## 3 Resveratrol and Free Radicals
### Effect of Resveratrol on Other Carcinogenic Pathways
Resveratrol can induce cancer cell death through the intrinsic apoptotic pathway, which is mediated by the formation of apoptosomes and the release of apoptogenic factors, such as cytochrome c and caspase 2/9 from the mitochondrial intermembrane space, or through the extrinsic apoptotic pathway involving the superfamily of TNF receptors, such as Fas (CD95 or APO-1) or TRAIL receptors (TNF-Related Apoptosis-Inducing Ligand). Resveratrol induces the arrest of the cell cycle at the level of the G0/G1 and S phase through the phosphorylation or acetylation of p53 at the level of the serine residue 15, thanks to the activation of MAPK, inducing an increase in the expression of pro-apoptotic proteins, activation of effector caspases, such as caspase 8/9, and a decrease in the expression of anti-apoptotic proteins, such as Bcl-2 [83; 84]. Recently, [PERSON] and co-workers explored more in detail the mechanism underlying the anticancer effect of resveratrol in both Her2/neu-positive breast and salivary cancer cell lines. It has been shown that the cytotoxic effect of resveratrol in these cell models is essentially related to the increase of phosphorylation of mTOR targets 4 EBP1 and P7056K, to a reduction of the basal autophagy, which cancer cells use to counteract their basal stress, and, finally, also to an increase of ROS production known to be detrimental for cancer cell survival [85]. Resveratrol also influences the activity of transcription factors known as FoxO (Forkhead box O), involved in numerous cellular processes, such as cell cycle progression, apoptosis, and the response to oxidative stress. In various types of cancer, the transcriptional activity of FoxO is inhibited due to phosphorylation mediated by constitutive activation of the PI3K/Akt pathway [112]. FoxO phosphorylation facilitates the interaction with 14-3-3 proteins and subsequent nuclear export. In this regard, resveratrol inhibits PI3K/Akt-mediated phosphorylation and consequently causes a decrease in phosphorylated FoxO levels. It also promotes nuclear translocation, an increase in DNA binding affinity, and, finally, the transcriptional activity of FoxO, which plays a significant role in the apoptotic process, being involved in the overexpression of pro-apoptotic proteins and downregulating the anti-apoptotic ones, finally inducing cell death [86]. Resveratrol also activates the action of SIRT1, which plays a dual role in cancer progression and suppression, by modulating the SIRT1/\(\beta\)-catenin signaling pathway and thus reversing EMT in tumor cells [87]. Furthermore, the activation and overexpression of SIRT1 is involved in the apoptotic process through the deacetylation of p53 or other proteins that act as tumor suppressors or transcription factors, such as FoxO and NF-kB [88]. In fact, the activation of SIRT1 by resveratrol involves the deacetylation of the p65 subunit of the NF-kB complex, thus promoting cell death [89]. The activation of SIRT1 by resveratrol also induces an increase in the expression of SOD, mediated by the FoxO transcription factor [90]. Finally, it is worth mentioning the role of resveratrol as a modulator of the tumor glucose metabolism. Compared to healthy tissues, tumor cells uptake and consume high amounts of glucose to meet their high energy demand. Their glycolytic metabolism is characterized by a large production of lactate, even in aerobic conditions (the so-called Warburg effect) [113]. Resveratrol has been reported to interfere with this metabolism in breast cancer by decreasing glucose uptake, mediated by the Glut1 transporter, and inhibiting the activity of 6-phosphofructo-1-kinase (PFK), one of the enzymes of the glycolytic metabolism, thus leading to a reduction in cell proliferation and viability [91; 92]. Resveratrol has also an effect on steroidal pathways by interacting with membrane-bound ERs and modulating its genomic and non-genomic activities, as well as by inhibiting steroidogenesis and estrogen biosynthesis at multiple steps along the pathway [93].