Abstract
Doxorubicin (DOX) is a topoisomerase II inhibitor commonly used in the treatment of several types of cancer. Despite its efficacy, DOX can potentially cause fatal adverse effects, like cardiotoxicity. This work aimed to assess the role of inflammation in DOX-treated infant and adult mice and its possible link to underlying cardiotoxicity. Two groups of CD-1 male mice of different ages (infants or adults) were subjected to biweekly DOX administrations, to reach a cumulative dose of 18.0 mg/kg, which corresponds approximately in humans to 100.6 mg/m2 for infants and 108.9 mg/m2 for adults a clinically relevant dose in humans. The classic plasmatic markers of cardiotoxicity increased, and that damage was confirmed by histopathological findings in both groups, although it was higher in adults. Moreover, in DOX-treated adults, an increase of cardiac fibrosis was observed, which was accompanied by an increase in specific inflammatory parameters, namely, macrophage M1 and nuclear factor kappa B (NF-κB) p65 subunit, with a trend toward increased levels of the tumor necrosis factor receptor 2 (TNFR2). On the other hand, the levels of myeloperoxidase (MPO) and interleukin (IL)-6 significantly decreased in DOX-treated adult animals. In infants, a significant increase in cardiac protein carbonylation and in the levels of nuclear factor erythroid-2 related factor 2 (Nrf2) was observed. In both groups, no differences were found in the levels of tumor necrosis factor (TNF-α), IL-1β, p38 mitogen-activated protein kinase (p38 MAPK) or NF-κB p52 subunit. In conclusion, using a clinically relevant dose of DOX, our study demonstrated that cardiac effects are associated not only with the intensity of the inflammatory response but also with redox response. Adult mice seemed to be more prone to DOX-induced cardiotoxicity by mechanisms related to inflammation, while infant mice seem to be protected from the damage caused by DOX, possibly by activating such antioxidant defenses as Nrf2.
Highlights
Doxorubicin (DOX) is a topoisomerase II inhibitor that binds and intercalates with the DNA, with a broad spectrum of activity against neoplastic cells [1]
The early myocardial changes caused by DOX were assessed in mice of two age groups and the major findings were: (1) DOX affected the animals’ body weight and food/water consumption; (2) DOX caused a significant elevation of plasma levels of creatine kinase-MB (CK-MB), total-CK, AST and AST/ALT ratio in adult mice, which was corroborated by histopathological findings; (3) the ratio between heart weight/brain weight was significantly decreased in both populations; (4) the levels of the macrophage M1 marker and of NF-κB p65 subunit increased in DOX-treated adult animals; (5) no differences were found in the levels of TNF-α, IL-1β, p38 MAPK, and NF-κB p52 in both evaluated
The decrease in the levels of MPO observed in adult animals may suggest early damage to the enzyme related to DOX exposure, leading to subsequent lower oxidative stress, while simultaneously blunting the protective nuclear factor erythroid-2 related factor 2 (Nrf2) activation
Summary
Doxorubicin (DOX) is a topoisomerase II inhibitor that binds and intercalates with the DNA, with a broad spectrum of activity against neoplastic cells [1]. This drug is widely used in chemotherapy regimens for solid tumors and hematological malignancies, including breast, prostate, uterus, ovary, esophagus, liver, bile ducts and stomach tumors, childhood tumors (e.g., Wilms’ tumor), osteosarcomas and soft tissue sarcomas, Kaposi’s sarcoma, multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphoma [2]. The total cumulative dose is the most powerful predictor for the development of DOX-induced cardiotoxicity. It has been estimated that 3% of patients develop DOX-related HF after a cumulative dose of
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