Cellular Mechanisms Mediating Exercise-Induced Protection against Cardiotoxic Anthracycline Cancer Therapy

Abstract

Anthracyclines such as doxorubicin are widely used chemotherapy drugs. A common side effect of anthracycline therapy is cardiotoxicity, which can compromise heart function and lead to dilated cardiomyopathy and heart failure. Dexrazoxane and heart failure medications (i.e., beta blockers and drugs targeting the renin-angiotensin system) are prescribed for the primary prevention of cancer therapy-related cardiotoxicity and for the management of cardiac dysfunction and symptoms if they arise during chemotherapy. However, there is a clear need for new therapies to combat the cardiotoxic effects of cancer drugs. Exercise is a cardioprotective stimulus that has recently been shown to improve heart function and prevent functional disability in breast cancer patients undergoing anthracycline chemotherapy. Evidence from preclinical studies supports the use of exercise training to prevent or attenuate the damaging effects of anthracyclines on the cardiovascular system. In this review, we summarise findings from experimental models which provide insight into cellular mechanisms by which exercise may protect the heart from anthracycline-mediated damage, and identify knowledge gaps that require further investigation. Improved understanding of the mechanisms by which exercise protects the heart from anthracyclines may lead to the development of novel therapies to treat cancer therapy-related cardiotoxicity.

Keywords: cardioprotection; cardiotoxicity; exercise; exerkines; sex differences.

Figure 1

Cellular mechanisms by which exercise protects the heart from the cardiotoxic effects of doxorubicin (DOX) and its metabolite, doxorubicinol (DOXoL). DOX induces cardiotoxicity via multiple mechanisms, including inhibition of topoisomerase 2β (Top2β) which leads to DNA damage and apoptosis; generation of reactive oxygen species (ROS), which causes oxidative stress and mitochondrial damage and dysfunction; contractile impairment arising from inhibition of the sarcomeric reticulum calcium pump (SERCA2a) and changes in myofilament composition and organisation; cardiac fibrosis; and vascular dysfunction. Some of the mechanisms by which exercise may exert cardioprotective effects in settings of DOX therapy include: (1) exerkine release from the heart and other tissues (e.g., skeletal muscle, adipose, liver); (2) upregulation of antioxidants; (3) preservation of mitochondrial structure and function; (4) increased SERCA2a expression; (5) maintenance of myosin heavy chain isoform expression and sarcomere integrity; (6) attenuation of fibrosis; and (7) maintenance of endothelial and smooth muscle cell function. IL-6: interleukin-6. Image created with Biorender.com.

Figure 2

Effects of exercise on mitochondrial processes involved in doxorubicin (DOX)-associated cardiotoxicity. Exercise increases expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) which binds to nuclear respiratory factors (Nrf1/2) and induces mitochondrial transcription factor A (TFAM) expression. Mitochondrial translocation of TFAM contributes to mitochondrial biogenesis. Exercise may reduce DOX accumulation in mitochondria by increasing expression of ATP-binding cassette (ABC) transporters (ABCB6, ABCB7, ABCB8 and ABCB10). Exercise increases Nrf2 expression, which is known to activate the antioxidant response element (ARE) and antioxidant gene expression. Antioxidants inhibit reactive oxygen species (ROS)-induced mitochondrial membrane permeability transition pore (MPTP) opening, a process that releases pro-apoptotic Bax and accumulates calcium (Ca²⁺). Image created with Biorender.com.

Figure 3

Mechanisms of DOX-associated cardiotoxicity and exercise-mediated cardiac protection, and knowledge gaps that need to be addressed by future research. Image created with Biorender.com.