**2.6 Signalling pathways blocked by polyphenols**

 In addition to the antioxidant effects above mentioned, these bioactive compounds can induce two phases during ROS activation. Phase I starts when polyphenols inhibit cytochrome P450 (CYPs) including CYP1A1 and CYP1B1, and the increase and excretion of polar metabolites and prevention of the formation of DNA adducts remark phase II [35, 44]. But, pro-oxidant activities mediated by polyphenols and phenolic compounds increase the ROS production. Lin et al. reported that resveratrol induced apoptosis in HeLa cell line [15]. The extract of *Cudrania tricuspidata* stem (CTS) on cell viability was investigated in HPV-positive cervical cancer cells. CTS induced apoptosis by downregulating the E6 and E7 viral oncogenes. Also, the mRNA expression levels of extrinsic pathway molecules such as Fas, death receptor 5 (DR5) and TNF-related apoptosis-inducing ligand (TRAIL) were increased by CTS. CTS induced apoptosis by activating the extrinsic pathway in SiHa cervical cancer cells. Chlorogenic acid has been reported to have anticancer, antioxidant and antidiabetic effects. Also, galangin increased ROS, which induced the activation of cell death via various mechanisms including apoptosis or arrest of cell cycle [15, 20, 25]. Bruges reported that pyrogallol induced mitochondrial apoptotic response. Mitochondrial pathway probably begins with the activation of BH3-only proteins. This protein causes the production of BAK1 and BAX, which promote a membrane permeabilisation. Last, in cytoplasm increasing cytochrome C level, this allows apoptosome formation and caspase-9 activations. In extrinsic apoptosis pathway, binding of the cell death ligands and cell death receptors activates caspase-8 and caspase-3 (**Figure 1**) [35, 45]. Similarly, *Terminalia sericea* enabled caspases-7 and -8 and poly (ADP-ribose) polymerase (PARP) in HeLa cancer cell line [31]. Also, pyrogallol induces superoxide anion, and this generates activation of caspase-3 and phosphatidylserine [45]. Silva et al. mentioned that the hexane partition derived from the crude extract presented cytotoxic effect in SiHa cells and initiates cell responses, such as DNA damage (H2AX activity), apoptosis via intrinsic pathway (cleavage of caspase-9, caspase-3, poly (ADP-ribose) polymerase (PARP) and mitochondrial

#### **Figure 1.**

*Effect of biocompounds in cellular processes. In the figure, it is observed that at low concentrations, biocompounds (left) can exert an antioxidant effect, whereby it acts by reducing reactive oxygen species. However, at high concentrations (right), biocompounds have pro-oxidant effects, which can affect both normal and carcinogenic cells and result in alteration of key pathways for homeostasis of the cell, causing cell cycle arrest and stop cell proliferation, damage to DNA and apoptosis, among others, cellular process.* 

 membrane depolarization) and decreased p21 expression by ubiquitin proteasome pathway [42]. Fusi et al. reported that the antioxidant activity of resveratrol, catechin, curcumin, etc. increases sirtuin 1 (SIRT1) expression and monophosphateactivated protein kinase (AMPK) activation in HeLa cell line [27, 44]. Prior reports indicated AMPK is an enzyme that inhibits anabolic process and increases catabolic activity. Perhaps, the relationship between SIRT1 and AMPK may protect against oxidative stress [27, 44]. On the other hand, pro-oxidant activities induced by polyphenols generate ROS and produce [1] cell cycle arrest, and [2] induction of apoptosis and DNA fragmentation. In HeLa cells, autophagy-signalling pathways are modulated by polyphenols, i.e. resveratrol, curcumin and genistein, and act on epidermal growth factor kinase B (EFGR)/AMPK, and this inhibits the mammalian target of rapamycin (mTORC1) via TSC1/2. Also, these three polyphenols inhibit nuclear factor kappa-light-enhancer of activated B cells (NF-κB), and these compounds plus quercetin stop phosphatidilinositide 3-kinases/protein kinase B (PI3K/Akt), and last, rottlerin breaks PKC5 [35, 44]. Last, safflower polysaccharide (SPS) is a major active component of *Carthamus tinctorius*. SPS inhibited proliferation and increased apoptosis of HeLa cells through downregulation of the phosphatidylinositol-3-kinase/ AKT pathway [46].
