Doxorubicin (DOX) is an effective antitumor agent used in cancer treatment. However, its clinical use is limited due to cardiotoxicity. Indeed, the side effects of DOX are irreversible and include the development of cardiomyopathy and ultimately congestive heart failure. Although many studies have investigated the events leading to DOX-induced cardiotoxicity, the mechanisms responsible for DOX-induced cardiotoxicity remain unknown. In general, evidence suggests that DOX-induced cardiotoxicity is associated with an increased generation of reactive oxygen species and oxidative damage, leading to the activation of cellular proteolytic systems. In this regard, the autophagy/lysosomal proteolytic system is a constitutively active catabolic process that is responsible for the degradation of both organelles and cytosolic proteins. We tested the hypothesis that systemic DOX administration results in altered cardiac gene and protein expression of mediators of the autophagy/lysosomal system. Our results support this hypothesis, as DOX treatment increased both the mRNA and protein levels of numerous key autophagy genes. Because exercise training has been shown to be cardioprotective against DOX-induced damage, we also determined whether exercise training before DOX administration alters the expression of important components of the autophagy/lysosomal system in cardiac muscle. Our findings show that exercise training inhibits DOX-induced cardiac increases in autophagy signaling. Collectively, our results reveal that DOX administration promotes activation of the autophagy/lysosomal system pathway in the heart, and that endurance exercise training can be a cardioprotective intervention against myocardial DOX-induced toxicity.

Doxorubicin (DOX) is a highly effective antitumor agent used for the treatment of a wide range of cancers. Unfortunately, DOX treatment results in cytotoxic side effects due to its accumulation within off-target tissues. DOX-induced cellular toxicity occurs as a result of increased oxidative damage, resulting in apoptosis and cell death. While there is no standard-of-care practice to prevent DOX-induced toxicity to healthy organs, exercise has been shown to prevent cellular dysfunction when combined with DOX chemotherapy. Endurance exercise stimulates numerous biochemical adaptations that promote a healthy phenotype in several vulnerable tissues without affecting the antineoplastic properties of DOX. Therefore, for the development of an effective strategy to combat the pathological effects of DOX, it is important to determine the appropriate exercise regimen to prescribe to cancer patients receiving DOX therapy and to understand the mechanisms responsible for exercise-induced protection against DOX toxicity to noncancer cells. This review summarizes the cytotoxic effects of DOX on the heart, skeletal muscle, liver, and kidneys and discusses the current understanding of the clinical benefits of regular physical activity and the potential mechanisms mediating the positive effects of exercise on each organ system.

This study investigated the effects of endurance exercise training on ileum antioxidant status, as well as tight junction, inflammatory, and nutrient transporter gene expression. Sprague–Dawley rats (4 month old) were assigned to sedentary (SED) or endurance exercise-training (EXE) groups (n = 8/group). EXE animals were trained on the treadmill for 10 days at a speed of 30 m/min at 0° incline for 60 min/day. SED and EXE animals were sacrificed (24 h after the final training bout) and the ileum was stored for analyses. The ileum of EXE had higher (p < 0.05) antioxidant protein levels of manganese superoxide dismutase and catalase compared to SED with no change (p > 0.05) in the lipid peroxidation biomarker 4-hydroxynonenal. Ileum mRNA expression of the tight junction gene zonulin increased (p < 0.05) and claudin 1 decreased (p < 0.05) in EXE compared to SED, but occludin and zonula occluden 1 were not different (p > 0.05) between SED and EXE. The ileum mRNA expressions of seven nutrient transporters (SLC5A8, SLC7A6, SLC6A19, SLC7A7, SLC27A2, SLC16A10, and SLC15A1) were not different between the two groups (p > 0.05). EXE had lower ileum TNFα mRNA expression (p < 0.05) compared to SED. No changes (p > 0.05) were found in the other inflammatory mRNAs including NFκB, IFNγ, IL6, CCL2, TLR4, and IL10. In addition, no changes in p-p65:p65 were detected. These findings suggest that 10 days of endurance exercise training up-regulates key endogenous antioxidant enzymes, decreases select inflammation markers, and alters select markers of tight junction permeability.