Low dose radiation prevents doxorubicin-induced cardiotoxicity

Abstract

This study aimed to develop a novel and non-invasive approach, low-dose radiation (LDR, 75 mGy X-rays), to prevent doxorubicin (DOX)-induced cardiotoxicity. BALB/c mice were randomly divided into five groups, Control, LDR (a single exposure), Sham (treated same as LDR group except for irradiation), DOX (a single intraperitoneal injection of DOX at 7.5 mg/kg), and LDR/DOX (received LDR and 72 h later received DOX). Electrocardiogram analysis displayed several kinds of abnormal ECG profiles in DOX-treated mice, but less in LDR/DOX group. Cardiotoxicity indices included histopathological changes, oxidative stress markers, and measurements of mitochondrial membrane permeability. Pretreatment of DOX group with LDR reduced oxidative damages (reactive oxygen species formation, protein nitration, and lipid peroxidation) and increased the activities of antioxidants (superoxide dismutase and glutathione peroxidase) in the heart of LDR/DOX mice compared to DOX mice. Pretreatment of DOX-treated mice with LDR also decreased DOX-induced cardiac cell apoptosis (TUNEL staining and cleaved caspase-3) and mitochondrial apoptotic pathway (increased p53, Bax, and caspase-9 expression and decreased Bcl2 expression and ΔΨm dissipation). These results suggest that LDR could induce adaptation of the heart to DOX-induced toxicity. Cardiac protection by LDR may attribute to attenuate DOX-induced cell death via suppressing mitochondrial-dependent oxidative stress and apoptosis signaling.

Single nanomolar doxorubicin exposure triggers compensatory mitochondrial responses in H9c2 cardiomyoblasts

“…An adaptive response to DOX has previously been shown in non-cancer cells (Anuszewska and Koziorowska, 1999), although the underlying mechanisms were not clarified. More recently, a study reported that the pretreatment with low-dose radiation was able to attenuate DOX-induced cardiotoxicity (Jiang et al, 2018). Here again, the molecular consequences of the stimulation with low-dose radiation were not totally clear, but the authors proposed that the radiation could lead to a small increase of ROS that promote the upregulation of antioxidant defenses.…”

Keeping heart homeostasis in check through the balance of iron metabolism

“…In low doses, iron supplementation might not exacerbate DOX toxicity because these levels of iron can be chelated by increased levels of ferritin (caused by DOX). In a rather similar manner, low doses of radiation do not potentiate DOX cardiotoxicity because they cause reactive upregulation of cellular antioxidative machinery . These observations might explain contradictory data concerning the role of iron in potentiating DOX toxicity .…”

Organ-Specific Effects of Low Dose Radiation Exposure: A Comprehensive Review

“…However, completely opposite results were suggested in studies to investigate the molecular events after LDR exposure in atherosclerosis models. LDR under 0.1 Gy was delivered to several cardiovascular disease models induced by type 1 diabetes, Apolipoprotein E deficiency, and doxorubicin treatment and reduced oxidative stress and inflammation in the heart were found in the models ( Zhang et al, 2011 , 2016a ; Mathias et al, 2015 ; Jiang et al, 2017 ). Therefore, LDR may be a threat for the cardiac tissue impairment, as well as relieve the cardiac damages through regulation of oxidative stress and pro-inflammatory responses.…”