## 3 Resveratrol and Free Radicals
### Effect of Resveratrol on Other Carcinogenic Pathways  
The antioxidant properties of resveratrol also include the regulation of numerous signaling pathways involved in the carcinogenesis process. This compound inhibits numerous kinases, such as PKC, MAPK, and IKK (IkB kinase), and some transcription factors, such as NF-kB, STAT3, HIF-1\(\alpha\), and AP-1 (Activator Protein-1), often activated by ROS, such as H\({}_{2}\)O\({}_{2}\)[73; 74]. As mentioned above, the inflammatory process contributes to the development and progression of carcinogenesis. An essential mediator of the tumor transformation induced by inflammation is the nuclear transcription factor NF-kB, a heterodimer consisting of two subunits, p65 and p50. Under normal conditions, NF-kB is bound to an inhibitor of kB (I-kB) in the cytoplasm. ROS accumulation mediates the phosphorylation of I-kB by a kinase (i.e., the IKK, inhibitor of NF-kB kinase), leading to its ubiquitination and degradation in the proteasome. This process facilitates the transfer of NF-kB into the nucleus, inside which it modulates the expression of genes related to the inflammatory response. The antioxidant and anti-cancer effects of resveratrol can be attributed to the inhibition of IKK and, consequently, an increase in the expression of I-kB\(\alpha\), the inactivation of NF-kB, and the latter's retention in the cytoplasm, inhibiting its translocation into the nucleus. Resveratrol can also block NF-kB activation induced by inflammatory mediators, such as IL-1\(\beta\) and tumor necrosis factor-\(\alpha\) (TNF-\(\alpha\)), with the subsequent suppression of cell proliferation, apoptosis, and angiogenesis and formation of metastases [75; 76]. Resveratrol also increases the expression level of programmed cell death ligand 1 (PD-L1), a modulator of the immune system whose blockade already proved to be a valid therapy for solid tumors, via HDAC3/p300-mediated NF-kB signaling [77]. Upregulation of PD-L1 was shown to be dose dependent in lung cancer cells and suppression of T cell function was already observed at relatively low--pharmacologically achievable--resveratrol concentrations [78]. The Wnt pathway proved to be critical for mediating the resveratrol-induced PD-L1 upregulation and, in particular, resveratrol activated SIRTI, which promoted Snail protein deacetylation, which, in turn, inhibited transcription of Axin2, thus leading to disassembly of destruction complex and enhanced binding of \(\beta\)-catenin/TCF to PD-L1 promoter. By combining biochemical, computational, and microscopy approaches, it was shown that resveratrol can directly target PD-L1 glycosylation and dimerization, thus interfering with the protein's stability and trafficking, ultimately impeding its targeting to the cancer cell plasma membrane and enhancing anti-tumor T-cell immunity [79]. In addition to modulating NF-kB expression to inhibit cancer progression, resveratrol can also inhibit the EMT induced by TGF-\(\beta\)1. This cytokine is involved in the regulation of EMT through Smad-dependent signaling pathways. Smad2 and Smad3 proteins, particularly their TGF-\(\beta\)1-regulated overexpression and phosphorylation, play a key role in the EMT transition of breast cancer. Resveratrol decreases the levels of these proteins by inhibiting their phosphorylation and, consequently, the EMT process responsible for the formation of metastases [80]. Resveratrol can also reduce angiogenesis by lowering the expression of VEGF and HIF-1\(\alpha\) and induce cell death by inhibiting anti-apoptotic proteins, such as proteins belonging to the Bcl-2 family, and activating pro-apoptotic proteins, such as Bad, Bax, and Bak [81]. All these mechanisms are related to the activation of the p53 oncosupressor, a transcription factor involved in cell cycle regulation and apoptosis [111]. This was recently confirmed by [PERSON] and colleagues, who demonstrated through RNA sequencing that genes affected by resveratrol treatment in MDA-MB-231 cells were mainly involved in apoptosis and the p53 signaling pathway [82].