Abstract
Doxorubicin is an anthracycline that is commonly used as a chemotherapy drug due to its cytotoxic effects. The clinical use of doxorubicin is limited due to its known cardiotoxic effects. Treatment with anthracyclines causes heart failure in 15–17% of patients, resulting in mitochondrial dysfunction, the accumulation of reactive oxygen species, intracellular calcium dysregulation, the deterioration of the cardiomyocyte structure, and apoptotic cell death. Polyphenols have a wide range of beneficial properties, and particular importance is given to Bergamot Polyphenolic Fraction; Oleuropein, one of the main polyphenolic compounds of olive oil; and Cynara cardunculus extract. These natural compounds have particular beneficial characteristics, owing to their high polyphenol contents. Among these, their antioxidant and antoproliferative properties are the most important. The aim of this paper was to investigate the effects of these three plant derivatives using an in vitro model of cardiotoxicity induced by the treatment of rat embryonic cardiomyoblasts (H9c2) with doxorubicin. The biological mechanisms involved and the crosstalk existing between the mitochondria and the endoplasmic reticulum were examined. Bergamot Polyphenolic Fraction, Oleuropein, and Cynara cardunculus extract were able to decrease the damage induced by exposure to doxorubicin. In particular, these natural compounds were found to reduce cell mortality and oxidative damage, increase the lipid content, and decrease the concentration of calcium ions that escaped from the endoplasmic reticulum. In addition, the direct involvement of this cellular organelle was demonstrated by silencing the ATF6 arm of the Unfolded Protein Response, which was activated after treatment with doxorubicin.
Highlights
Doxorubicin (DOXO) is a common chemotherapeutic drug that is widely prescribed in oncology due to its cytotoxic effects [1,2,3,4]
Since it is known that DOXO can cause significant damage to the mitochondria, and that these cellular organelles are linked to the endoplasmic reticulum (ER) through direct crosstalk, we investigated whether the induction of DOXO damage affects the ER
No reduction in cell viability was observed at any of the concentrations of BPF, OLE, or CYN considered. In light of this result, the most non-toxic and potentially cytoprotective doses of BPF, OLE, or CYN were tested to determine their protection against DOXO
Summary
Doxorubicin (DOXO) is a common chemotherapeutic drug that is widely prescribed in oncology due to its cytotoxic effects [1,2,3,4]. The clinical use of DOXO is limited, as its accumulation is associated with progressive myocardial damage, which leads to congestive heart failure [5,6,7,8]. For this reason, patients have often been forced to discontinue. A careful cellular and molecular analysis showed that DOXO exerts its negative effects on mitochondrial health, predisposing patients to oxidative stress through the accumulation of reactive oxygen species (ROS) [12,13]. DOXO-induced cardiotoxicity represents a major challenge in the development of treatments capable of reducing its side effects
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