Concomitant low-dose doxorubicin treatment and exercise

Abstract

Cardiotoxicity is a side effect for cancer patients treated with doxorubicin (DOX). We tested the hypothesis that low-intensity aerobic exercise concomitant with DOX treatment would offset DOX-induced cardiotoxicity while also improving the therapeutic efficacy of DOX on tumor progression. B16F10 melanoma cells (3 ϫ 10 5 ) were injected subcutaneously into the scruff of 6-to 8-wk-old male C57BL/6 mice (n ϭ 48). A 4 mg/kg cumulative dose of DOX was administered over 2 wk, and exercise (EX) consisted of treadmill walking (10 m/min, 45 min/day, 5 days/ wk, 2 wk). Four experimental groups were tested: 1) sedentary (SED) ϩ vehicle, 2) SED ϩ DOX, 3) EX ϩ vehicle, and 4) EX ϩ DOX. Tumor volume was attenuated in DOX and lowest in EX ϩ DOX. DOX-treated animals had less gain in body weight, reduced heart weights (HW), smaller HW-to-body weight ratios, and shorter tibial lengths by the end of the protocol; and exercise did not reverse the cardiotoxic effects of DOX. Despite decreased left ventricular (LV) mass with DOX, cardiomyocyte cross-sectional area, ␤-myosin heavy chain gene expression, and whole heart systolic (fractional shortening) and diastolic (E/A ratio) function were similar among groups. DOX also resulted in increased LV fibrosis with lower LV end diastolic volume and stroke volume. Myocardial protein kinase B activity was increased with both DOX and EX treatments, and tuberous sclerosis 2 (TSC2) abundance was reduced with EX. Downstream phosphorylation of TSC2 and mammalian target of rapamycin were similar across groups. We conclude that exercise increases the efficacy of DOX in inhibiting tumor growth without mitigating subclinical DOXinduced cardiotoxicity in a murine model of melanoma. neoplasm; drug therapy; cardiotoxicity; heart DOXORUBICIN (DOX) is an anthracycline with broad clinical application across the cancer spectrum as an effective antineoplastic agent (14, 30). However, progressive and dose-dependent early and late-onset cardiotoxicity limits the clinical efficacy of DOX (9). Acute cardiotoxicity is associated with arrhythmias and transient left ventricular (LV) dysfunction, whereas late-onset cardiomyopathy, which can occur up to 15 years after DOX administration, can manifest with overt LV dysfunction and heart failure (35). This is a significant clinical issue given cancer survivors already face a 15-fold increased rate of heart failure (27).There are numerous transcriptional and posttranslational pathophysiological mechanisms associated with DOX-induced cardiotoxicity, including increased generation of reactive oxygen species and lipid peroxidation, mitochondrial damage, DNA damage, reduction in protein synthesis, increased apoptosis, and alterations in ␤-adrenergic signaling and Ca 2ϩ handling (28). A recent study also showed that DOX caused nearly full extinction of competent cardiac progenitor cells. Subsequent intramyocardial injections of syngeneic cardiac progenitors rescued the heart from DOX-induced cardiotoxicity (7). These data suggest that a reduction in cardiomyocyte cell number...

Anthracycline Therapy Is Associated With Cardiomyocyte Atrophy and Preclinical Manifestations of Heart Disease

“…Similar findings have been reported in experimental studies with animals showing myocyte atrophy (4–6) to be related to LV mass reduction during anthracycline treatment.…”

“…Recent experimental studies demonstrated that early and subclinical myocardial effects of AIC included increased levels of interstitial fibrosis, edema, and reduced cardiomyocyte size (4–6), which may all be potentially characterized by cardiac magnetic resonance (CMR).…”

Age-Related Changes in Doxorubicin-Induced Oxidative Damage: Protective and Pretreatment Effects of Short-Term Aerobic Exercise

“…The use of DOX is limited for chemotherapy due to its toxicity (26,27). It disrupts the oxidant-antioxidant systems, resulting in tissue damage caused by lipid peroxidation and protein oxidation (28). The present study revealed severe biochemical changes as well as an oxidative damage in cardiac tissue after treatment with 20mg.kg -1 of DOX.…”

Nutrition, Nitrogen Requirements, Exercise and Chemotherapy-Induced Toxicity in Cancer Patients. A puzzle of Contrasting Truths?

“…Regular exercise improves metabolism and especially mitochondrial capacity in the hearts of former Doxo patients. A study showed that low-intensity aerobic exercise, concomitant with low-dose Doxo administration (cumulative dose of 4mg/kg) would mitigate the Doxo-induced cardiotoxicity while also improving the therapeutic efficacy of Doxo in a murine model of melanoma [138]. Exercise training protects against Doxoinduced myopathy in both heart and skeletal muscles, by reducing FoxO1 and FoxO3 expression, and the transcription of their target genes [i.e., atrogin-1/muscle atrophy F-box (MaFbx), muscle ring finger-1 (MuRF-1), and BCL2/adenovirus E1B 19 kDa proteininteracting protein 3 (BNIP3)].…”