Trastuzumab-induced cardiac dysfunction: A 'dual-hit'

Abstract

Trastuzumab (Trz) is a monoclonal antibody against the human epidermal growth factor receptor 2 that is found to be overexpressed in 25% to 30% of breast cancer patients. In spite of the therapeutic benefits of Trz, cardiotoxic side effects are still an issue. This effect is potentiated particularly when Trz is administered following doxorubicin (DOX) treatment. Among the various mechanisms that may account for DOX and Trz-induced cardiotoxicity, the role of oxidative stress has gained significant support. The present review discusses the evidence supporting the hypothesis that oxidative stress comes from multiple sources through an increase in the production of reactive oxygen species and/or a decrease in antioxidant defense systems. The adjuvant use of Trz can potentiate cardiomyocyte damage through a 'dual-hit' mechanism, which includes inhibition of the neuregulin-1 survival signalling pathway and angiotensin II-induced activation of NADPH oxidase, with the ability to further increase reactive oxygen species production. Preventive therapies for DOX- and Trz-induced cardiac dysfunction have eluded investigators, but may include the prophylactic use of angiotensin-converting enzyme inhibitors, beta-blockers and use of antioxidants. Thus, a better understanding of the mechanisms leading to this characteristic drug-induced cardiomyopathy, as well as potential cardioprotective strategies is required.

Keywords: Doxorubicin; Epidermal growth factor; Heart failure; Oxidative stress; Renin-angiotensin system.

Figure 1)

Neuregulin signalling in cell survival. Binding of neuregulin to HER4 leads to its dimerization with receptor HER2. This dimerization activates cell survival pathways involving ERK 1/2, phosphoinositide 3 kinase (PI3K)/AKT and the focal adhesion kinase (FAK)/Src complex. ROS Reactive oxygen species

Figure 2)

Schematic representation of potential mechanisms involved in doxorubicin/trastuzumab-induced cardiotoxicity. Binding of trastuzumab to HER2 inhibits its dimerization with the neuregulin-induced HER4 receptor. Binding of angiotensin II to its receptor AT1 leads to NADPH oxidase activation, production of a superoxide radical and an increase in oxidative stress. Adjunct treatment with doxorubicin also increases oxidative stress. Such an increase in oxidative stress leads to the activation of ASK-1 and p38/jun N-terminal kinase (JNK)-associated pathways, leading to apoptosis and heart failure

Figure 3)

Endocardial velocity using tissue Doppler imaging in a C57Bl/6 mouse receiving a combination of doxorubicin and trastuzumab at baseline (upper panel), which decreased from 3.0 cm/s at baseline to 1.4 cm/s at 24 h (lower panel). This acute change in tissue Doppler imaging values precedes the drop in left ventricular ejection fraction, which occurs at day 3 following the administration of doxorubicin and trastuzumab