Exercise training does not affect anthracycline antitumor efficacy while attenuating cardiac dysfunction

Abstract

Highly effective anthracyclines, like doxorubicin (DOX), have limited clinical use due to protracted cardiotoxic effects. While exercise is known to be cardioprotective, it is unclear whether exercise compromises chemotherapy treatment efficacy. To determine the effect of exercise training on DOX antitumor efficacy as well as DOX-induced cardiotoxicity, female Fisher 344 rats were randomly assigned to sedentary + saline (SED+SAL), SED+DOX, wheel run exercise training + SAL (WR+SAL), or WR+DOX. On week 11, animals were inoculated with 1×10(6) MatBIII tumor cells. Once tumors reached ∼1 cm in diameter, animals were treated with 12 mg/kg of DOX or SAL. Animals were killed 1, 3, or 5 days following treatment. Tumor growth and cardiac function were measured at each interval. DOX accumulation and multidrug resistance protein (MRP) expression were quantified in tumor and heart tissue. No significant difference (P > 0.05) existed between DOX-treated SED and WR groups for tumor measurements. Exercise preserved cardiac function up to 5 days following DOX treatment. Exercise reduced ventricular DOX accumulation and upregulated ventricular MPR1 and MPR2. In contrast, no differences were observed in DOX accumulation or MRP expression in tumors of SED and WR animals. Endurance exercise had no effect on DOX antitumor efficacy as evidenced by a definitive DOX-induced reduction in tumor growth in both the SED and WR groups. Although exercise did not affect the antitumor efficacy of DOX, it still provided protection against cardiac dysfunction. These effects may be mediated by the degree of DOX tissue accumulation secondary to the regulation of MRP expression.

Mitochondrial accumulation of doxorubicin in cardiac and diaphragm muscle following exercise preconditioning

“…A key consideration in implementing an adjuvant therapy to prevent DOX myotoxicity is its ability to maintain the anti-cancer properties of DOX. In this regard, several studies have demonstrated delayed tumor growth in exercise-trained animals receiving DOX treatment (Jones et al, 2005;Parry and Hayward, 2015;Sturgeon et al, 2014). In addition, Parry et al demonstrated that while chronic voluntary wheel running prior to tumor inoculation and DOX treatment results in a reduction in left ventricle accumulation of DOX at day one after exposure, it has no effect on the accumulation of DOX in the tumor or on the anti-cancer properties of DOX (Parry and Hayward, 2015).…”

“…Upregulation of specific members of the ABC transporter family within cancer cells can increase the efflux of DOX and lower intracellular chemotherapeutic drug concentrations leading to a reduction in patient survival (Arnason and Harkness, 2015). In contrast, it is hypothesized that increased expression of ABC transport proteins may be required for the extrusion of DOX from muscle cells resulting in cytoprotection to nontumor cells (Jensen et al, 2013;Parry and Hayward, 2015). Specifically, it has been demonstrated that exercise results in an increase in the protein expression of several ABC transporters (e.g.…”

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

“…It is clear, however, that anemia must be resolved before exercise can be initiated (5). Furthermore, there is increasing evidence that exercise is beneficial for attenuating the cardiotoxicity of various anticancer treatments, with aerobic exercise found to reduce oxidative stress and improve systolic function without affecting the antitumor activity of doxorubicin in preclinical models (89,99). Since fatigue is one of the most disturbing consequences of cancer cachexia and can vary in severity between patients (1), the mode and intensity of exercise training must be tailored to each individual, based on their physical capacities.…”

Doxorubicin-Induced Cardiotoxicity

“…The protective effects of exercise on DOX-induced cardiac injury may be attributed to increased antioxidant ability, increased expression of heat shock proteins and antiapoptotic proteins, improved mitochondrial quality control, maintenance of calcium handling, and altered delivery of DOX to myocardium [90,91,93]. Importantly, exercise training has no effect on antitumor efficacy of DOX [94]. However, these preclinical and clinical findings need to be verified by studies involving a large cohort of patients.…”