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

Sobuzoxane (MST-16) is an approved anticancer agent, a pro-drug of bisdioxopiperazine analog ICRF-154. Due to the structural similarity of ICRF-154 to dexrazoxane (ICRF-187), MST-16 deserves attention as a cardioprotective drug. This study presents for the first time UHPLC-MS/MS assay of MST-16, ICRF-154 and its metabolite (EDTA-diamide) in cell culture medium, buffer, plasma and cardiac cells and provides data on MST-16 bioactivation under conditions relevant to investigation of cardioprotection of this drug. The analysis of these compounds that differ considerably in their lipophilicity was achieved on the Zorbax SB-Aq column using a mixture of aqueous ammonium formate and methanol as a mobile phase. The biological samples were either diluted or precipitated with methanol, which was followed by acidification for the assay of MST-16. The method was validated for determination of all compounds in the biological materials. The application of the method for analysis of samples from in vitro experiments provided important findings, namely, that (1) MST-16 is quickly decomposed in biological environments, (2) the cardiac cells actively metabolize MST-16, and (3) MST-16 readily penetrates into the cardiac cells and is converted into ICRF-154 and EDTA-diamide. These data are useful for the in-depth examination of the cardioprotective potential of this drug.

• MeSH
• EDTA chemie   MeSH
• kardiomyocyty cytologie   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• piperaziny analýza   MeSH
• potkani Wistar MeSH
• protinádorové látky analýza   metabolismus   MeSH
• razoxan analogy a deriváty   chemie   metabolismus   MeSH
• tandemová hmotnostní spektrometrie MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1,2-bis(3,5-dioxopiperazin-1-yl)ethane MeSH Prohlížeč
• EDTA MeSH
• piperaziny MeSH
• protinádorové látky MeSH
• razoxan MeSH
• sobuzoxane MeSH Prohlížeč

Anthracyclines (such as doxorubicin or daunorubicin) are among the most effective anticancer drugs, but their usefulness is hampered by the risk of irreversible cardiotoxicity. Dexrazoxane (ICRF-187) is the only clinically approved cardioprotective agent against anthracycline cardiotoxicity. Its activity has traditionally been attributed to the iron-chelating effects of its metabolite with subsequent protection from oxidative stress. However, dexrazoxane is also a catalytic inhibitor of topoisomerase II (TOP2). Therefore, we examined whether dexrazoxane and two other TOP2 catalytic inhibitors, namely sobuzoxane (MST-16) and merbarone, protect cardiomyocytes from anthracycline toxicity and assessed their effects on anthracycline antineoplastic efficacy. Dexrazoxane and two other TOP2 inhibitors protected isolated neonatal rat cardiomyocytes against toxicity induced by both doxorubicin and daunorubicin. However, none of the TOP2 inhibitors significantly protected cardiomyocytes in a model of hydrogen peroxide-induced oxidative injury. In contrast, the catalytic inhibitors did not compromise the antiproliferative effects of the anthracyclines in the HL-60 leukemic cell line; instead, synergistic interactions were mostly observed. Additionally, anthracycline-induced caspase activation was differentially modulated by the TOP2 inhibitors in cardiac and cancer cells. Whereas dexrazoxane was upon hydrolysis able to significantly chelate intracellular labile iron ions, no such effect was noted for either sobuzoxane or merbarone. In conclusion, our data indicate that dexrazoxane may protect cardiomyocytes via its catalytic TOP2 inhibitory activity rather than iron-chelation activity. The differential expression and/or regulation of TOP2 isoforms in cardiac and cancer cells by catalytic inhibitors may be responsible for the selective modulation of anthracycline action observed.

• MeSH
• antracykliny farmakologie   MeSH
• biokatalýza účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• daunomycin farmakologie   MeSH
• dexrazoxan farmakologie   MeSH
• DNA-topoisomerasy typu II metabolismus   MeSH
• doxorubicin farmakologie   MeSH
• glutathion metabolismus   MeSH
• glutathiondisulfid metabolismus   MeSH
• HL-60 buňky MeSH
• inhibitory topoisomerasy II farmakologie   MeSH
• kardiomyocyty cytologie   účinky léků   metabolismus   MeSH
• kaspasy metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• lékové interakce MeSH
• lidé MeSH
• novorozená zvířata MeSH
• piperaziny farmakologie   MeSH
• potkani Wistar MeSH
• proliferace buněk účinky léků   MeSH
• průtoková cytometrie MeSH
• thiobarbituráty farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antracykliny MeSH
• daunomycin MeSH
• dexrazoxan MeSH
• DNA-topoisomerasy typu II MeSH
• doxorubicin MeSH
• glutathion MeSH
• glutathiondisulfid MeSH
• inhibitory topoisomerasy II MeSH
• kaspasy MeSH
• merbarone MeSH Prohlížeč
• piperaziny MeSH
• sobuzoxane MeSH Prohlížeč
• thiobarbituráty MeSH

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