Abstract
Introduction Skin reactions and cardiotoxicity are one of the most common side effects of doxorubicin in cancer patients. The main mechanisms based on the etiopathogenesis of these reactions are mediated by the overproduction of proinflammatory cytokines, metalloproteases, and the disruption of mitochondrial homeostasis. Ozone therapy demonstrated anti-inflammatory effects in several preclinical and clinical studies. The aim of this research is based on the evaluation of cardioprotective and dermatoprotective effects of ozone during incubation with doxorubicin, giving preliminary evidences for further studies in the field of cardio-oncology. Methods Human skin fibroblast cells and human fetal cardiomyocytes were exposed to doxorubicin at subclinical concentration (100 nM) alone or combined with ozone concentrated from 10 up to 50 μg/mL. Cell viability and multiple anti-inflammatory studies were performed in both cell lines, with particular attention on the quantification of interleukins, leukotriene B4, NF-κB, and Nrf2 expressions during treatments. Results Ozone decreased significantly the cytotoxicity of doxorubicin in skin fibroblasts and cardiomyocytes after 24 h of incubation. The best cytoprotective effect of ozone was reached to 30 μg/mL with a plateau phase at higher concentration. Ozone also demonstrated anti-inflammatory effects decreasing significantly the interleukins and proinflammatory mediators in both cells. Conclusion Ozone exerts cardioprotective and dermatoprotective effects during incubation with doxorubicin, and the involved mechanisms are mediated by its anti-inflammatory effects. The overall picture described herein is a pilot study for preclinical studies in oncology.
Highlights
Skin reactions and cardiotoxicity are one of the most common side effects of doxorubicin in cancer patients. e main mechanisms based on the etiopathogenesis of these reactions are mediated by the overproduction of proinflammatory cytokines, metalloproteases, and the disruption of mitochondrial homeostasis
We have shown that ozone is able to improve the tumor microenvironment by reducing the production of cytokines involved in cancer cell survival and chemoresistance; these effects could be of great interest in oncology considering that the tumor microenvironment has a key role in the management of the chemoresistance phenomena to many drugs like the anthracyclines as well as to immunotherapies. e aim of this study is based on demonstrating, for the first time, the cardioprotective and dermatoprotective effects of ozone, at different concentrations, during exposure of cells to doxorubicin, through the analysis of mitochondrial homeostasis, cellular inflammatory state, and the expression of the Nuclear factor erythroid 2-related factor 2 (Nrf2)
A similar but lower significative behaviour was seen in skin fibroblasts with an overall cytoprotective effects of 10–15% of ozone at higher concentration coincubated with doxorubicin
Summary
Skin reactions and cardiotoxicity are one of the most common side effects of doxorubicin in cancer patients. e main mechanisms based on the etiopathogenesis of these reactions are mediated by the overproduction of proinflammatory cytokines, metalloproteases, and the disruption of mitochondrial homeostasis. Anthracyclines and target-based drugs like anti-ERB2 and VEGF antibodies are conventionally used in cancer patients both in combination or in monotherapy Their clinical use is limited by a wide spectrum of reversible and irreversible side effects like cardiovascular diseases as well as skin inflammation [1, 2]. We have shown that ozone is able to improve the tumor microenvironment by reducing the production of cytokines involved in cancer cell survival and chemoresistance; these effects could be of great interest in oncology considering that the tumor microenvironment has a key role in the management of the chemoresistance phenomena to many drugs like the anthracyclines as well as to immunotherapies. E aim of this study is based on demonstrating, for the first time, the cardioprotective and dermatoprotective effects of ozone, at different concentrations, during exposure of cells to doxorubicin, through the analysis of mitochondrial homeostasis, cellular inflammatory state, and the expression of the Nrf We have shown that ozone is able to improve the tumor microenvironment by reducing the production of cytokines involved in cancer cell survival and chemoresistance; these effects could be of great interest in oncology considering that the tumor microenvironment has a key role in the management of the chemoresistance phenomena to many drugs like the anthracyclines as well as to immunotherapies. e aim of this study is based on demonstrating, for the first time, the cardioprotective and dermatoprotective effects of ozone, at different concentrations, during exposure of cells to doxorubicin, through the analysis of mitochondrial homeostasis, cellular inflammatory state, and the expression of the Nrf
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