Cardiotoxicity of copper-based antineoplastic drugs casiopeinas is related to inhibition of energy metabolism.
Isolated rat hearts were perfused with glucose, octanoate or glucose + octanoate and different concentrations of the copper-based antineoplastic drugs casiopeina II-gly (CSII) or casiopeina III-i-a (CSIII). In isolated perfused hearts with glucose + octanoate, both casiopeinas induced diminution in cardiac work and O2 consumption with half-maximal inhibitory concentrations (IC50) of 4 (CSII) and 4.6 (CSIII) microM, after 1 h of perfusion. Strong inhibition of the pyruvate and 2-oxoglutarate dehydrogenases as well as total creatine kinase by casiopeinas suggested that ATP generation by oxidative phosphorylation and its transfer towards myofibrils were targets for these drugs. In consequence, the cellular contents of ATP and phosphocreatine were also lowered by casiopeinas. Remarkably, casiopeinas were less toxic than adriamycin (IC50 = 2.6 microM), a well-known potent cardiotoxic and antineoplastic drug, which has a wide clinical use. In an open-chest animal, which is a more physiological model than the isolated heart, femoral administration of 1 microM drug revealed that CSII was innocuous very likely due to strong binding to serum albumin, whereas adriamycin induced again a potent cardiotoxic effect (diminution in heart rate and severe depression of systolic blood pressure). Thus, it seems that casiopeinas are a group of new antineoplastic drugs with milder secondary toxic effects than proven drugs such as adriamycin.
Hernández-Esquivel
Luz
L
Instituto Nacional de Cardiología, Departamento de Bioquímica, Juan Badiano No. 1, Col. Sección XVI, 14080 Tlalpan DF, México.
Marín-Hernández
Alvaro
A
Pavón
Natalia
N
Carvajal
Karla
K
Moreno-Sánchez
Rafael
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D015415:Biomarkers; D001794:Blood Pressure / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity; D003300:Copper / Q000633:toxicity*; D003627:Data Interpretation, Statistical; D004317:Doxorubicin / Q000633:toxicity; D004734:Energy Metabolism / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D006334:Heart Function Tests; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology; D009942:Organometallic Compounds / Q000633:toxicity*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats
D000970:Antineoplastic Agents; D015415:Biomarkers; D009942:Organometallic Compounds; C505569:casiopeina II-glycine; C461490:casiopeina IIIi; D003300:Copper; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D002945:Cisplatin