Phenolic acids are the simplest phenolic compounds, formed of only one phenolic ring with multiple hydroxy or methoxy groups attached to their backbone. Hydroxycinnamic acids are aromatic carboxylic acids with unsaturation in the side chain (commonly of trans-configuration) and are more abundant than hydroxybenzoic acids. Cinnamic acids work as phytohormones, which are important components of lignin and the precursors of chalcones, flavonoids, anthocyanins, and stilbenes (El-Seedi et al., 2012). Hydroxycinnamic acids are considered potent antitumor agents due to the presence of α, β-unsaturation, acting as Michael acceptors (De et al., 2011). Relevant hydroxycinnamic acids include caffeic, ferulic, p-coumaric, and sinapic acids, and the most representative hydroxybenzoic acids include gallic, vanillic, syringic, protocatechuic, and p-hydroxybenzoic acids. Phenolic acids can be found in vegetable-derived foods including cereals, legumes, soybeans, coffee, tea, rosemary, thyme, apples, various berries, plums, cherries, and citrus fruits (Clifford and Scalbert, 2000; El-Seedi et al., 2012). Different health effects have been related to phenolic acids. Chlorogenic acid has exhibited its anticancer potential by inducing differentiation through an increase of KHSRP, p53, and p21, a decrease of poor differentiation-related genes c-Myc and CD44, and downregulation of oncogenic miRNA-17 family members in cancer cell lines (Huang et al., 2019). Other mechanisms involve epigenetic regulation; gallic acid inhibits DNMT1 activity through the negative regulation of p-Akt, reducing the nuclear import and stability of DNMT1. Potential epigenetic targets include CCNE2, CCND3, CDKN1A, and CCNB1 genes, which play important roles in the GADD45 signaling pathway (Weng et al., 2018).

Flavonoids are ubiquitous compounds in plants that are responsible for the fragrance, color, and flavor of fruits, seeds, and flowers, with important roles in pollination and protecting plants from ultraviolet (UV) light and acting as detoxifying agents and as signaling molecules, and they may play important roles in cold and heat acclimation (Koes et al., 1994; Panche et al., 2016). There are nearly 6,000 flavonoid-related compounds, including their derivatives flavanones, flavones, isoflavones, flavanols, flavonols, and anthocyanidins. Benzo-γ-pyrone is the basic chemical structure of flavonoids characterized by the presence of 15 carbon atoms as the base skeleton, organized in the form C6–C3–C6 (A+C–B) (two benzenic rings A and B) and linked by a unit of three carbons that may or not form a third-ring structure (pyran ring C). Flavonoids can occur as aglycones and as hydroxylated, methylated, and glycosylated derivatives and have great relevance for the sensory quality of citrus fruits. For example, flavonoids such as naringerin and neohesperidin are responsible for bitterness (Wang et al., 2017). Regular consumers of tea may have intakes of over 1,000 mg/day; however, normal diets only provide between 20 and 200 mg/day (Birt and Jeffery, 2013), and a regular dietary intake of flavonoids (500 mg/day) has been related to a diminished mortality risk (Bondonno et al., 2019).

Stilbenoids are nonflavonoid polyphenols derived from the phenylpropanoid pathway, in the form of hydroxylated derivatives of stilbene backbone C6–C2–C6 (two aromatic rings linked by a methylene bridge), with two possible planar configurations (cis or trans). Stilbenoids are usually found as aglycones, glycosidic/methoxyl conjugates, or oligomeric units (viniferins). Stilbenoids act as phytoalexins and 1,000 of these compounds have been identified to date (Xiao et al., 2008; Mekinić et al., 2016). Stilbenoid-rich sources include the plants of the Gnetaceae, Pinaceae, Cyperaceae, Fabaceae, and Dipterocarpaceae families; however, their content is <10% of that found in the Vitaceae family, and the richest sources of stilbenoids are wine, berries, and grape juice (Niesen et al., 2013; El Khawand et al., 2018). Resveratrol represents by far the most important compounds of its kind, followed by gnetol, piceid, astringin, pterostilbene, piceatannol, viniferins, etc. The bioactivities of stilbenoids include anticancer effects. Pterostilbene has shown upregulation of PTEN in prostate cancer cells and xenografts through the reduction of levels of oncogenic miR-17, miR-20a, and miR-106b (Dhar et al., 2015), thus highlighting the potential health effects of stilbenoids in terms of their being promising candidates as novel therapeutic agents.

p53 represents the most important human tumor suppressor and a central element for cell-cycle control and apoptosis. p53 is composed of 393 amino acid (aa) residues and includes the following six domains: two N-terminus transactivation domains (TAD, including TAD1 and TAD2); a proline-rich domain (PRD); a central DNA-binding domain (DBD); a tetramerization domain (TD); and a C-terminus regulatory domain (CRD) (a rich-lysine region). The acidic nature of TAD (∼20%) contributes to the efficacy of the transactivation (Raj and Attardi, 2017). TAD are important for interaction with regulators including Mdm2 and MdmX and for the recruitment of chromatin modifiers CBP/p300, the latter prompting chromatin opening and p53 stabilization through the acetylation of CRD, preventing its ubiquitination (Raj and Attardi, 2017). The DBD contains six “hotspots” where the most frequent mutations occur in cancer. While R248Q and R273H disrupt p53/DNA binding, others produce local (R248Q; R273H) and global (R175H; R282W) conformational distortions (Brosh and Rotter, 2009; Baugh et al., 2018). TD facilitates p53 tetramerization, contains a nuclear export signal hidden in a tetrameric form that allows for nuclear accumulation, also influences the strength and conformation of DNA/p53 complexes, and is important for protein-protein interactions (CK2, PKC, and RelA bind to p53 through TD) (Chène, 2001; Gencel-Augusto and Lozano, 2020). CRD is required for the binding of promoters and structural changes in DBD (Laptenko et al., 2015) and undergoes extensive posttranslational modifications (PTM) on Lys residues.

p53 is under strict regulation because of its role as a central hub in the signal transduction of many cellular processes. In fact, while p53-null mice can live, those lacking Mdm2 and those that are incapable of regulating p53 die (Jones et al., 1995). The p53 half-life accounts for from 5 to 20 min in nearly all cell types, but after stress signals, senescence, or DNA damage, its stability is increased (Giaccia and Kastan, 1998). Negative regulators of p53 include Mdm2 and MdmX. Mdm2 promotes Lys ubiquitination at the C-terminus, targeting p53 for proteasomal degradation and abolishing the acetylation essential for the p53-mediated stress response (Tang et al., 2008). MdmX regulates p53 by direct interaction with TAD independent of E3-ubiquitin ligase activity (Raj and Attardi, 2017); however, MdmX can associate with Mdm2, enhancing its E3-ligase activity (Badciong and Haas, 2002). Recently, it has been demonstrated that MdmX inhibits the p53/DNA-binding function in association with CK1α (Wei et al., 2016). All of these control mechanisms highlight the importance of p53 regulation, which renders it an important therapeutic target due to its central role in cell fate control.

p53 control is carried out by a variety of mechanisms, and the regulatory activities of polyphenols on p53 are widely reported in the literature. p53 undergoes extensive PTM (Figure 2), including phosphorylation, acetylation, ubiquitination, and methylation, which influence its stability, localization, and function; in addition, polyphenols may influence the posttranslational status of p53. It was recently described that curcumin promotes hyperphosphorylation in Ser15, thus promoting the expression of proapoptotic Bex genes in neuroblastoma cells (Sidhar and Giri, 2017). However, curcumin may also impair p53 folding into the required conformation for its phosphorylation, which affects its tumor-suppression function (Moos et al., 2004). Curcumin may alter p53/p300 interaction through p53 acetylation (Lys373), leading to the transcription of BAX, PUMA, and Noxa, thus enabling p53-mediated apoptosis in breast cancer cells (Sen et al., 2011). p53/p300 Interaction is important, considering that the genotoxic stress-related transcriptional activity of p53 is regulated by its interaction with its transcriptional coactivator p300. Nrf2 plays a protective role against oxidative stress in mammals by the regulation of antioxidant and detoxifying enzyme transcription (Saha et al., 2020). Dalton’s lymphoma has low levels of Nrf2; treatment with curcumin restores Nrf2 messenger RNA (mRNA) levels and enhances the binding of the protein Nrf2 to ARE and the NF-2E consensus sequence, thus increasing the levels of endogenous antioxidants and enhancing the general antioxidant status. Interestingly, curcumin increased p53 mRNA and protein levels, and this increase was related to the stabilization of Nrf2 expression (Das and Vinayak, 2015). Nrf2 induces the expression of the antioxidant enzyme NQO1 that, aside from its primary function, forms a complex with p53, leading to its stabilization in curcumin-treated cervical cancer cells (Patiño-Morales et al., 2020).

Several anticancer effects have been linked to treatment with resveratrol. Resveratrol induces phosphorylation in Ser20, promoting p53 stabilization, thus leading to the activation of target genes and the induction of apoptosis (Hernandez-Valencia et al., 2018). Polyphenols may contribute to p53 stabilization through the prevention of Mdm2-mediated ubiquitination or by the modulation of deubiquitinating enzymes. Ubiquitination plays an important role in p53 degradation and localization. USP10 (a cytosolic deubiquitinating enzyme) with an affinity for p53 reverses Mdm2-mediated ubiquitination, cytoplasmatic degradation, and nuclear export and impacts the transcriptional activity of p53 (Sun and Dai, 2014). Resveratrol binds to G3BP1 and interrupts the G3BP1/USP10 interaction, releasing USP10 and promoting its deubiquitinating activity, increasing p53-mediated apoptosis in melanoma (Oi et al., 2015). Without the disruption of the p53/USP10 complex by G3BP1, p53-deubiquitination results were affected, leading to its proteasomal degradation.

SET7/9 methyltransferases regulate p53 through monomethylation in Lys372, resulting in protein stabilization and activation. Resveratrol treatment in colon cancer cells induces p53 methylation, leading to BAX and PUMA gene expression. The absence of SET7/9 abolishes p53 proapoptotic effects; hence, their presence appears to be essential for cell death (Liu L. D. et al., 2019).

Flavonols possess important regulatory activities on p53. Quercetin upregulates p53 mRNA and protein levels as well as increases caspase 3/7 activity in mesothelioma (Lee et al., 2015). Combined treatments of curcumin and quercetin augment phosphorylation and acetylation levels in lung carcinogenesis with the downregulation of Bcl2 and the upregulation of p21 and BAX, leading to apoptosis (Zhang and Zhang, 2018). An important premise with respect to polyphenols relies on their apparent affinity for inducing regulatory effects in cancer cells, but not in normal cells. Quercetin induces cytotoxic effects in leukemic and breast cancer cells but did not affect normal cells through direct quercetin/DNA interaction, thus increasing p53 and p-p53 levels, leading to the induction of apoptosis and cell-cycle arrest in the S phase. Quercetin reduced tumors, improved lifespan, and had no adverse effects in mice (Srivastava et al., 2016). A combination of quercetin with the chemotherapeutic MG132 (a specific 26S proteasome inhibitor) appears promising. This combination demonstrated a synergistic effect, extending the half-life of p53 from 74 to 184 min, stabilizing p53 through Ser15 phosphorylation, and preventing ubiquitination in HepG2 cells (Tanigawa et al., 2008).

Kaempferol, which is another important flavonol, also exhibits relevant bioactivities in p53 in cancer. Kaempferol treatment of human cancer cell lines containing mutant p53 led to apoptotic cell death with an increase of cleaved PARP and caspase (3, 7, 9) levels, the release of cytochrome c, and DNA fragmentation (Lee et al., 2014). In another study, human colon cancer cell lines (HCT116, HCT15, and SW480) were treated with kaempferol; molecular markers cleaved PARP and caspase-3 increased after treatment. The proapoptotic effects of kaempferol may be exerted through the regulation of different pathways; the expression of p53, p21, and p-p38 was upregulated, whereas p-JNK and p-ERK were attenuated. Interestingly, the proapoptotic effects of kaempferol were related to an increase in the intracellular ROS level (Choi et al., 2018).

Catechins, present in many tea-derived products, also possess important regulatory activities. EGCG promotes p53 accumulation, increases transcriptional activity through phosphorylation on Ser15 and Ser20, and prevents p53/Mdm2 interaction, increasing the half-life from 40 to 90 min in lung cancer (Jin et al., 2013). EGCG increases p53 acetylation in Lys382, enhancing its stabilization and DNA binding, increases p21 expression, downregulates HDAC-4, -5, and -6, and stimulates apoptotic induction in lung cancer cells (Oya et al., 2017). Relevant mechanisms of EGCG regulation on p53 include direct interaction between p53 and p53. EGCG binds to the N-terminal domain of p53 (aa involved in this interaction include W23 and W25, F54, G52, and T55) and shields p53 TAD, which is the Mdm2 interaction site (involving p53 residues F19, L22, T23, L26, G58, E68, V75, and C77), thus inhibiting Mdm2-mediated ubiquitination (Nagata et al., 2014; Karakostis et al., 2016; Zhao et al., 2021).

Flavones have also been linked to bioactivities against important types of cancer. Apigenin modulates the balance between prosurvival and proapoptotic pathways by the activation of p53, the repression of STAT-3, and decreased ROS levels in lymphoma cells (Granato et al., 2017). Apigenin enhances the response to Cisplatin-induced apoptosis by disruption of the p53/Mdm2 interaction and favors MAPK-mediated p53 Ser15 phosphorylation, protecting it from proteasomal degradation (Liu et al., 2017). The combination of apigenin with TRAIL has been related to apoptotic effects on non-small-cell lung cancer (NSCLC) in a p53-dependent manner. This combination revealed a synergistic effect by increasing the mRNA levels of DR4, DR5, and protein p53. TRAIL interaction with DR4/5 leads to the formation of the death-inducing signaling complex (DISC), with the subsequent binding of caspase-8, which activates the caspase cascade. The use of the p53 inhibitor (PFT-α) abolished the effect of the combined treatment; hence, these effects showed to be p53-dependent. Proapoptotic effects on lung cancer cells were related to the upregulation of BAX and Bad and to a prominent reduction of Bcl-2 and Bcl-xL levels (Chen et al., 2016).

As discussed so far, polyphenols appear to possess promising activities in p53 regulation through different mechanisms; however, several studies must be performed to elucidate the fully implicated mechanisms and consequences of polyphenol treatments in p53 regulation for the development of new, efficient, and safe cancer therapies.

MAPK belong to serine/threonine kinases central to one of the principal signaling cascades involved in the control of cell growth, differentiation, survival, and cell death. MAPK signaling is activated in response to intra- and extracellular signals; these signals activate transmembrane glycoproteins of the tyrosine kinase receptor type, leading to the regulation of target genes. MAPK signaling cascades are composed of three main players as follows: the stress-activated protein kinase c-Jun NH2-terminal kinase (JNK), the stress-activated protein kinase 2 (SAPK2, p38), and the extracellular signal-regulated protein kinases (ERK1/2, p44/p42). JNK and p38 are activated by cytokines, hypoxia, genotoxicity, and oxidative stress; ERK is activated by mitogens and cytokines, principally by means of the activation of RAS family members (Rodríguez-Berriguete et al., 2012).

The dysregulation of MAPK can lead to cell transformation; the RAS–Raf–MEK–ERK axis is altered in 40% of human cancers, principally in RAS (30%) (Santarpia et al., 2012). RAS represents a family of GTPases composed of 150 G-proteins (HRAS, KRAS, and NRAS) and represents the first actors in the MAPK/ERK phosphorylation cascade (Johnson and Chen, 2012). Activation of RAS will result in ERK phosphorylation and activation; therefore, ERK translocates to the nucleus and promotes the activation of transcription factors such as c-Fos and c-Jun (Eblen, 2018).

JNK and p38 are known as stress-activated protein kinases. JNK translocates from the cytosol to the nuclei and evokes c-Jun activation through Ser63 and Ser73 phosphorylation, changing the expression patterns of BAX and Bcl-2 (Zhou et al., 2015). The role of JNK in cancer development is found in its multiple targets that are implicated in many cell-regulation mechanisms, such as STAT1/3, c-Jun, c-Myc, FOXO4, Bcl-2, ATF2, Smad2/3, PPARγ1, and RXRα (Dou et al., 2019). Multiple JNK-activated targets render JNK an important objective for targeted cancer therapies.

The p38 MAPK family comprises four isoforms expressed by different genes. Isoform p38α is ubiquitously expressed in all tissues, whereas isoforms β, γ, and δ are tissue-specific. Isoforms of p38 MAPK engage in redundant activities; however, the absence of p38α is lethal (Gerits et al., 2007). As many as 200–300 substrates are phosphorylated by p38 MAPK, including kinases involved in gene regulation, such as MSK1/2 (implicated in the regulation of transcription factors NF-κB p65 and STAT1/3), cytoplasmatic substrates such as cyclin D1, CDK inhibitors, Bcl-2 family proteins, and nuclear substrates including p53 (Cuadrado and Nebreda, 2010). Several interesting activities have been related to p38α, including, but not limited to, the suppression of ERK and JNK signaling by neutralizing RAS transformation, leading to senescence and cell-cycle arrest (Wang et al., 2002; Hui et al., 2007) and to the neutralization of tumorigenesis in lung, breast, colon, and liver through ROS production in response to oncogene activation, leading to the induction of p38-dependent apoptosis (Dolado et al., 2007). However, its role in tumor neutralization is only exerted at early stages; once the tumor is established, p38 promotes tumor growth and metastasis (Igea and Nebreda, 2015; Vidula et al., 2017).

The vast number of pathways regulated by MAPK make them ideal candidates for targeted therapies, and polyphenols may emerge as a promising alternative for the regulation of key players of MAPK pathways.

The bioactivities exerted by natural phenolic compounds rely on their different regulation mechanisms, which strongly contribute to their anticancer activities. Polyphenols have been associated with promising regulatory activities in MAPK pathways (Figure 3).

Curcumin as one of the most promising anticancer agents has exhibited different regulation mechanisms in MAPK. Curcumin treatment in Ishikawa cells (endometrial carcinoma) induces apoptosis, cell-cycle arrest in phase S, and the downregulation of ERK and Jun mRNA, as well as the reduction of the p-ERK-2/c-Jun pathway. Interestingly, curcumin reduced cell invasion by the downregulation of p-ERK/c-Jun and diminishing AP-1 synthesis, thus decreasing MMP2/9 transcription (Zhang et al., 2019). The effects of curcumin on MAPK pathways are not only limited to in vitro results. Curcumin treatment in the xenograft prostate cancer model demonstrated a reduction in tumor development. In this study, the mechanism involved in prostate cancer reduction by curcumin was related to a reduction of p-JNK, and curcumin was also effective for p-c-Jun reduction, leading to a decrease in Bcl-2 and Bcl-xL mRNA levels (Zhao W. et al., 2018). Stilbenoids have also revealed relevant activities for MAPK inhibition in different cancers. Resveratrol was effective in increasing p-p38 levels, leading to a decrease of Bcl-2 and an increase in Bad expression, as well as acting as a potent tumor growth inhibitor. The involvement of p38 was assessed using its inhibitor SB203580, which abolished the protective effects of the resveratrol treatment (Yuan et al., 2016). Urologic cancers represent a major concern. Resveratrol treatment reduces cell proliferation and the metastatic potential of renal-cancer cells. Resveratrol regulates ERK1/2 signaling pathways, specifically by altering the expression of ERK1/2, p-ERK1/2, E-cadherin, MMP-2, and MMP-9 (Zhao Y. et al., 2018). The apigenin treatment of melanoma-cancer cells A375 and C8161 promoted growth arrest through the downregulation of p-ERK1/2, p-Akt, and p-mTOR (Zhao et al., 2017). Tea polyphenols may act as potent anticancer agents alone or in combination with another chemotherapy. EGCG has demonstrated synergy with Sunitinib in cancer cell lines; both compounds decreased cell viability and suppressed the ERK pathway (Zhou et al., 2016). Kaempferol and quercetin stand as two of the most promising flavonols for cancer treatment. Quercetin possesses activities against colon cancer with mutant-type KRAS through JNK-pathway regulation; such activity results are very promising since KRAS is considered undruggable. In this study, quercetin selectively inhibited Akt and activated the p-JNK/c-Jun axis, leading to caspase-3 activation and subsequent apoptosis (Yang et al., 2019). In fact, flavonols can act as chemosensitizers. Kaempferol treatment overcomes resistance to 5-FU in resistant colon cancer cells. Concomitant treatment led to an increase in apoptosis, cell-cycle arrest, and modulated the protein expression of the JAK/STAT3, MAPK (ERK, p38), PI3K/Akt, and NF-κB involved in the progression and development of colorectal cancer (Riahi-Chebbi et al., 2019). All of these regulatory activities on MAPK pathways highlight the pharmacological importance that polyphenols may possess for the treatment of cancer by inhibiting these pathways; however, more research is necessary to fully elucidate the mechanisms involved.

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and the mammalian target of rapamycin (mTOR) are signaling pathways that regulate survival and growth processes (Hemmings and Restuccia, 2012). These pathways are activated through several cellular stimuli and control essential cellular functions such as proliferation, transcription, translation, survival, and growth (Liu R. et al., 2020).

There are three classes of PI3K isoforms. Class I PI3K are heterodimer lipid kinases composed of the p110 catalytic subunit and the p85 regulatory subunit. Akt, also known as protein kinase B (due to its similarity with PKA and PKC) is a serine protein kinase, activated by growth factors in a PI3K-dependent manner (Hemmings and Restuccia, 2012). PI3K phosphorylates the inositol ring of the membrane phospholipid, phosphatidylinositol-4,5-biphosphate (PI-4,5-P2), to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) on the cytoplasmic side of the cellular membrane (Rathinaswamy and Burke, 2019). PIP3 recruits a subset of pleckstrin homology (PH) domain-containing proteins, such as the same protein kinase Akt and the constitutively active phosphoinositide-dependent kinase 1 (PDK1). In turn, PDK1 phosphorylates Akt into T308 (Ding et al., 2010); however, maximal activation of Akt requires its additional phosphorylation in S473 located at the carboxyl-terminus site, mediated by mTORC2 (Ikenoue et al., 2008).

mTOR is one of the downstream signaling targets of PI3K/Akt, which regulates several cellular processes, such as cell growth, motility, survival, and metabolism (Saxton and Sabatini, 2017). mTOR exists in two protein complexes, that is, mTORC1 and mTORC2, of which mTORC1 is directly inhibited by Rapamycin, a macrolide and antifungal compound; however, mTORC2 is insensitive to rapamycin (Saxton and Sabatini, 2017). mTORC1 controls cell growth and proliferation mainly by promoting transcription, translation, ribosome biogenesis, and autophagic regulation. On the other hand, mTORC2 regulates proliferation and survival primarily by phosphorylating several members of the AGC family of protein kinases (Fu and Hall, 2020).

Akt inhibits the tuberous sclerosis complex (TSC) that limits mTORC1 signaling. The TSC complex is composed of the following three subunits: TSC1 (Harmatin), TSC2 (Tuberin), and TBC1D7. Akt phosphorylates TSC2 in five residues (S939, S981, S1130, S1132, and T1462), leading to its inactivation. The TSC complex is a negative regulator of the small GTPase Rheb (RAS homolog enriched in brain) (Takahashi et al., 2003) via the stimulation of GTP hydrolysis. On the other hand, Rheb-GTP is translocated into the lysosomal membrane, where it directly interacts with the catalytic domain of mTOR, promoting its activation (Dibble and Manning, 2013; Kim and Guan, 2019).

PI3K/Akt/mTOR pathways are one of the main prosurvival pathways that are activated in human cancers (Noorolyai et al., 2019). The PI3K/Akt/mTOR pathway is found deregulated in cancer, which is characterized by an overexpression/hyperactivation of its effector proteins and alterations in the genes that encode those proteins (Revathidevi and Munirajan, 2019).

The PI3K/Akt/mTOR pathway has been considered a major drug target due to its frequent hyperactivation in cancer (Liu Z. et al., 2020; Pevzner et al., 2021). Plant-derived natural compounds are one of the most reliable resources for cancer therapy. Several polyphenols, such as resveratrol, curcumin, apigenin, epigallocatechin 3-gallate, and quercetin, target numerous signaling pathways to exert tumor inhibitory and antiproliferative effects. One of these pathways is PI3K/Akt/mTOR (Figure 4).

Hyperactivation of Akt signaling is frequent in several cancers, which maintains a high oxidative state in a tumor microenvironment that is necessary for tumor adaptation. Antioxidants are proposed to exhibit anticancer roles by interfering with the tumor microenvironment. Resveratrol is a natural antioxidant and affects cellular oxidative stress and mitochondrial membrane potential by interfering with the PI3K/Akt signaling pathway in SCLC H446 cell lines (Li et al., 2020). In another study conducted by Jiao and collaborators (2015), resveratrol inhibited invasive behaviors in vitro and in vivo by PI3K/Akt/NF-κB suppression and the inhibition of MMP-2 secretion in glioblastoma (Jiao et al., 2015). An alternative antioxidant ubiquitously found in dietary sources with potential health-promising effects is quercetin, a bioactive flavonoid that has been identified as having antioxidant and anticancer effects. Many reports showed that quercetin possesses anticancer activities via Akt inhibition. Recently, it was found that quercetin attenuates cell survival, inflammation, and angiogenesis by modulating Akt signaling in lymphoma-bearing mice (Maurya and Vinayak, 2017).

The PI3K/Akt/mTOR is known to be involved in drug resistance (Liu R. et al., 2020). In agreement with this, resveratrol prevents resistance to Adriamycin by decreasing the expression of multidrug resistance protein (MRP1) through PI3K/Akt/Nrf2 in acute myeloid leukemia (Li Y. et al., 2019). Earlier researchers observed that green tea polyphenols such as EGCG act as a chemosensitizer, leading to minimizing chemoresistance and enhancing the chemosensitivity of tumor cells. EGCG and theaflavin (TF) synergistically inhibited the growth of HeLa cells through PI3K/Akt inhibition (Chakrabarty et al., 2019). TF or EGCG reduced the expression of both p85 (the regulatory subunit of PI3K) and phosphorylated Akt (Ser473), and interestingly, the reduction of protein expression was observed in a much higher amount in the case of the combination of these doses of polyphenols. This synergistic activity might be due to stronger microtubule depolymerization by the simultaneous binding of TF and EGCG to a different site on tubulin. This stronger microtubule depolymerization results in a higher G2/M arrest of the cell cycle and more drastic mitochondrial damage and synergistic augmentation of apoptosis (Chakrabarty et al., 2019).

Resveratrol possesses antitumor activity when used alone or in combination. Bian et al. examined that the coadministration of resveratrol and rapamycin significantly reduced the phosphorylation of Akt and p70S6K compared to treatment with rapamycin alone. This coadministration ablates mTOR function and prevents Akt activation, which overcomes the feedback activation of Akt and improves the antitumor effects (Bian et al., 2020). In an investigation, it was shown that combining the grape polyphenol resveratrol, quercetin, and catechin at equimolar concentrations inhibits mTOR signaling by means of a dual mechanism of PI3K/Akt and AMPK regulation and potentiates breast cancer to anti-EGFR therapy with Gefitinib, suggesting that this mixture may have synergistic effects against cancer (Castillo-Pichardo and Dharmawardhane, 2012).

PTEN is a tumor suppressor often deleted or mutated in a variety of cancers at a high frequency (Codrich et al., 2021; Zhang et al., 2021). It acts as a phosphatase that specifically catalyzes the dephosphorylation of the 3-phosphate of the inositol ring in phosphatidylinositol (3,4,5)-trisphosphate (PIP3), leading to the biphosphate product PIP2. The dephosphorylation of PIP3 results in the inactivation of the PI3K/Akt signaling pathway, because PIP3 is critical for the activation of Akt.

Resveratrol possesses anticancer activity through upregulating the bone morphogenetic protein 7 (BMP7) in order to inactivate the PI3K/Akt signaling pathway through partly suppressing the phosphorylation of PTEN in colorectal cancer. On the other hand, curcumin inhibits the proliferation of glioblastoma, and this effect is associated with the inhibition of both Akt and mTOR phosphorylation by promoting PTEN and p53 expression (Wang et al., 2020).

Accumulating evidence indicates that the PI3K/Akt/mTORC1 pathway is a negative regulator of autophagy (Yu et al., 2015). Autophagy is a process of the digestion of long-lived proteins and the damage of organelles and superfluously unwanted materials (Tavakol et al., 2019). According to the latter, it was demonstrated that resveratrol induces autophagic and apoptotic cell death through decreasing the phosphorylation of Akt in Ser473 and increasing the protein levels of phosphorylated AMPKα in Thr172. Resveratrol simultaneously enhanced the protein level of autophagy-associated proteins and the mRNA expression of the autophagic genes Atg5, Atg12, Beclin-1, and LC3-II in Cisplatin-resistant human oral cancer CAR cells (Chang et al., 2017). Interestingly, curcumin also induced autophagy and apoptosis in gastric cancer cells by activating p53 and the inhibition of the PI3K pathway (Fu et al., 2018).

Curcumin is a potent anticancer agent for the treatment of leukemia. A study by Zhou et al. in 2021 concluded that curcumin had stronger cytotoxic activity against acute myeloid leukemia cells compared with three other types of phytochemicals (epigallocatechin 3-gallate, genistein, and resveratrol). Mechanistically, curcumin treatment suppressed Akt activation, leading to cell-cycle arrest and apoptosis (Zhou et al., 2021).

mTORC1 functions as a downstream effector for PI3K/Akt, resulting in mTORC1 hyperactivation in a high percentage of human cancers (Saxton and Sabatini, 2017). Curcumin repressed mTORC1 signaling by two mechanisms involving the loss of IRS-1/Akt/PRAS40/Raptor/mTOR signaling and the activation of AMPK (Kaur and Moreau, 2021). These authors demonstrated that curcumin decreases the abundance of IRS-1 protein and inhibits the p-Akt (Ser473). Therefore, this led to a decrease in the phosphorylation of PRAS40 (Thr246), a negative regulator of mTORC1 (Kaur and Moreau, 2021).

On the other hand, in head-and-neck cancers, curcumin reduced the expression of phospholipase D1 (PLD1), the enzyme that catalyzes the production of phosphatidic acid (Borges et al., 2020). PLD1 binds to mTOR and displaces the mTOR-interacting protein (DEPTOR), an mTOR endogenous inhibitor, which results in mTORC1 activation and stabilization. In this manner, curcumin downregulates the PI3K/Akt/mTOR pathway and finally induces an arrest in the G2 phase of the cell cycle and induces cell death by apoptosis (Borges et al., 2020).

The PI3K/Akt pathway plays an important role in cancer progression, related to cell survival, growth, angiogenesis, and metastasis (Liu Z. et al., 2020; Lu et al., 2020). An important process in the progression of metastasis comprises vasculogenic mimicry (VM), the de novo formation of perfusable and vessel-like networks by aggressive tumor cells without endothelial cells. Several genes, such as vascular endothelial cadherin (VE-cadherin), participate in the formation of VM (Delgado-Bellido et al., 2017). Curcumin inhibits the VM of HCC cells by downregulating the Akt pathway (Chiablaem et al., 2014). Recently, it was shown that EGCG reduced p-Akt and Akt expression and reduced the ability of the VM of PC-3 cells. EGCG inhibited the nuclear localization of twist, followed by the downregulation of VE-cadherin expression, which in turn impaired the Akt pathway (Yeo et al., 2020). On the other hand, EGCG suppresses invasion and migration by preventing the cadherin switch and decreasing the expression level of TCF8/ZEB1, β-catenin, and vimentin in pancreatic cancer. Mechanistically, EGCG inhibited the Akt pathways in a time-dependent manner by suppressing IGFR phosphorylation and inducing Akt degradation (Wei et al., 2019). It has been reported that quercetin suppresses the mobility of breast cancer by the inhibition of glycolysis through the Akt-mTOR pathway and the activation of autophagy (Jia et al., 2018). Recently, it was shown that flavonoids quercetin and myricetin suppressed the HGF and TGF-α induced migration of HuH7 cells due to the attenuation of the PIK3/Akt pathway (Yamada et al., 2020).

RAS proteins are eukaryotic small GTPases that cycle back and forth between the GDP-bound inactive state and the GTP-bound active state. RAS-GTP leads to the activation of various signaling pathways, such as MAPK, PI3K, and RAL-GEF, promoting a variety of crucial cellular processes including cell proliferation, differentiation, and survival in response to extracellular stimuli. RAS family members are encoded by three highly homologous genes that encode four highly homologous proteins: HRAS, NRAS, KRAS4A, and KRAS4B (the results of alternative splicing at the C-terminus) (Weiss, 2020).

RAS signaling responds to many extracellular stimuli, such as soluble growth factors. Growth factor binding to cell-surface receptors creates intracellular docking sites for adaptor molecules and signal-relay proteins that recruit and activate guanine nucleotide-exchange factors (GEF). GEF displace guanine nucleotides from RAS and permit passive biding to GTP, which is abundant in the cytosol. On the other hand, RAS proteins are negatively regulated by GTPase-activating proteins (GAP), which markedly stimulate intrinsic GTPase activity by stabilizing a high energy-transition state that occurs during the RAS-GTP hydrolysis reaction (Fernández-Medarde et al., 2021).

Human cancers frequently express mutant RAS proteins, termed “oncogenic RAS.” RAS oncogene mutations are those that result in a persistent GTP-bound, active state. The most common oncogenic RAS mutation comprises the substitution of a single amino acid at positions 12, 13, or 61, which induces a constitutively active RAS phenotype (Muñoz-Maldonado et al., 2019).

KRAS is the most frequently mutated RAS family member that can potentiate tumor-promoting activity. These KRAS alterations have been identified in 25% of all cancers, such as blood, breast, colorectal, gynecological, lung, prostate, and pancreatic cancer, in which some cancers, pancreatic cancer (90%), colorectal cancer (52%), and lung adenocarcinoma (32%) have extremely high mutation rates (Mustachio et al., 2021).

The RAS oncogene is particularly difficult to target with specific therapeutics. These RAS-mutated cancers respond poorly to standard chemotherapy; thus, targeted approaches need to be found (Sheffels and Kortum, 2021). Significant efficacy has been demonstrated in the treatment of tumors with various polyphenols, in particular the majority of polyphenols that entertain specificity toward tumor cells that express mutated KRAS and not so in normal cells.

Several flavonoids were tested on HRAS-transformed cells. Of these, apigenin, kaempferol, and genistein were able to reverse the transformed phenotypes, affecting cellular proliferation, morphological change, and colony formation in soft agar. The antitumor effect of resveratrol on oncogenic RAS was explored using a WR-21 cell line derived from a submandibular salivary adenocarcinoma. These WR-21 cells express an activated human HRAS transgene (mutated Asp12) RAS protein, as well as p53. This established that resveratrol inhibited cell proliferation and induced cell death by apoptosis, through p53 without direct modulation of the expression of both mRNA and the protein of mutant HRAS (Young et al., 2005).

Manna et al. examined the in vivo antitumor efficiency of black tea polyphenols such as theaflavin, EGCG, and ECG in lung cancer. Treatment with these polyphenols inhibited benzo(a)pyrene-induced lung carcinogenesis in mice; moreover, it significantly reduced the expression of proliferation-associated genes such as HRAS, c-Myc, and cyclin D1 compared to the B(a)P-treated lung lesions (Manna et al., 2009).

It was shown that polyphenols such as curcumin and resveratrol, on being supplemented in a diet, can prevent the formation and growth of tumors by downregulating KRAS expression (Limtrakul et al., 2001; Saud et al., 2014). EGCG inhibited cell proliferation induced by oncogenic RAS in intestinal epithelial cells and blocked cell-cycle transition at the G1 phase via inhibition of cyclin D1 expression, and EGCG exhibited a stronger inhibitory effect on cell proliferation in transformed cells than on nontransformed cells (Peng et al., 2006). The latter demonstrated the potential of the natural compound EGCG as effective adjuvant therapy for colon tumors bearing RAS mutations.

An in vivo investigation was conducted by Saud and collaborators (2014) to evaluate the preventive and antitumor effect of resveratrol using a genetically engineered mouse model for colorectal cancer that has a conditional knock-out of both copies of APC combined with a latent activated gain-of-function in the KRASG12D mutation specifically in the distal colon. The finding demonstrated that resveratrol orally administered at human equivalent doses (210 mg/day) prevented initial tumor formation and retarded the growth of established tumors. Resveratrol suppressed the expression of KRAS both in vitro and in vivo and induced the expression of miR-96, a microRNA (miRNA) previously shown to regulate KRAS translation. These data indicate that resveratrol can prevent the formation and growth of colorectal tumors by downregulating KRAS expression (Saud et al., 2014).

Oncogenic RAS has been shown to sensitize colon cancer cells to treatment with quercetin; moreover, this quercetin preferentially reduces the half-time life of the oncogenic RAS protein vs. the wild-type RAS (Psahoulia et al., 2007). Epicatechin-rich cocoa polyphenol extract inhibits the growth of human premalignant and malignant KRAS-activated pancreatic ductal adenocarcinoma. This finding demonstrated that both the extract and epicatechin alone reduced the GTP-bound active RAS protein level without having any effect on total protein. Moreover, they showed that this extract decreased PI3K/Akt and MAPK signaling by inhibiting KRAS activity (Siddique et al., 2012).