## 3 Resveratrol and Free Radicals
### Other Effects  
Resveratrol is also used as a chemoprotective agent against the toxic effects caused by numerous chemotherapy drugs, such as anthracyclines and, in particular, doxorubicin (DOX). DOX, one of the most important antineoplastic agents against breast cancer, can intercalate in the DNA double helix, thus inhibiting the activity of DNA and RNA polymerase. However, the use of this anticancer drug involves several undesirable effects, including oxidative stress, especially at the heart tissue level, by increasing ROS production, lipid peroxidation, and reduction of endogenous antioxidants [95]. For this reason, DOX and some of its alcoholic metabolites (DOXol) are responsible for chronic cardiotoxicity. It has been verified that the co-administration of natural antioxidants, such as resveratrol, lowers the ROS levels and, at the same time, increases the expression of some antioxidant enzymes, such as SOD and CAT [96]. Furthermore, ROS generated by doxorubicin treatment can cause a release of Ca\({}^{2+}\) ions from the sarcoplasmic reticulum, leading to an increase in the intracellular calcium levels. This leads to an increased uptake of calcium in the mitochondria that induce the release of cytochrome c in the cytosol, i.e., a promotion of the apoptotic process of cardiomyocytes.  
In addition, DNA damage, linked directly to the action of DOX or indirectly to the action of the ROS generated by it, results in an increase in the expression and activation of p53, which overexpresses genes related to pro-apoptotic proteins, such as Bax. Resveratrol limits the apoptotic effect of DOX by activating SIRT1, which reduces the cell death process by inhibiting the activation of p38 MAPK and the activation of caspases, or by inducing cytoprotective autophagy, a cellular process of removal and degradation of damaged cytoplasmic components (including ROS) by acting on the PI3K/Akt/mTOR/AMPK pathway [97; 98]. Resveratrol is able to activate AMPK, which inhibits mTOR1, thus promoting autophagy.  
Resveratrol was also delivered in conjunction with tamoxifen, a non-steroidal estrogen antagonist in ER+ breast cancer therapeutics, through layer-by-layer nanoparticles, which showed potent cytotoxicity and enhanced apoptosis in both MCF-7 and CAL-51 human breast cancer cell lines by increasing the expression of p53 and caspase-8 [114].  
Resveratrol also increases the effectiveness of some chemotherapy drugs, such as cisplatin, sensitiizing the cancer cells towards apoptosis in a synergistic way, also reducing the side effects of the chemotherapeutic [115]. This effect is probably induced by a reduced expression of TGF-\(\beta\)1 and an increased expression of E-cadherin, inhibiting cell invasion and migration through EMT. Thanks to its multiple effects and therapeutic potential in cancer, it is being evaluated as an adjuvant drug or dietary supplement in several clinical trials. Furthermore, it has been shown that resveratrol significantly increased the apoptotic effect of ionizing radiation treatment in the MCF-7 breast cancer cell line, most likely by increasing ROS generation with involvement of intrinsic or extrinsic apoptotic pathways [99].