Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection.
CONCLUSIONS
Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes.


BACKGROUND
A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants.


RESULTS
The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice.


CONCLUSIONS
Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation.
Department of Pharmacology, Charles University in Prague, Hradec Králové, Czech Republic. sterbam@lfhk.cuni.cz
Martin
M
Stěrba
Olga
O
Popelová
Anna
A
Vávrová
Eduard
E
Jirkovský
Petra
P
Kovaříková
Vladimír
V
Geršl
Tomáš
T
Simůnek
D018943:Anthracyclines / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D002614:Chelating Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008670:Metals / Q000009:adverse effects*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011929:Razoxane / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D018943:Anthracyclines; D000970:Antineoplastic Agents; D000975:Antioxidants; D002316:Cardiotonic Agents; D002614:Chelating Agents; D008670:Metals; D017382:Reactive Oxygen Species; D011929:Razoxane