauritzen, L. Kleppa, J. M. Aronsen et al., “Impaired dynamics and function of mitochondria caused by mtDNA toxicity leads to heart failure,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 309, no. 3, pp. H434–H449, 2015. View at Publisher · View at Google Scholar · View at Scopus
  4. A. A. Lombardi and J. W. Elrod, “mtDNA damage in the development of heart failure,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 309, no. 3, pp. H393–H395, 2015. View at Publisher · View at Google Scholar · View at Scopus
  5. L. S. Järvelä, J. Kemppainen, H. Niinikoski et al., “Effects of a home-based exercise program on metabolic risk factors and fitness in long-term survivors of childhood acute lymphoblastic leukemia,” Pediatric Blood & Cancer, vol. 59, no. 1, pp. 155–160, 2012. View at Publisher · View at Google Scholar · View at Scopus
  6. M. van Brussel, T. Takken, J. . . Net et al., “Physical function and fitness in long-term survivors of childhood leukaemia,” Pediatric Rehabilitation, vol. 9, no. 3, pp. 267–274, 2006. View at Publisher · View at Google Scholar · View at Scopus
  7. K. K. Ness, K. S. Baker, D. R. Dengel et al., “Body composition, muscle strength deficits and mobility limitations in adult survivors of childhood acute lymphoblastic leukemia,” Pediatric Blood & Cancer, vol. 49, no. 7, pp. 975–981, 2007. View at Publisher · View at Google Scholar · View at Scopus
  8. C. Scheede-Bergdahl and R. T. Jagoe, “After the chemotherapy: potential mechanisms for chemotherapy-induced delayed skeletal muscle dysfunction in survivors of acute lymphoblastic leukaemia in childhood,” Frontiers in Pharmacology, vol. 4, p. 49, 2013. View at Publisher · View at Google Scholar · View at Scopus
  9. S. Larsen, J. Nielsen, C. N. Hansen et al., “Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects,” The Journal of Physiology, vol. 590, no. 14, pp. 3349–3360, 2012. View at Publisher · View at Google Scholar · View at Scopus
  10. L. A. A. Gilliam and D. K. St. Clair, “Chemotherapy-induced weakness and fatigue in skeletal muscle: the role of oxidative stress,” Antioxidants & Redox Signaling, vol. 15, no. 9, pp. 2543–2563, 2011. View at Publisher · View at Google Scholar · View at Scopus
  11. J. M. Argilés, F. J. López-Soriano, and S. Busquets, “Muscle wasting in cancer: the role of mitochondria,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 18, no. 3, pp. 221–225, 2015. View at Publisher · View at Google Scholar · View at Scopus
  12. A. S. Dobs, R. V. Boccia, C. C. Croot et al., “Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial,” The Lancet Oncology, vol. 14, no. 4, pp. 335–345, 2013. View at Publisher · View at Google Scholar · View at Scopus
  13. R. E. Scully and S. E. Lipshultz, “Anthracycline cardiotoxicity in long-term survivors of childhood cancer,” Cardiovascular Toxicology, vol. 7, no. 2, pp. 122–128, 2007. View at Publisher · View at Google Scholar · View at Scopus
  14. K. L. Syrjala, S. L. Langer, J. R. Abrams, B. E. Storer, and P. J. Martin, “Late effects of hematopoietic cell transplantation among 10-year adult survivors compared with case-matched controls,” Journal of Clinical Oncology, vol. 23, no. 27, pp. 6596–6606, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. K. S. Courneya, J. K. Vallance, M. L. McNeely, K. H. Karvinen, C. J. Peddle, and J. R. Mackey, “Exercise issues in older cancer survivors,” Critical Reviews in Oncology/Hematology, vol. 51, no. 3, pp. 249–261, 2004. View at Publisher · View at Google Scholar · View at Scopus
  16. J. C. Sorensen, B. D. Cheregi, C. A. Timpani, K. Nurgali, A. Hayes, and E. Rybalka, “Mitochondria: inadvertent targets in chemotherapy-induced skeletal muscle toxicity and wasting?” Cancer Chemotherapy and Pharmacology, vol. 78, no. 4, pp. 673–683, 2016. View at Publisher · View at Google Scholar · View at Scopus
  17. K. K. Talvensaari, A. Jamsen, H. Vanharanta, and M. Lanning, “Decreased isokinetic trunk muscle strength and performance in long-term survivors of childhood malignancies: correlation with hormonal defects,” Archives of Physical Medicine and Rehabilitation, vol. 76, no. 11, pp. 983–988, 1995. View at Publisher · View at Google Scholar · View at Scopus
  18. K. van Norren, A. van Helvoort, J. M. Argilés et al., “Direct effects of doxorubicin on skeletal muscle contribute to fatigue,” British Journal of Cancer, vol. 100, no. 2, pp. 311–314, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. L. A. A. Gilliam, K. H. Fisher-Wellman, C.-T. Lin, J. M. Maples, B. L. Cathey, and P. D. Neufer, “The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle,” Free Radical Biology & Medicine, vol. 65, pp. 988–996, 2013. View at Publisher · View at Google Scholar · View at Scopus
  20. K. Min, O. S. Kwon, A. J. Smuder et al., “Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy,” The Journal of Physiology, vol. 593, no. 8, pp. 2017–2036, 2015. View at Publisher · View at Google Scholar · View at Scopus
  21. M. S. Ewer and S. M. Ewer, “Cardiotoxicity of anticancer treatments: what the cardiologist needs to know,” Nature Reviews Cardiology, vol. 7, no. 10, pp. 564–575, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. J. Kluza, P. Marchetti, M. A. Gallego et al., “Mitochondrial proliferation during apoptosis induced by anticancer agents: effects of doxorubicin and mitoxantrone on cancer and cardiac cells,” Oncogene, vol. 23, no. 42, pp. 7018–7030, 2004. View at Publisher · View at Google Scholar · View at Scopus
  23. S. M. Swain, F. S. Whaley, and M. S. Ewer, “Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials,” Cancer, vol. 97, no. 11, pp. 2869–2879, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. D. D. von Hoff, M. W. Layard, P. Basa et al., “Risk factors for doxorubicin-induced congestive heart failure,” Annals of Internal Medicine, vol. 91, no. 5, pp. 710–717, 1979. View at Publisher · View at Google Scholar
  25. D. Montaigne, C. Hurt, and R. Neviere, “Mitochondria death/survival signaling pathways in cardiotoxicity induced by anthracyclines and anticancer-targeted therapies,” Biochemistry Research International, vol. 2012, Article ID 951539, 12 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  26. M. S. Oliveira, M. B. Melo, J. L. Carvalho et al., “Doxorubicin cardiotoxicity and cardiac function improvement after stem cell therapy diagnosed by strain echocardiography,” Journal of Cancer Science & Therapy, vol. 5, no. 2, pp. 52–57, 2013. View at Publisher · View at Google Scholar · View at Scopus
  27. D. Cappetta, F. Rossi, E. Piegari et al., “Doxorubicin targets multiple players: a new view of an old problem,” Pharmacological Research, vol. 127, pp. 4–14, 2018. View at Publisher · View at Google Scholar · View at Scopus
  28. G. Minotti, P. Menna, E. Salvatorelli, G. Cairo, and L. Gianni, “Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity,” Pharmacological Reviews, vol. 56, no. 2, pp. 185–229, 2004. View at Publisher · View at Google Scholar · View at Scopus
  29. N. Sarvazyan, “Visualization of doxorubicin-induced oxidative stress in isolated cardiac myocytes,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 271, no. 5, pp. H2079–H2085, 1996. View at Publisher · View at Google Scholar
  30. Y. Xiong, X. Liu, C.-P. Lee, B. H. L. Chua, and Y.-S. Ho, “Attenuation of doxorubicin-induced contractile and mitochondrial dysfunction in mouse heart by cellular glutathione peroxidase,” Free Radical Biology & Medicine, vol. 41, no. 1, pp. 46–55, 2006. View at Publisher · View at Google Scholar · View at Scopus
  31. H.-C. Yen, T. D. Oberley, C. G. Gairola, L. I. Szweda, and D. K. St. Clair, “Manganese superoxide dismutase protects mitochondrial complex I against adriamycin-induced cardiomyopathy in transgenic mice,” Archives of Biochemistry and Biophysics, vol. 362, no. 1, pp. 59–66, 1999. View at Publisher · View at Google Scholar · View at Scopus
  32. A. Mordente, E. Meucci, A. Silvestrini, G. E. Martorana, and B. Giardina, “Anthracyclines and mitochondria,” Advances in Experimental Medicine and Biology, vol. 942, pp. 385–419, 2012. View at Publisher · View at Google Scholar · View at Scopus
  33. E. Salvatorelli, P. Menna, O. Gonzalez Paz et al., “Pharmacokinetic characterization of amrubicin cardiac safety in an ex vivo human myocardial strip model. II. Amrubicin shows metabolic advantages over doxorubicin and epirubicin,” Journal of Pharmacology and Experimental Therapeutics, vol. 341, no. 2, pp. 474–483, 2012. View at Publisher · View at Google Scholar · View at Scopus
  34. E. Salvatorelli, P. Menna, O. G. Paz et al., “The novel anthracenedione, pixantrone, lacks redox activity and inhibits doxorubicinol formation in human myocardium: insight to explain the cardiac safety of pixantrone in doxorubicin-treated patients,” Journal of Pharmacology and Experimental Therapeutics, vol. 344, no. 2, pp. 467–478, 2013. View at Publisher · View at Google Scholar · View at Scopus
  35. M. P. Murphy, “How mitochondria produce reactive oxygen species,” Biochemical Journal, vol. 417, no. 1, pp. 1–13, 2009. View at Publisher · View at Google Scholar · View at Scopus
  36. K. J. Davies and J. H. Doroshow, “Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase,” Journal of Biological Chemistry, vol. 261, no. 7, pp. 3060–3067, 1986. View at Google Scholar
  37. T. Simunek, M. Sterba, O. Popelova, M. Adamcova, R. Hrdina, and V. Gersl, “Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron,” Pharmacological Reports, vol. 61, no. 1, pp. 154–171, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. Y. Chen, P. Jungsuwadee, M. Vore, D. A. Butterfield, and D. K. St. Clair, “Collateral damage in cancer chemotherapy: oxidative stress in nontargeted tissues,” Molecular Interventions, vol. 7, no. 3, pp. 147–156, 2007. View at Publisher · View at Google Scholar · View at Scopus
  39. M. Tokarska-Schlattner, M. Zaugg, C. Zuppinger, T. Wallimann, and U. Schlattner, “New insights into doxorubicin-induced cardiotoxicity: the critical role of cellular energetics,” Journal of Molecular and Cellular Cardiology, vol. 41, no. 3, pp. 389–405, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. O. Marcillat, Y. Zhang, and K. J. A. Davies, “Oxidative and non-oxidative mechanisms in the inactivation of cardiac mitochondrial electron transport chain components by doxorubicin,” Biochemical Journal, vol. 259, no. 1, pp. 181–189, 1989. View at Publisher · View at Google Scholar · View at Scopus
  41. H. G. Keizer, H. M. Pinedo, G. J. Schuurhuis, and H. Joenje, “Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity,” Pharmacology & Therapeutics, vol. 47, no. 2, pp. 219–231, 1990. View at Publisher · View at Google Scholar · View at Scopus
  42. D. B. Sawyer, X. Peng, B. Chen, L. Pentassuglia, and C. C. Lim, “Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection?” Progress in Cardiovascular Diseases, vol. 53, no. 2, pp. 105–113, 2010. View at Publisher · View at Google Scholar · View at Scopus
  43. D. Cappetta, A. De Angelis, L. Sapio et al., “Oxidative stress and cellular response to doxorubicin: a common factor in the complex milieu of anthracycline cardiotoxicity,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 1521020, 13 pages, 2017. View at Publisher · View at Google Scholar
  44. G. S. Supinski and L. A. Callahan, “Free radical-mediated skeletal muscle dysfunction in inflammatory conditions,” Journal of Applied Physiology, vol. 102, no. 5, pp. 2056–2063, 2007. View at Publisher · View at Google Scholar · View at Scopus
  45. K. A. Sarosiek, T. Ni Chonghaile, and A. Letai, “Mitochondria: gatekeepers of response to chemotherapy,” Trends in Cell Biology, vol. 23, no. 12, pp. 612–619, 2013. View at Publisher · View at Google Scholar · View at Scopus
  46. D. Lebrecht, B. Setzer, U. P. Ketelsen, J. Haberstroh, and U. A. Walker, “Time-dependent and tissue-specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy,” Circulation, vol. 108, no. 19, pp. 2423–2429, 2003. View at Publisher · View at Google Scholar · View at Scopus
  47. L. A. A. Gilliam, L. F. Ferreira, J. D. Bruton et al., “Doxorubicin acts through tumor necrosis factor receptor subtype 1 to cause dysfunction of murine skeletal muscle,” Journal of Applied Physiology, vol. 107, no. 6, pp. 1935–1942, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. M. M. Sayed-Ahmed, M. M. Khattab, M. Z. Gad, and A.-M. M. Osman, “Increased plasma endothelin-1 and cardiac nitric oxide during doxorubicin-induced cardiomyopathy,” Pharmacology and Toxicology, vol. 89, no. 3, pp. 140–144, 2001. View at Google Scholar
  49. M. Štěrba, O. Popelová, A. Vávrová et al., “Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection,” Antioxidants & Redox Signaling, vol. 18, no. 8, pp. 899–929, 2013. View at Publisher · View at Google Scholar · View at Scopus
  50. A. Albini, E. Cesana, F. Donatelli et al., “Cardio-oncology in targeting the HER receptor family: the puzzle of different cardiotoxicities of HER2 inhibitors,” Future Cardiology, vol. 7, no. 5, pp. 693–704, 2011. View at Publisher · View at Google Scholar · View at Scopus
  51. H. C. Yen, T. D. Oberley, S. Vichitbandha, Y. S. Ho, and D. K. St Clair, “The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice,” The Journal of Clinical Investigation, vol. 98, no. 5, pp. 1253–1260, 1996. View at Publisher · View at Google Scholar · View at Scopus
  52. K. Adachi, Y. Fujiura, F. Mayumi et al., “A deletion of mitochondrial DNA in murine doxorubicin-induced cardiotoxicity,” Biochemical and Biophysical Research Communications, vol. 195, no. 2, pp. 945–951, 1993. View at Publisher · View at Google Scholar · View at Scopus
  53. A. D. Hanna, A. Lam, S. Tham, A. F. Dulhunty, and N. A. Beard, “Adverse effects of doxorubicin and its metabolic product on cardiac RyR2 and SERCA2A,” Molecular Pharmacology, vol. 86, no. 4, pp. 438–449, 2014. View at Publisher · View at Google Scholar · View at Scopus
  54. Y. Octavia, C. G. Tocchetti, K. L. Gabrielson, S. Janssens, H. J. Crijns, and A. L. Moens, “Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies,” Journal of Molecular and Cellular Cardiology, vol. 52, no. 6, pp. 1213–1225, 2012. View at Publisher · View at Google Scholar · View at Scopus
  55. D. Cappetta, G. Esposito, R. Coppini et al., “Effects of ranolazine in a model of doxorubicin-induced left ventricle diastolic dysfunction,” British Journal of Pharmacology, vol. 174, no. 21, pp. 3696–3712, 2017. View at Publisher · View at Google Scholar · View at Scopus
  56. S. Moreno, V. Imbroglini, E. Ferraro et al., “Apoptosome impairment during development results in activation of an autophagy program in cerebral cortex,” Apoptosis, vol. 11, no. 9, pp. 1595–1602, 2006. View at Publisher · View at Google Scholar · View at Scopus
  57. A. De Angelis, E. Piegari, D. Cappetta et al., “SIRT1 activation rescues doxorubicin-induced loss of functional competence of human cardiac progenitor cells,” International Journal of Cardiology, vol. 189, pp. 30–44, 2015. View at Publisher · View at Google Scholar · View at Scopus
  58. D. Cappetta, G. Esposito, E. Piegari et al., “SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy,” International Journal of Cardiology, vol. 205, pp. 99–110, 2016. View at Publisher · View at Google Scholar · View at Scopus
  59. M. Gharanei, A. Hussain, O. Janneh, and H. L. Maddock, “Doxorubicin induced myocardial injury is exacerbated following ischaemic stress via opening of the mitochondrial permeability transition pore,” Toxicology and Applied Pharmacology, vol. 268, no. 2, pp. 149–156, 2013. View at Publisher · View at Google Scholar · View at Scopus
  60. L. A. A. Gilliam, D. S. Lark, L. R. Reese et al., “Targeted overexpression of mitochondrial catalase protects against cancer chemotherapy-induced skeletal muscle dysfunction,” American Journal of Physiology-Endocrinology and Metabolism, vol. 311, no. 2, pp. E293–E301, 2016. View at Publisher · View at Google Scholar · View at Scopus
  61. P. Bai, C. Cantó, H. Oudart et al., “PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation,” Cell Metabolism, vol. 13, no. 4, pp. 461–468, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. L. A. A. Gilliam, J. S. Moylan, L. A. Callahan, M. P. Sumandea, and M. B. Reid, “Doxorubicin causes diaphragm weakness in murine models of cancer chemotherapy,” Muscle & Nerve, vol. 43, no. 1, pp. 94–102, 2011. View at Publisher · View at Google Scholar · View at Scopus
  63. D. G. Deavall, E. A. Martin, J. M. Horner, and R. Roberts, “Drug-induced oxidative stress and toxicity,” Journal of Toxicology, vol. 2012, Article ID 645460, 13 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  64. L. A. A. Gilliam, J. S. Moylan, E. W. Patterson et al., “Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes,” American Journal of Physiology-Cell Physiology, vol. 302, no. 1, pp. C195–C202, 2012. View at Publisher · View at Google Scholar · View at Scopus
  65. R. Hayward, D. Hydock, N. Gibson, S. Greufe, E. Bredahl, and T. Parry, “Tissue retention of doxorubicin and its effects on cardiac, smooth, and skeletal muscle function,” Journal of Physiology and Biochemistry, vol. 69, no. 2, pp. 177–187, 2013. View at Publisher · View at Google Scholar · View at Scopus
  66. S. Fabris and D. A. MacLean, “Skeletal muscle an active compartment in the sequestering and metabolism of doxorubicin chemotherapy,” PLoS One, vol. 10, no. 9, article e0139070, 2015. View at Publisher · View at Google Scholar · View at Scopus
  67. J. H. Doroshow, C. Tallent, and J. E. Schechter, “Ultrastructural features of adriamycin-induced skeletal and cardiac muscle toxicity,” The American journal of pathology., vol. 118, no. 2, pp. 288–297, 1985. View at Google Scholar
  68. M. K. Shigenaga, T. M. Hagen, and B. N. Ames, “Oxidative damage and mitochondrial decay in aging,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 23, pp. 10771–10778, 1994. View at Publisher · View at Google Scholar · View at Scopus
  69. J. Du, X. Wang, C. Miereles et al., “Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions,” The Journal of Clinical Investigation, vol. 113, no. 1, pp. 115–123, 2004. View at Publisher · View at Google Scholar
  70. M. D. Brand, “The sites and topology of mitochondrial superoxide production,” Experimental Gerontology, vol. 45, no. 7-8, pp. 466–472, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. S. K. Powers and M. J. Jackson, “Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production,” Physiological Reviews, vol. 88, no. 4, pp. 1243–1276, 2008. View at Publisher · View at Google Scholar · View at Scopus
  72. H. E. Mohamed, M. E. Asker, S. I. Ali, and T. M. Abd El Fattah, “Protection against doxorubicin cardiomyopathy in rats: role of phosphodiesterase inhibitors type 4,” Journal of Pharmacy and Pharmacology, vol. 56, no. 6, pp. 757–768, 2004. View at Publisher · View at Google Scholar · View at Scopus
  73. S. K. Powers, A. N. Kavazis, and K. C. DeRuisseau, “Mechanisms of disuse muscle atrophy: role of oxidative stress,” American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, vol. 288, no. 2, pp. R337–R344, 2005. View at Publisher · View at Google Scholar · View at Scopus
  74. K. Yamada, S. Sugiyama, K. Kosaka, M. Hayakawa, and T. Ozawa, “Early appearance of age-associated deterioration in mitochondrial function of diaphragm and heart in rats treated with doxorubicin,” Experimental Gerontology, vol. 30, no. 6, pp. 581–593, 1995. View at Publisher · View at Google Scholar · View at Scopus
  75. T. Li, I. Danelisen, and P. K. Singal, “Early changes in myocardial antioxidant enzymes in rats treated with adriamycin,” Molecular and Cellular Biochemistry, vol. 232, no. 1/2, pp. 19–26, 2002. View at Publisher · View at Google Scholar · View at Scopus
  76. J. H. Doroshow, G. Y. Locker, I. Ifrim, and C. E. Myers, “Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine,” The Journal of Clinical Investigation, vol. 68, no. 4, pp. 1053–1064, 1981. View at Publisher · View at Google Scholar · View at Scopus
  77. E. H. Herman, V. J. Ferrans, C. E. Myers, and J. F. Van Vleet, “Comparison of the effectiveness of (±)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) and N-acetylcysteine in preventing chronic doxorubicin cardiotoxicity in beagles,” Cancer Research, vol. 45, no. 1, pp. 276–281, 1985. View at Google Scholar
  78. A. R. Dresdale, L. H. Barr, R. O. Bonow et al., “Prospective randomized study of the role of N-acetyl cysteine in reversing doxorubicin-induced cardiomyopathy,” American Journal of Clinical Oncology, vol. 5, no. 6, pp. 657–664, 1982. View at Publisher · View at Google Scholar
  79. C. Myers, R. Bonow, S. Palmeri et al., “A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine,” Seminars in Oncology, vol. 10, Supplement 1, no. 1, pp. 53–55, 1983. View at Google Scholar
  80. D. V. Unverferth, J. M. Jagadeesh, B. J. Unverferth, R. D. Magorien, C. V. Leier, and S. P. Balcerzak, “Attempt to prevent doxorubicin-induced acute human myocardial morphologic damage with acetylcysteine,” Journal of the National Cancer Institute, vol. 71, no. 5, pp. 917–920, 1983. View at Publisher · View at Google Scholar
  81. M. Niere, S. Kernstock, F. Koch-Nolte, and M. Ziegler, “Functional localization of two poly(ADP-ribose)-degrading enzymes to the mitochondrial matrix,” Molecular and Cellular Biology, vol. 28, no. 2, pp. 814–824, 2008. View at Publisher · View at Google Scholar · View at Scopus
  82. W. Ying, P. Garnier, and R. A. Swanson, “NAD+ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes,” Biochemical and Biophysical Research Communications, vol. 308, no. 4, pp. 809–813, 2003. View at Publisher · View at Google Scholar · View at Scopus
  83. W. X. Zong, D. Ditsworth, D. E. Bauer, Z. Q. Wang, and C. B. Thompson, “Alkylating DNA damage stimulates a regulated form of necrotic cell death,” Genes & Development, vol. 18, no. 11, pp. 1272–1282, 2004. View at Publisher · View at Google Scholar · View at Scopus
  84. P. Bai, C. Canto, A. Brunyánszki et al., “PARP-2 regulates SIRT1 expression and whole-body energy expenditure,” Cell Metabolism, vol. 13, no. 4, pp. 450–460, 2011. View at Publisher · View at Google Scholar · View at Scopus
  85. J. I. Kourie, “Interaction of reactive oxygen species with ion transport mechanisms,” American Journal of Physiology-Cell Physiology, vol. 275, no. 1, pp. C1–C24, 1998. View at Publisher · View at Google Scholar
  86. T. L. Hilder, G. M. Carlson, T. A. J. Haystead, E. G. Krebs, and L. M. Graves, “Caspase-3 dependent cleavage and activation of skeletal muscle phosphorylase b kinase,” Molecular and Cellular Biochemistry, vol. 275, no. 1-2, pp. 233–242, 2005. View at Publisher · View at Google Scholar · View at Scopus
  87. G. W. Wang, J. B. Klein, and Y. J. Kang, “Metallothionein inhibits doxorubicin-induced mitochondrial cytochrome c release and caspase-3 activation in cardiomyocytes,” The Journal of Pharmacology and Experimental Therapeutics, vol. 298, no. 2, pp. 461–468, 2001. View at Google Scholar
  88. Y. Yamamoto, Y. Hoshino, T. Ito et al., “Atrogin-1 ubiquitin ligase is upregulated by doxorubicin via p38-MAP kinase in cardiac myocytes,” Cardiovascular Research, vol. 79, no. 1, pp. 89–96, 2008. View at Publisher · View at Google Scholar · View at Scopus
  89. F. Zorzato, G. Salviati, T. Facchinetti, and P. Volpe, “Doxorubicin induces calcium release from terminal cisternae of skeletal muscle. A study on isolated sarcoplasmic reticulum and chemically skinned fibers,” Journal of Biological Chemistry, vol. 260, no. 12, pp. 7349–7355, 1985. View at Google Scholar
  90. J. J. Abramson, E. Buck, G. Salama, J. E. Casida, and I. N. Pessah, “Mechanism of anthraquinone-induced calcium release from skeletal muscle sarcoplasmic reticulum,” Journal of Biological Chemistry, vol. 263, no. 35, pp. 18750–18758, 1988. View at Google Scholar
  91. S. Mantarro, M. Rossi, M. Bonifazi et al., “Risk of severe cardiotoxicity following treatment with trastuzumab: a meta-analysis of randomized and cohort studies of 29,000 women with breast cancer,” Internal and Emergency Medicine, vol. 11, no. 1, pp. 123–140, 2016. View at Publisher · View at Google Scholar · View at Scopus
  92. A. Negro, B. K. Brar, Y. Gu, K. L. Peterson, W. Vale, and K. F. Lee, “erbB2 is required for G protein-coupled receptor signaling in the heart,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 43, pp. 15889–15893, 2006. View at Publisher · View at Google Scholar · View at Scopus
  93. T. Eschenhagen, T. Force, M. S. Ewer et al., “Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology,” European Journal of Heart Failure, vol. 13, no. 1, pp. 1–10, 2011. View at Publisher · View at Google Scholar · View at Scopus
  94. M. Zeglinski, A. Ludke, D. S. Jassal, and P. K. Singal, “Trastuzumab-induced cardiac dysfunction: a ‘dual-hit’,” Experimental & Clinical Cardiology, vol. 16, no. 3, pp. 70–74, 2011. View at Google Scholar
  95. E. A. Perez and R. Rodeheffer, “Clinical cardiac tolerability of trastuzumab,” Journal of Clinical Oncology, vol. 22, no. 2, pp. 322–329, 2004. View at Publisher · View at Google Scholar · View at Scopus
  96. L. Moja, L. Tagliabue, S. Balduzzi et al., “Trastuzumab containing regimens for early breast cancer,” Cochrane Database of Systematic Reviews, vol. 18, no. 4, 2012. View at Publisher · View at Google Scholar
  97. S. Balduzzi, S. Mantarro, V. Guarneri et al., “Trastuzumab-containing regimens for metastatic breast cancer,” Cochrane Database of Systematic Reviews, vol. 12, no. 6, 2014. View at Publisher · View at Google Scholar · View at Scopus
  98. M. Bonifazi, M. Franchi, M. Rossi et al., “Trastuzumab-related cardiotoxicity in early breast cancer: a cohort study,” The Oncologist, vol. 18, no. 7, pp. 795–801, 2013. View at Publisher · View at Google Scholar · View at Scopus
  99. V. Guarneri, D. J. Lenihan, V. Valero et al., “Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience,” Journal of Clinical Oncology, vol. 24, no. 25, pp. 4107–4115, 2006. View at Publisher · View at Google Scholar · View at Scopus
  100. G. A. Viani, S. L. Afonso, E. J. Stefano, L. I. De Fendi, and F. V. Soares, “Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials,” BMC Cancer, vol. 7, no. 1, p. 153, 2007. View at Publisher · View at Google Scholar · View at Scopus
  101. E. J. A. Bowles, R. Wellman, H. S. Feigelson et al., “Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study,” Journal of the National Cancer Institute, vol. 104, no. 17, pp. 1293–1305, 2012. View at Publisher · View at Google Scholar · View at Scopus
  102. N. Maurea, C. Coppola, G. Ragone et al., “Women survive breast cancer but fall victim to heart failure: the shadows and lights of targeted therapy,” Journal of Cardiovascular Medicine, vol. 11, no. 12, pp. 861–868, 2010. View at Publisher · View at Google Scholar · View at Scopus
  103. D. J. Slamon, B. Leyland-Jones, S. Shak et al., “Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2,” The New England Journal of Medicine, vol. 344, no. 11, pp. 783–792, 2001. View at Publisher · View at Google Scholar · View at Scopus
  104. H. Azim, H. A. Azim Jr., and B. Escudier, “Trastuzumab versus lapatinib: the cardiac side of the story,” Cancer Treatment Reviews, vol. 35, no. 7, pp. 633–638, 2009. View at Publisher · View at Google Scholar · View at Scopus
  105. S. A. Crone, Y. Y. Zhao, L. Fan et al., “ErbB2 is essential in the prevention of dilated cardiomyopathy,” Nature Medicine, vol. 8, no. 5, pp. 459–465, 2002. View at Publisher · View at Google Scholar · View at Scopus
  106. C. Ozcelik, B. Erdmann, B. Pilz et al., “Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 13, pp. 8880–8885, 2002. View at Publisher · View at Google Scholar · View at Scopus
  107. Y. H. Zhao, M. Zhou, H. Liu et al., “Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth,” Oncogene, vol. 28, no. 42, pp. 3689–3701, 2009. View at Publisher · View at Google Scholar · View at Scopus
  108. Y. Ding, Z. Liu, S. Desai et al., “Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism,” Nature Communications, vol. 3, no. 1, p. 1271, 2012. View at Publisher · View at Google Scholar · View at Scopus
  109. Y. Sun, H. Lin, Y. Zhu, C. Ma, J. Ye, and J. Luo, “Induction or suppression of expression of cytochrome C oxidase subunit II by heregulin β 1 in human mammary epithelial cells is dependent on the levels of ErbB2 expression,” Journal of Cellular Physiology, vol. 192, no. 2, pp. 225–233, 2002. View at Publisher · View at Google Scholar · View at Scopus
  110. S. C. Wang and M. C. Hung, “Nuclear translocation of the epidermal growth factor receptor family membrane tyrosine kinase receptors,” Clinical Cancer Research, vol. 15, no. 21, pp. 6484–6489, 2009. View at Publisher · View at Google Scholar · View at Scopus
  111. L. I. Gordon, M. A. Burke, A. T. K. Singh et al., “Blockade of the erbB2 receptor induces cardiomyocyte death through mitochondrial and reactive oxygen species-dependent pathways,” Journal of Biological Chemistry, vol. 284, no. 4, pp. 2080–2087, 2009. View at Publisher · View at Google Scholar · View at Scopus
  112. L. P. Grazette, W. Boecker, T. Matsui et al., “Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy,” Journal of the American College of Cardiology, vol. 44, no. 11, pp. 2231–2238, 2004. View at Publisher · View at Google Scholar · View at Scopus
  113. W. C. Stanley and M. P. Chandler, “Energy metabolism in the normal and failing heart: potential for therapeutic interventions,” Heart Failure Reviews, vol. 7, no. 2, pp. 115–130, 2002. View at Publisher · View at Google Scholar · View at Scopus
  114. M. J. Piccart-Gebhart, M. Procter, B. Leyland-Jones et al., “Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer,” The New England Journal of Medicine, vol. 353, no. 16, pp. 1659–1672, 2005. View at Publisher · View at Google Scholar · View at Scopus
  115. E. H. Romond, E. A. Perez, J. Bryant et al., “Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer,” The New England Journal of Medicine, vol. 353, no. 16, pp. 1673–1684, 2005. View at Publisher · View at Google Scholar · View at Scopus
  116. C. M. Cahill, G. Tzivion, N. Nasrin et al., “Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA binding and function via 14-3-3-dependent and 14-3-3-independent pathways,” Journal of Biological Chemistry, vol. 276, no. 16, pp. 13402–13410, 2001. View at Publisher · View at Google Scholar · View at Scopus
  117. D. De Zio, M. Bordi, E. Tino et al., “The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage,” Cell Death & Differentiation, vol. 18, no. 3, pp. 516–527, 2011. View at Publisher · View at Google Scholar · View at Scopus
  118. D. De Zio, F. Molinari, S. Rizza et al., “Apaf1-deficient cortical neurons exhibit defects in axonal outgrowth,” Cellular and Molecular Life Sciences, vol. 72, no. 21, pp. 4173–4191, 2015. View at Publisher · View at Google Scholar · View at Scopus
  119. M. S. Ewer and S. M. Lippman, “Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity,” Journal of Clinical Oncology, vol. 23, no. 13, pp. 2900–2902, 2005. View at Publisher · View at Google Scholar · View at Scopus
  120. G. Riccio, C. Coppola, G. Piscopo et al., “Trastuzumab and target-therapy side effects: is still valid to differentiate anthracycline type I from type II cardiomyopathies?” Human Vaccines & Immunotherapeutics, vol. 12, no. 5, pp. 1124–1131, 2016. View at Publisher · View at Google Scholar · View at Scopus
  121. J. L. Zamorano, P. Lancellotti, D. R. Muñoz et al., “2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for practice guidelines: the task force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC),” European Journal of Heart Failure, vol. 19, no. 1, pp. 9–42, 2017. View at Publisher · View at Google Scholar · View at Scopus
  122. N. L. Spector, Y. Yarden, B. Smith et al., “Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 25, pp. 10607–10612, 2007. View at Publisher · View at Google Scholar · View at Scopus
  123. D. S. Krause and R. A. Van Etten, “Tyrosine kinases as targets for cancer therapy,” The New England Journal of Medicine, vol. 353, no. 2, pp. 172–187, 2005. View at Publisher · View at Google Scholar · View at Scopus
  124. B. B. Hasinoff, “The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity,” Toxicology and Applied Pharmacology, vol. 244, no. 2, pp. 190–195, 2010. View at Publisher · View at Google Scholar · View at Scopus
  125. R. Kerkela and T. Force, “Recent insights into cardiac hypertrophy and left ventricular remodeling,” Current Heart Failure Reports, vol. 3, no. 1, pp. 14–18, 2006. View at Publisher · View at Google Scholar · View at Scopus
  126. L. Prezioso, S. Tanzi, F. Galaverna et al., “Cancer treatment-induced cardiotoxicity: a cardiac stem cell disease?” Cardiovascular & Hematological Agents in Medicinal Chemistry, vol. 8, no. 1, pp. 55–75, 2010. View at Publisher · View at Google Scholar · View at Scopus
  127. C. F. Greineder, S. Kohnstamm, and B. Ky, “Heart failure associated with sunitinib: lessons learned from animal models,” Current Hypertension Reports, vol. 13, no. 6, pp. 436–441, 2011. View at Publisher · View at Google Scholar · View at Scopus
  128. V. Chintalgattu, D. Ai, R. R. Langley et al., “Cardiomyocyte PDGFR-β signaling is an essential component of the mouse cardiac response to load-induced stress,” The Journal of Clinical Investigation, vol. 120, no. 2, pp. 472–484, 2010. View at Publisher · View at Google Scholar · View at Scopus
  129. T. F. Chu, M. A. Rupnick, R. Kerkela et al., “Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib,” The Lancet, vol. 370, no. 9604, pp. 2011–2019, 2007. View at Publisher · View at Google Scholar · View at Scopus
  130. R. Kerkela, K. C. Woulfe, J. B. Durand et al., “Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase,” Clinical and Translational Science, vol. 2, no. 1, pp. 15–25, 2009. View at Publisher · View at Google Scholar · View at Scopus
  131. T. Force, D. S. Krause, and R. A. Van Etten, “Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition,” Nature Reviews Cancer, vol. 7, no. 5, pp. 332–344, 2007. View at Publisher · View at Google Scholar · View at Scopus
  132. P. Zhang, X. Hu, X. Xu et al., “AMP activated protein kinase-α2 deficiency exacerbates pressure-overload–induced left ventricular hypertrophy and dysfunction in mice,” Hypertension, vol. 52, no. 5, pp. 918–924, 2008. View at Publisher · View at Google Scholar · View at Scopus
  133. M. Arad, C. E. Seidman, and J. G. Seidman, “AMP-activated protein kinase in the heart: role during health and disease,” Circulation Research, vol. 100, no. 4, pp. 474–488, 2007. View at Publisher · View at Google Scholar · View at Scopus
  134. H. E. Gruber, M. E. Hoffer, D. R. McAllister et al., “Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes, and injury,” Circulation, vol. 80, no. 5, pp. 1400–1411, 1989. View at Publisher · View at Google Scholar · View at Scopus
  135. K. Terai, Y. Hiramoto, M. Masaki et al., “AMP-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress,” Molecular and Cellular Biology, vol. 25, no. 21, pp. 9554–9575, 2005. View at Publisher · View at Google Scholar · View at Scopus
  136. B. B. Hasinoff, D. Patel, and K. A. O'Hara, “Mechanisms of myocyte cytotoxicity induced by the multiple receptor tyrosine kinase inhibitor sunitinib,” Molecular Pharmacology, vol. 74, no. 6, pp. 1722–1728, 2008. View at Publisher · View at Google Scholar · View at Scopus
  137. Y. Zhao, T. Xue, X. Yang et al., “Autophagy plays an important role in sunitinib-mediated cell death in H9c2 cardiac muscle cells,” Toxicology and Applied Pharmacology, vol. 248, no. 1, pp. 20–27, 2010. View at Publisher · View at Google Scholar · View at Scopus
  138. S. J. Cushen, D. G. Power, M. Y. Teo et al., “Body composition by computed tomography as a predictor of toxicity in patients with renal cell carcinoma treated with sunitinib,” American Journal of Clinical Oncology, vol. 40, no. 1, pp. 47–52, 2017. View at Publisher · View at Google Scholar · View at Scopus
  139. O. Huillard, O. Mir, M. Peyromaure et al., “Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer patients,” British Journal of Cancer, vol. 108, no. 5, pp. 1034–1041, 2013. View at Publisher · View at Google Scholar · View at Scopus
  140. F. Pretto, C. Ghilardi, M. Moschetta et al., “Correction: Sunitinib prevents cachexia and prolongs survival of mice bearing renal cancer by restraining STAT3 and MuRF-1 activation in muscle,” Oncotarget, vol. 7, no. 25, article 38973, 2016. View at Publisher · View at Google Scholar · View at Scopus
  141. A. J. Smuder, A. N. Kavazis, K. Min, and S. K. Powers, “Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle,” Journal of Applied Physiology, vol. 110, no. 4, pp. 935–942, 2011. View at Publisher · View at Google Scholar · View at Scopus
  142. A. Ascensao, R. Ferreira, and J. Magalhaes, “Exercise-induced cardioprotection—biochemical, morphological and functional evidence in whole tissue and isolated mitochondria,” International Journal of Cardiology, vol. 117, no. 1, pp. 16–30, 2007. View at Publisher · View at Google Scholar · View at Scopus
  143. B. B. Rasmussen and W. W. Winder, “Effect of exercise intensity on skeletal muscle malonyl-CoA and acetyl-CoA carboxylase,” Journal of Applied Physiology, vol. 83, no. 4, pp. 1104–1109, 1997. View at Publisher · View at Google Scholar
  144. B. B. Rasmussen, C. R. Hancock, and W. W. Winder, “Postexercise recovery of skeletal muscle malonyl-CoA, acetyl-CoA carboxylase, and AMP-activated protein kinase,” Journal of Applied Physiology, vol. 85, no. 5, pp. 1629–1634, 1998. View at Publisher · View at Google Scholar
  145. D. L. Coven, X. Hu, L. Cong et al., “Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise,” American Journal of Physiology-Endocrinology and Metabolism, vol. 285, no. 3, pp. E629–E636, 2003. View at Publisher · View at Google Scholar
  146. A. Guma, V. Martinez-Redondo, I. Lopez-Soldado, C. Canto, and A. Zorzano, “Emerging role of neuregulin as a modulator of muscle metabolism,” American Journal of Physiology-Endocrinology and Metabolism, vol. 298, no. 4, pp. E742–E750, 2010. View at Publisher · View at Google Scholar · View at Scopus
  147. X. Peng, B. Chen, C. C. Lim, and D. B. Sawyer, “The cardiotoxicology of anthracycline chemotherapeutics: translating molecular mechanism into preventative medicine,” Molecular Interventions, vol. 5, no. 3, pp. 163–171, 2005. View at Publisher · View at Google Scholar · View at Scopus
  148. A. Ascensão, J. Magalhães, J. M. C. Soares et al., “Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 289, no. 2, pp. H722–H731, 2005. View at Publisher · View at Google Scholar · View at Scopus
  149. C. G. Tocchetti, A. Carpi, C. Coppola et al., “Ranolazine protects from doxorubicin-induced oxidative stress and cardiac dysfunction,” European Journal of Heart Failure, vol. 16, no. 4, pp. 358–366, 2014. View at Publisher · View at Google Scholar · View at Scopus
  150. A. De Angelis, D. Cappetta, E. Piegari et al., “Long-term administration of ranolazine attenuates diastolic dysfunction and adverse myocardial remodeling in a model of heart failure with preserved ejection fraction,” International Journal of Cardiology, vol. 217, pp. 69–79, 2016. View at Publisher · View at Google Scholar · View at Scopus
  151. F. Molinari, N. Malara, V. Mollace, G. Rosano, and E. Ferraro, “Animal models of cardiac cachexia,” International Journal of Cardiology, vol. 219, pp. 105–110, 2016. View at Publisher · View at Google Scholar · View at Scopus
  152. E. Ferraro, A. M. Giammarioli, S. Caldarola et al., “The metabolic modulator trimetazidine triggers autophagy and counteracts stress-induced atrophy in skeletal muscle myotubes,” The FEBS Journal, vol. 280, no. 20, pp. 5094–5108, 2013. View at Publisher · View at Google Scholar · View at Scopus
  153. E. Ferraro, F. Pin, S. Gorini et al., “Improvement of skeletal muscle performance in ageing by the metabolic modulator trimetazidine,” Journal of Cachexia, Sarcopenia and Muscle, vol. 7, no. 4, pp. 449–457, 2016. View at Publisher · View at Google Scholar · View at Scopus
  154. F. Molinari, F. Pin, S. Gorini et al., “The mitochondrial metabolic reprogramming agent trimetazidine as an ‘exercise mimetic’ in cachectic C26-bearing mice,” Journal of Cachexia, Sarcopenia and Muscle, vol. 8, no. 6, pp. 954–973, 2017. View at Publisher · View at Google Scholar · View at Scopus