Review article
New insights into doxorubicin-induced cardiotoxicity: The critical role of cellular energetics

https://doi.org/10.1016/j.yjmcc.2006.06.009Get rights and content

Abstract

Cardiotoxic side-effects represent a serious complication of anticancer therapy with anthracyclines, in particular with doxorubicin (DXR) being the leading drug of the group. Different hypotheses, accentuating various mechanisms and/or targets, have been proposed to explain DXR-induced cardiotoxicity. This review focuses on the myocardial energetic network as a target of DXR toxic action in heart and highlights the recent advances in understanding its role in development of the DXR related cardiac dysfunction. We present a survey of DXR-induced defects in different steps of cardiac energy metabolism, including reduction of oxidative capacity of mitochondria, changes in the profile of energy substrate utilization, disturbance of energy transfer between sites of energy production and consumption, as well as defects in energy signaling. Considering the wide spectrum and diversity of the changes reported, we attempt to integrate these facts into a common framework and to discuss important functional and temporal relationships between DXR-induced events and the possible underlying molecular mechanisms.

Section snippets

Clinical aspects and morphological characteristics of DXR-induced cardiomyopathy

Chronic cardiomyopathy usually occurs within the first year after therapy (early onset), but occasionally much later [17]. Such late onset cardiac toxicity was documented especially in children. The probability of developing cardiomyopathy is clearly dose-dependent [18]. At a dose of 550 mg/m2 the incidence is up to 7%. However, subclinical cardiac damage can be observed at doses much lower than this threshold using echocardiography or radionuclide ventriculography. The clinical course and

Experimental models

Effects of DXR on the global cardiac energetic network or its individual components have been studied in different model systems, including animal models, as well as in vitro models of different complexity, such as perfused heart, cultured cardiomyocytes, isolated mitochondria, submitochodrial particles, or purified proteins. Very few data are available from studies in humans.

A comparison between models, as well as a critical evaluation of the demonstrated effects of DXR, must consider the fact

DXR-induced cell death

A common endpoint of anthracycline-therapy in cardiomyocytes and non-myocytes is cell death, although this is likely to be only the final response to a variety of upstream events and longer-lasting stress conditions. Adult cardiomyocytes are terminally differentiated muscle cells which do no longer proliferate. Therefore, repetitive induction of cardiomyocyte cell death in the absence of sufficient regenerative capacity is a plausible mechanism for DXR-induced, irreversible cardiotoxicity.

Myocardial high-energy phosphate levels

The heart requires large amounts of energy to sustain its contractile performance. Adenosine triphosphate (ATP) serves as primary, immediate source of energy, however intracellular ATP pools are rather small (ca. 5 mmol/kg heart wet weight). Upon increasing demand, ATP can be efficiently replenished from the larger intracellular pools of phosphocreatine (PCr; ca. 10 mmol/kg heart wet weight [41], [42]). DXR has been reported to diminish cardiac energy reserves, by reducing both ATP and PCr

Mitochondrial function

More than 90% of the ATP utilized by cardiomyocytes is produced by mitochondrial respiration [12]. Therefore, any alterations of mitochondrial structure and function will likely manifest themselves in terms of cardiomyocyte function. Progression of DXR cardiotoxicity is associated already at an early stage with morphological abnormalities of mitochondria, including mitochondrial swelling that is typical for apoptotic cells. Such ultrastructural changes have been observed in different

Fatty acid oxidation

The heart metabolizes multiple substrates to synthesize ATP. Fatty acids are known to be a major cardiac energy source under aerobic conditions. During the development of cardiac pathologies, at least in their early stages, a decrease in fatty acid oxidation is accompanied by up-regulation of glucose utilization as a compensatory response. DXR-induced cardiomyopathy is associated with a decreased utilization of both substrates (Table 4). Wakasugi and colleagues [79] have demonstrated in

High energy phosphate storage and transfer

DXR not only diminishes general energy production, but already very early leads to a rather specific impairment of creatine kinase (CK) isoenzymes (Table 5). Cytosolic and mitochondrial CK isoenzymes, together with easily diffusible creatine (Cr) and phosphocreatine (PCr), provide an important cellular energy buffer and energy transport system, bridging sites of energy production and consumption (for reviews see [60], [94], [95]) that is particularly important in heart [96]. CK isoenzymes are

Molecular mechanisms

Existing evidence points to a complex situation with a multitude of molecular mechanisms involved in DXR-induced impairment of cardiac energetics and other cellular targets, finally leading to cardiac dysfunction (Fig. 1).

An important factor, which can mediate the toxic action of DXR, especially in mitochondria, is high affinity binding of DXR to cardiolipin, an anionic phospholipid specific for the inner mitochondrial membrane, which has been recognized as an essential phospholipid in

Concluding remarks

Alterations in myocardial energy metabolism have been recognized as a hallmark for different cardiac pathologies ([10], [11], Nahrendorf, 2006 #390, [12], [174]). This review summarized the amazing spectrum of changes in cardiac energy metabolism caused by DXR. The drug induces damage at multiple sites of cardiac energy metabolism, including a fall of basal high energy phosphate levels, PCr and ATP, a reduction of oxidative capacity of mitochondria, changes in the profile of energy substrate

Acknowledgments

The authors apologize to those colleagues whose works have not been cited because of space limitations. The related work from the authors’ laboratories was supported by the Swiss National Science Foundation (Marie Heim-Vögtlin grant 3234-069276 to M.T.-S.; grant 3100A0-102075 to T.W. and U.S., and grant 3200B0-103980/1 to M.Z.), Schweizerische Herzstiftung (to T.W. and U.S.), Wolfermann-Nägeli-Stiftung (to M.T.-S., U.S. and T.W.), Schweizer Krebsliga (to T.W. and U.S.), Zentralschweizer

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