Toll-like receptor 4 (TLR4) expression is correlated with T2* iron deposition in response to doxorubicin treatment: cardiotoxicity risk assessment

Abstract

Although doxorubicin (Dox) is an effective antitumor antibiotic in the anthracycline class, it often induces the undesirable side effect of cardiomyopathy leading to congestive heart failure, which limits its clinical use. The primary goal of this study is to evaluate a reliable translational method for Dox-induced cardiotoxicity (CTX) screening, aiming to identify a high-risk population and to discover new strategies to predict and investigate this phenomenon. Early identification of the presence of iron deposits and genetic and environmental triggers that predispose individuals to increased risk of Dox-induced CTX (e.g., overexpression of Toll-like receptor 4 (TLR4)) will enable the early implementation of countermeasure therapy, which will improve the patient’s chance of survival. Our cohort consisted of 25 consecutive patients with pathologically confirmed cancer undergoing Dox chemotherapy and 12 control patients. The following parameters were measured: serum TLR4 (baseline), serum transferrin (baseline and 6-week follow-up) and iron deposition (baseline and 6-week follow-up). The average number of gene expression units was 0.121 for TLR4 (range 0.051–0.801). We subsequently correlated serum TLR4 levels in our cohort with myocardial iron overload using the cardiac magnetic resonance (CMR) T2* technique, the ventricular function (% ejection fraction, %EF) and serum transferrin levels. There is a strong negative linear relationship between serum TLR4 and CMR T2* values (r = − 0.9106, ****P < 0.0001). There is also a linear correlation (either positive or negative) with EF and transferrin; no established relationship related to the sex of the patients was found. Patients with elevated serum TLR4 at baseline also exhibited an increase in serum transferrin levels and Dox-induced left ventricular dysfunction with a decreased EF (< 50%); this phenomenon was observed in 7 of 25 patients (28%) at the 6-week follow-up. There were no significant differences or correlations based on sex. We concluded that there is a direct relationship between Dox-induced CTX (indicated by elevated serum TLR4) and the times (ms) for T2* (decreases in which correspond to immediate and rapid iron overload).

Nano-Curcumin Prevents Cardiac Injury, Oxidative Stress and Inflammation, and Modulates TLR4/NF-κB and MAPK Signaling in Copper Sulfate-Intoxicated Rats

“…Activation of TLR4 signaling in the heart of Cu-intoxicated rats is a direct consequence of excessive ROS generation and cell injury [ 34 ]. Activation of TLR4 occurs in cardiotoxicity, cardiomyopathy, HF, and other cardiac alterations [ 36 ]. TLR4 triggers both the MyD88-dependent and -independent pathways, leading to the activation of transcription factors such as NF-κB and the production of pro-inflammatory mediators [ 35 ].…”

“…Upon activation, TLR4 triggers the release of pro-inflammatory mediators through promoting NF-κB and MAPKs [ 35 ]. TLR4 is activated in several cardiac alterations, such as cardiotoxicity, cardiomyopathy, and HF [ 36 ]. However, the possible involvement of TLR4 signaling in Cu cardiotoxicity has not been demonstrated.…”

Therapeutic Targets for DOX-Induced Cardiomyopathy: Role of Apoptosis vs. Ferroptosis

“…This DOX-induced iron uptake occurs through a transferrin receptor-dependent mechanism, and the administration of anti-transferrin receptor antibodies dramatically suppress DOX-induced iron uptake, intracellular oxidant production, and cell death. In clinical practice, serum transferrin levels in patients receiving DOX chemotherapy correlate with left ventricular dysfunction severity [118]. Treatment of the HL-1 cell line with DOX caused a time-dependent increase in cytoplasmic and mitochondrial free iron pools, resulting in a loss of mitochondrial membrane potential [102].…”

Toll-like Receptor 4 Inflammatory Perspective on Doxorubicin-Induced Cardiotoxicity

“…Clinical studies have shown the important role of systemic TLR4 on cardiac function in patients with hematological malignancy who received a Dox regimen [46,47]. After 6 months of Dox administration, blood sampling was collected to determine TLR4 expression, together with measuring the non-invasive cardiac function in Dox-treated patients [46,47].…”