Exercise stimulates beneficial adaptations to diminish doxorubicin-induced cellular toxicity

Abstract

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.

The Acute Effects of 5 Fluorouracil on Skeletal Muscle Resident and Infiltrating Immune Cells in Mice

“…Chemotherapy has been shown to mitigate the in ammatory response with exercise (53,64), induce leukopenia/cytopenia (19), and disrupt cardiacmacrophage in ltration (65). To the best of our knowledge, this is the rst study to demonstrate that chemotherapeutic 5FU has deleterious effects on immune cell abundance in otherwise healthy uninjured skeletal muscle.…”

The Impact of Immune Cells on the Skeletal Muscle Microenvironment During Cancer Cachexia

“…However, muscle contractions induced by neuromuscular electrical stimulation was recently shown to improve muscle mass in breast cancer patients receiving chemotherapy ( Guigni et al, 2019 ; Toth et al, 2020 ). Both resistance ( Bredahl et al, 2020 ) and endurance ( Smuder, 2019 ; Huertas et al, 2020 ; Montalvo et al, 2020 ) exercise have shown promise in mitigating chemotherapy-induced skeletal muscle toxicities in preclinical rats. Additionally, resistance ( Hardee et al, 2016 , 2018 ) and endurance ( Puppa et al, 2012 ; Vanderveen et al, 2020 ) exercise can improve muscle mass and function in cachectic mice.…”

“…Our understanding of chemotherapy’s deleterious off-target effects on skeletal muscle has improved over the last decade highlighting a key role for metabolic and DNA/cell stress ( Gilliam et al, 2009 ; Barreto et al, 2016b ; Morton et al, 2019 ; Sougiannis et al, 2019 ). Targeting the generation of mitochondrial reactive oxygen species (ROS), by exercise or antioxidants, has shown promise in mitigating Doxorubicin (DOX)-induced skeletal muscle dysfunction ( Smuder, 2019 ; Montalvo et al, 2020 ), and targeting the activation of MAPKs with ACVR2B/Fc and MEK1 inhibitors has been proposed to alleviate 5-FU induced mitochondrial dysfunction ( Barreto et al, 2016b , 2017 ). Inflammatory signaling has been demonstrated to regulate chemotherapy-induced E3 ligase activation through modulating TNF-α ( Gilliam et al, 2009 ).…”

Exercise May Affect Metabolism in Cancer-Related Cognitive Impairment

“…However, DOX shows cytotoxicity to noncancer cells such as heart, skeletal muscle, liver, and kidney cells, leading to adverse effect. Recently, exercise is reported to show a beneficial adaptation to reduce the DOX-induced cellular toxicity [ 59 ]. However, the mechanisms underlying the exercise-induced protection against DOX cytotoxicity are not clear.…”