Multitissue analysis of exercise and metformin on doxorubicin-induced iron dysregulation

Abstract

Doxorubicin (DOX) is an effective chemotherapeutic treatment with lasting side effects in heart and skeletal muscle. DOX is known to bind with iron, contributing to oxidative damage resulting in cardiac and skeletal muscle toxicity. However, major cellular changes to iron regulation in response to DOX are poorly understood in liver, heart, and skeletal muscle. Additionally, two cotreatments, exercise (EX) and metformin (MET), were studied for their effectiveness in reducing DOX toxicity by ameliorating iron dysregulation and preventing oxidative stress. The purposes of this study were to 1) characterize the DOX-induced changes of the major iron regulation pathway in liver, heart, and skeletal muscle and 2) to determine whether EX and MET exert their benefits by minimizing DOX-induced iron dysregulation. Mice were assigned to receive saline or DOX (15 mg/kg) treatments, paired with either EX (5 days) or MET (500 mg/kg), and were euthanized 3 days after DOX treatment. Results suggest that the cellular response to DOX is protective against oxidative stress by reducing iron availability. DOX increased iron storage capacity through elevated ferritin levels in liver, heart, and skeletal muscle. DOX reduced iron transport capacity through reduced transferrin receptor levels in heart and skeletal muscle. EX and MET cotreatments had protective effects in the liver through reduced transferrin receptor levels. At 3 days after DOX, oxidative stress was mild, as shown by normal glutathione and lipid peroxidation levels. Together these results suggest that the cellular response to reduce iron availability in response to DOX treatment is sufficient to match oxidative stress.

Predictive Value of C-reactive Protein, Lactate Dehydrogenase, Ferritin and D-dimer Levels in Diagnosing COVID-19 Patients: a Retrospective Study

“…Ferritin is an iron storage form; it is one of the biomarkers of inflammation. In bacterial or viral infection, an increase in ferritin occurs due to ironreleasein the endoplasmic reticulum and to a decline in its transport capacity due to spleen and liver damage ( 9 ). Lactate dehydrogenase (LDH) is an enzyme involved in glycolysis, catalyzes pyruvate to lactate conversion and present in all tissues.…”

Exercise stimulates beneficial adaptations to diminish doxorubicin-induced cellular toxicity

“…Significantly, preclinical studies have demonstrated that aerobic exercise training can modify DOX-induced hepatotoxicity and prevent DOX-induced maladaptations to the liver. Specifically, preconditioning protocols utilizing treadmill exercise ranging from 6 wk to 5 days before DOX administration provided valuable modifications to hepatocyte signaling (1,2,50,79,128). These studies demonstrate improvements in oxidative stress signaling, mitochondrial function, iron dysregulation, and insulin-like growth factor signaling and support the inclusion of exercise training as an advantageous therapy to preclude DOX hepatotoxicity (1,2,50,79,128).…”

LCZ696 Attenuates ROS/NLRP3 Mediated Pyroptosis in Trastuzumab-induced H9C2 Cell Model Via Ameliorating Sirt3 Expression

“…Chemotherapy is a kind of common treatment for cancer, but both traditional drugs, such as doxorubicin, cisplatin or paclitaxel, and targeted drugs, like trastuzumab or immune checkpoint inhibitors, can cause a certain degree of cardiotoxicity. Taking doxorubicin as an example, current studies have shown that doxorubicin can cause iron overload in cardiomyocytes, further aggravate oxidative stress [10,11,12] , at the same time, cardiomyocytes metabolism disorder and structural change are contributed to myocardial cell apoptosis, necrosis and even increasing Gasdermin D sequentially leading to membrane dissolution [13,14] . However, the speci c mechanism of cardiotoxicity caused by targeted drugs has been on studying, but metabolism disorder, oxidative stress and in ammation are potential reasons.…”