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Role of microRNAs in doxorubicin-induced cardiotoxicity: an overview of preclinical models and cancer patients.

ABSTRACT: Cardiotoxicity is a well-known side effect of doxorubicin (DOX), but the mechanisms leading to this phenomenon are still not completely clear. Prediction of drug-induced dysfunction onset is difficult and is still largely based on detection of cardiac troponin (cTn), a circulating marker of heart damage. In the last years, several investigations focused on the possible involvement of microRNAs (miRNAs) in DOX-induced toxicity in vitro, with contrasting results. Recently, several groups employed animal models to mimic patient's condition, investigate the biological pathways perturbed by DOX, and identify diagnostic markers of cardiotoxicity. We reviewed the results from several studies investigating cardiac miRNAs expression in rodent models of DOX-treatment. We also discussed the data from two publications indicating the possible use of circulating miRNA as biomarkers of DOX-induced cardiotoxicity. Unfortunately, limited information was derived from these studies, as selection methods of candidate-miRNAs and heterogeneity in cardiotoxicity assessment greatly hampered the novelty and robustness of the findings. Nevertheless, at least one circulating miRNA, miR-1, showed a good potential as early biomarker of drug-mediated cardiac dysfunction onset. The use of animal models to investigate DOX-induced cardiotoxicity surely helps narrowing the gap between basic research and clinical practice. Despite this, several issues, including selection of relevant miRNAs and less-than-optimal assessment of cardiotoxicity, greatly limited the results obtained so far. Nonetheless, the association of patients-based studies with the use of preclinical models may be the key to address the many unanswered questions regarding the pathophysiology and early detection of cardiotoxicity.

SUBMITTER: Ruggeri C

PROVIDER: S-EPMC5756562 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cancer treatment with doxorubicin (DOX) can induce cumulative dose-dependent cardiotoxicity. Currently, there are no specific biomarkers that can identify patients at risk during the initial doses of chemotherapy. The aim of this study was to examine plasma cytokines/chemokines and potential cardiovascular biomarkers for the prediction of DOX-induced cardiotoxicity. Plasma samples were collected before (T0), and after the first (T1) and the second (T2) cycles of DOX-based chemotherapy of 27 breast cancer patients, including five patients who presented with >10% decline of left ventricular ejection fraction (LVEF), five patients with LVEF decline of 5-10%, and 17 patients who maintained normal LVEF at the end of chemotherapy (240 mg/m2 cumulative dose of DOX from four cycles of treatment). Multiplex immunoassays were used to screen plasma samples for 40 distinct chemokines, nine matrix metalloproteinases, 33 potential markers of cardiovascular diseases, and the fourth-generation cardiac troponin T assay. The results showed that the patients with abnormal decline of LVEF (>10%) had lower levels of CXCL6 and sICAM-1 and higher levels of CCL23 and CCL27 at T0; higher levels of CCL23 and lower levels of CXCL5, CCL26, CXCL6, GM-CSF, CXCL1, IFN-?, IL-2, IL-8, CXCL11, CXCL9, CCL17, and CCL25 at T1; and higher levels of MIF and CCL23 at T2 than the patients who maintained normal LVEF. Patients with LVEF decline of 5-10% had lower plasma levels of CXCL1, CCL3, GDF-15, and haptoglobin at T0; lower levels of IL-16, FABP3, and myoglobin at T1; and lower levels of myoglobin and CCL23 at T2 as compared to the patients who maintained normal LVEF. This pilot study identified potential biomarkers that may help predict which patients are vulnerable to DOX-induced cardiotoxicity although further validation is needed in a larger cohort of patients. Impact statement Drug-induced cardiotoxicity is one of the major concerns in drug development and clinical practice. It is critical to detect potential cardiotoxicity early before onset of symptomatic cardiac dysfunction or heart failure. Currently there are no qualified clinical biomarkers for the prediction of cardiotoxicity caused by cancer treatment such as doxorubicin (DOX). By using multiplex immunoassays, we identified proteins with significantly changed plasma levels in a group of breast cancer patients who were treated with DOX-based chemotherapy and produced cardiotoxicity. These proteins were associated with immune response and were identified before DOX treatment or at early doses of treatment, thus they could be potential predictive biomarkers of cardiotoxicity although further validation is required to warrant their clinical values.

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Role of microRNAs in doxorubicin-induced cardiotoxicity: an overview of preclinical models and cancer patients.

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