Anthracycline Cardiotoxicity: In vivo and in vitro Effects on Biochemical Parameters and Heart Ultrastructure of the Rat

Abstract

The premise of this study is that mitochondrial lesions caused by anthracyclines lead directly to cardiotoxicity. We compared several biochemical parameters, including endogenous cellular respiration, adenosine and guanosine triphosphate levels, and ¹⁴C-amino acid incorporation, of rat hearts treated with doxorubicin and some of its derivatives, recent products of pharmacological research aimed at selecting less toxic antiblastic agents. In rats treated in vivo, we further examined the ultrastructural changes induced by anthracycline antibiotics in order to elucidate which biochemical parameters were consistent with the morphological lesions. Our data indicate that mitochondria are the target of the anthracycline effects and that oxygen uptake and nucleotide levels may be regarded as markers of the toxicity when evaluating new drugs before their clinical use. The lack of cytoplasmatic or endoplasmatic reticulum alterations may account for the failure of anthracyclines to affect amino acid incorporation. In any event, the rate of protein synthesis cannot serve as a marker of cardiac toxicity. In this context, epidoxorubicin and iododoxorubicin are two derivatives characterized by less cardiotoxic potential than doxorubicin and thus appear to be promising antiblastic agents.

Cardiac cytochrome c and cardiolipin depletion during anthracycline-induced chronic depression of mitochondrial function

“…Two particular aspects of sub-chronic/chronic mitochondrial cardiac alterations appear to exist in DOX-treated animal models and in human samples treated in vitro with DOX, namely loss of mitochondrial calcium-loading capacity (Montaigne et al, 2011;Santos et al, 2002;Solem et al, 1994;Wallace, 2007) and chronic decrease of mitochondrial respiration (Cini Neri et al, 1991;Ferrero et al, 1976;Santos et al, 2002;Solem et al, 1996;Solem et al, 1994;Zhou et al, 2001). Both events, of still unknown origin, appear to be cardio-selective.…”

The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice.

“…Mitochondria are the primary source of endogenous superoxide radicals under normal physiological conditions (13), and are susceptible to oxidative damage, especially in myocardial tissue (14,15). Although mitochondrial dysfunction, as documented by inhibition of oxidative phosphorylation, decreased ATP synthesis, and disrupted calcium homeostasis with subsequent cell death, has been observed in ADR-induced cardiac toxicity (1,8,(16)(17)(18)(19), additional subcellular alterations including intracytoplasmic vacuoles, dilated sarcoplasmic reticulum, and myofibril disarray have also been identified (1). Therefore, it is not clear whether mitochondria are indeed the primary target for ADRinduced cardiac toxicity, or whether the mitochondrial injury is a secondary event after the damage of other organelles.…”

The protective effect of cardiac gene transfer of CuZn–sod in comparison with the cardioprotector monohydroxyethylrutoside against doxorubicin-induced cardiotoxicity in cultured cells

“…This is probably a result of doxorubicin-induced reduction of the cellular ATP levels. 36 Five-fold increase in the level of CuZn-sod did not protect against doxorubicin cytotoxicity. The absence of protection can be attributed to the presence of insufficient levels of CuZn-sod that cannot counteract the free radicals produced by doxorubicin.…”