Topoisomerase II alpha and beta (TOP2A and TOP2B) isoenzymes perform essential and non-redundant cellular functions. Anthracyclines induce their potent anti-cancer effects primarily via TOP2A, but at the same time they induce a dose limiting cardiotoxicity through TOP2B. Here we describe the development of the obex class of TOP2 inhibitors that bind to a previously unidentified druggable pocket in the TOP2 ATPase domain to act as allosteric catalytic inhibitors by locking the ATPase domain conformation with the capability of isoform-selective inhibition. Through rational drug design we have developed topobexin, which interacts with residues that differ between TOP2A and TOP2B to provide inhibition that is both selective for TOP2B and superior to dexrazoxane. Topobexin is a potent protectant against chronic anthracycline cardiotoxicity in an animal model. This demonstration of TOP2 isoform-specific inhibition underscores the broader potential to improve drug specificity and minimize adverse effects in various medical treatments.

• MeSH
• antracykliny * škodlivé účinky   farmakologie   MeSH
• DNA-topoisomerasy typu II * metabolismus   chemie   MeSH
• inhibitory topoisomerasy II * farmakologie   chemie   MeSH
• kardiotonika * farmakologie   chemie   MeSH
• kardiotoxicita * prevence a kontrola   MeSH
• lidé MeSH
• myši MeSH
• proteiny vázající poly-ADP-ribosu antagonisté a inhibitory   metabolismus   chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antracykliny * MeSH
• DNA-topoisomerasy typu II * MeSH
• inhibitory topoisomerasy II * MeSH
• kardiotonika * MeSH
• proteiny vázající poly-ADP-ribosu MeSH
• TOP2A protein, human MeSH Prohlížeč
• TOP2B protein, human MeSH Prohlížeč

SIGNIFICANCE: 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. RECENT ADVANCES: 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. CRITICAL ISSUES: 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. FUTURE DIRECTIONS: 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.

• MeSH
• antioxidancia chemie   farmakologie   MeSH
• antracykliny škodlivé účinky   chemie   farmakologie   MeSH
• chelátory škodlivé účinky   chemie   farmakologie   MeSH
• kardiotonika škodlivé účinky   chemie   farmakologie   MeSH
• kovy škodlivé účinky   MeSH
• lidé MeSH
• myokard metabolismus   MeSH
• oxidace-redukce MeSH
• oxidační stres * MeSH
• protinádorové látky škodlivé účinky   chemie   farmakologie   MeSH
• razoxan škodlivé účinky   chemie   farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• signální transdukce * MeSH
• srdce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antioxidancia MeSH
• antracykliny MeSH
• chelátory MeSH
• kardiotonika MeSH
• kovy MeSH
• protinádorové látky MeSH
• razoxan MeSH
• reaktivní formy kyslíku MeSH

BACKGROUND: Dexrazoxane (DEX, ICRF-187) is the only clinically approved cardioprotectant against anthracycline cardiotoxicity. It has been traditionally postulated to undergo hydrolysis to iron-chelating agent ADR-925 and to prevent anthracycline-induced oxidative stress, progressive cardiomyocyte degeneration and subsequent non-programmed cell death. However, the additional capability of DEX to protect cardiomyocytes from apoptosis has remained unsubstantiated under clinically relevant in vivo conditions. METHODS: Chronic anthracycline cardiotoxicity was induced in rabbits by repeated daunorubicin (DAU) administrations (3 mg kg(-1) weekly for 10 weeks). Cardiomyocyte apoptosis was evaluated using TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling) assay and activities of caspases 3/7, 8, 9 and 12. Lipoperoxidation was assayed using HPLC determination of myocardial malondialdehyde and 4-hydroxynonenal immunodetection. RESULTS: Dexrazoxane (60 mg kg(-1)) co-treatment was capable of overcoming DAU-induced mortality, left ventricular dysfunction, profound structural damage of the myocardium and release of cardiac troponin T and I to circulation. Moreover, for the first time, it has been shown that DEX affords significant and nearly complete cardioprotection against anthracycline-induced apoptosis in vivo and effectively suppresses the complex apoptotic signalling triggered by DAU. In individual animals, the severity of apoptotic parameters significantly correlated with cardiac function. However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation. CONCLUSION: This study identifies inhibition of apoptosis as an important target for effective cardioprotection against chronic anthracycline cardiotoxicity and suggests that lipoperoxidation-independent mechanisms are involved in the cardioprotective action of DEX.

• MeSH
• antracykliny antagonisté a inhibitory   toxicita   MeSH
• apoptóza účinky léků   MeSH
• kardiomyocyty cytologie   účinky léků   MeSH
• kardiotonika farmakologie   MeSH
• kardiotoxiny antagonisté a inhibitory   toxicita   MeSH
• králíci MeSH
• nemoci srdce chemicky indukované   patologie   prevence a kontrola   MeSH
• razoxan farmakologie   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antracykliny MeSH
• kardiotonika MeSH
• kardiotoxiny MeSH
• razoxan MeSH