title: [Ranolazine in the prevention of anthracycline-related cardiotoxicity].
abstract: Anthracyclines rank among the most effective anticancer drugs. They may however cause a dose-dependent and cumulative cardiotoxicity, eventually leading to heart failure. The antitumoral cytotoxicity of anthracyclines and their cardiotoxicity are believed to be due to different mechanisms, and there is therefore an active search for developing drugs able to protect the heart without impairing their chemotherapeutic efficacy. The foremost hypothesis explaining cardiotoxicity is the anthracycline-dependent production of reactive oxygen species (ROS). A ROS-induced calcium (Ca 2+)-calmodulin-dependent protein kinase II (CaMKII) hyperactivity can cause diastolic Ca2+ overload secondary to the activation of the late sodium (Na+) current (INaL). Furthermore, INaL hyperactivation can initiate a vicious cycle leading to sustained oxidative stress and energetic stress, with serious ATP depletion, similar to that occurring after the exposure of hearts or isolated cardiomyocytes exposed to anthracyclines. We hypothesize that anthracyclines may cause, through a ROS-dependent CaMKII hyperactivation, increased INaL, leading to a vicious cycle that worsens the redox imbalance with resulting mechanical and electrophysiological dysfunction and heart failure. In this light, we here review the molecular and clinical characteristics of ranolazine, the most powerful and selective clinical inhibitor of INaL, and speculate on the possibility that it may be used as an effective drug protecting against anthracycline-related cardiotoxicity.
authors.affiliation: Instituto di Cardiologia, c/o Ospedale SS. Annuziata, Università degli Studi G d'Amunzio, Chieti. rdecater@unich.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Corradi
authors.forename: Luca
authors.initials: L
authors.lastname: Paolini
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
mesh_terms: D000083:Acetanilides / Q000627:therapeutic use*; D018943:Anthracyclines / Q000378:metabolism / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D006801:Humans; D010879:Piperazines / Q000627:therapeutic use*; D000069458:Ranolazine
chemical_list: D000083:Acetanilides; D018943:Anthracyclines; D004791:Enzyme Inhibitors; D010879:Piperazines; D000069458:Ranolazine