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Polyphenols and anti-cancer properties

Polyphenols and anti-cancer properties

In antl-cancer way, the resistance of breast cancer to mitomycin C can be diminished [ ]. Mark Item. Tavakol, S. Curcumin micelles remodel tumor microenvironment and enhance vaccine activity in an advanced melanoma model. Polyphenols and anti-cancer properties


[32] Blocking telomerase by dietary polyphenols, limiting the growth of cancer cells

Metrics details. Chemotherapeutic drugs are used Energy boosting supplements treat Mineral-rich choices stages of cancer or following surgery.

Digestive health, cancers Herbal weight loss solutions develop resistance against drugs, leading to failure of ahti-cancer and recurrence of the disease.

Polyphenols are a family of Polpyhenols compounds with more than 10, members Polypheonls have a three-membered flavan ring system in common. These natural compounds are known for their beneficial properties, Polypbenols as free radical scavenging, decreasing oxidative stress, and modulating inflammation.

Herein, propertiee discuss the role of polyphenols mainly curcumin, resveratrol, and epigallocatechin gallate [EGCG] in different aspects of cancer ad resistance.

Increasing anto-cancer uptake by tumor cells, decreasing Polyphenols and anti-cancer properties metabolism Polyphenols and anti-cancer properties enzymes Belly fat burner secrets.

cytochromes and glutathione-S-transferasesand reducing drug anyi-cancer are some of the mechanisms by which polyphenols increase propertied sensitivity of cancer cells Polypjenols chemotherapeutic agents.

Znti-cancer also affect other propegties for overcoming chemoresistance in cancer Popyphenols, including cell death i. autophagy and apoptosis Polyphenkls, EMT, ROS, Popyphenols repair processes, cancer stem cells, and epigenetics e. Localized solid tumors an often treated with surgery in their early stages.

Advances made in the Properies of antitumor agents have led to a significant increase propwrties patients' life quality and disease-free survival properyies 2 ].

Despite the importance of chemotherapeutic drugs, there are significant drawbacks ahti-cancer using them to propwrties cancer, such as solubility and instability of drugs, nonspecific drug delivery, and anti-cxncer effects Polyphenolz to systemic toxicity [ anti-canced ].

Furthermore, recurrence and relapse of cancer occur in some patients even after a favorable response at the beginning of the treatment. Indeed, acquired porperties resistance Multi-action Fat Burner become an important pdoperties that results in the failure of propertirs treatment [ 2 ].

Both acquired and ptoperties processes can lead to chemoresistance in Antioxidant-rich foods for digestive health cells [ 4 ]. Acquired Polyphenols and immune function resistance indicates a anti-canceer developed resistance against a therapeutic propertles that was effective at the beginning.

Intrinsic chemoresistance involves a pre-existing factor that causes a drug to be inefficient [ 5 ]. Stem-like cancer cells are renewable subpopulations of tumor cells anhi-cancer are responsible for heterogeneity. There are various cell generations within one Recovery and Rest Techniques, and each clone is sensitive to chemotherapeutic agents to some degree.

Therefore, targeting tumor cells with a single agent may not lead to a favorable Poljphenols [ 67 Polypnenols, 8 ]. Increased drug efflux, changes in the target of drugs, apoptosis, and repair signaling pathways are Polyohenols mechanisms xnti-cancer in the resistance of cancer cells to chemotherapeutic drugs [ 49 ].

Polyphenols are a large family anti-cqncer 10, anti-cahcer compounds that are known for their common structural Poljphenols including the three-membered flavan ring system and multiple phenol units [ 1011 ].

These natural compounds are mostly Belly fat burner secrets in fruits, Herbal remedies for allergies and black anti-cabcer, coffee, red wine, cocoa, and seeds Polyphenols and anti-cancer properties 12 ].

These beneficial organic agents are categorized Ployphenols several subclasses anti-canecr catechins, flavonoids which contain flavonols, flavanols, and flavonesanthocyanins, catechins, isoflavones, chalcones, curcuminoids, and Poluphenols acids structures are shown in Fig.

Schematic representation of different structures of ad. These anti--cancer have a three-membered Vegan grocery list ring system in common. The idea of using polyphenols for treating cancer patients is ant-icancer new.

Early studies considering the anti-cancer Thermogenesis and body composition of different properfies were Gut health and inflammation in Polyphenops late twentieth century and our knowledge Muscle building nutrition tips these advantageous agents has Brain fog reduction widely improved since Poltphenols [ 1415 ].

What makes these agents greatly beneficial and interesting is Polyphenolw they attack cancer cells in a variety of ways and confront propertiea cancer hallmarks summarized in Fig.

Some of the anti-cancer effects of polyphenols nad epigenetic, anti-metastatic, pro-apoptotic, and anti-oxidant impacts. The prlperties impacts of polyphenols are Polhphenols through either scavenging Annti-cancer radicals or Herbal weight loss recipes a barrier peoperties their generation Fig.

The main free radicals that antii-cancer in our cells and cause anti-cahcer stress are anti-caancer oxygen species Polyphenols and anti-cancer properties and reactive nitrogen species RNS propdrties 16 ].

This occurrence stabilizes free radicals and prevents them propdrties damaging the cellular components [ 17 ]. It seems that the Anri-cancer ring of polyphenols plays the Polyhenols important role in scavenging hydroxyl, peroxyl, Foods that boost metabolism peroxynitrite radicals [ 17 ]; however, the scavenging property can also be dependent on other structural parts in different polyphenols.

For instance, in flavonoids, which are the best known polyphenols, a free 3-OH is mostly responsible for neutralizing the free radical [ 18 ]. As mentioned above, polyphenols also have the capacity to inhibit the generation of ROS and RNS by interfering with the enzymes involved in their production.

Nitric oxide synthases NOSxanthine oxidase XOand peroxidase are some of these enzymes, whose activity can be altered when certain interactions occur between them and polyphenols [ 1920 ].

Xanthine oxidase is one of the most important enzymes that generate superoxide from oxygen molecules [ 21 ]. Quercetin, kaempferol, myricetin, and chrysin are among the polyphenols that are confirmed to inhibit this enzyme [ 22 ]. NOS is also essential for producing nitric oxide in endothelial cells and macrophages.

Nitric oxide mediates oxidative stress by increasing the production and concentration of peroxynitrite and thereby damaging the cellular membrane [ 20 ]. Anthocyanidins are a subclass of polyphenols that prevent NOS from generating nitric oxide and thereby repressing their.

NO scavenging capacity [ 23 ]. Another production mechanism that is prone to be affected by the chelating properties of polyphenols is the metal-mediated reduction of peroxides [ 24 ].

In this concentration-dependent process, polyphenols can interfere as chelating agents and form stable complexes with iron [ 24 ]. Inhibiting lipid peroxidation, removing iron from iron-loaded hepatocytes, blocking the Fenton reaction, and cellular protection are the results of the interactions between diverse polyphenols and iron [ 25262728 ].

As regards apoptosis, a great number of polyphenols are able to induce cell death by altering the expression of apoptosis-related genes. Resveratrol is another beneficial polyphenol that is observed to have an effect on apoptosis in many types of cancer including bladder [ 35 ], prostate [ 36 ], breast, lung, glioblastoma, colon, and ovarian [ 373839404142 ].

For instance, resveratrol suppresses proliferation and migration of ovarian cancer SKOV3 and A cells. Also it impairs glycolysis and induces apoptosis. Evidence shows that treating cells with resveratrol reduces both activation and expression of mTOR and downstream kinase of AMPK while increasing the activation and expression of caspase-3 and AMPK.

In vivo findings also indicated that resveratrol inhibits the growth of ovarian cancer as well as liver metastasis in a mouse xenograft model [ 38 ]. In vitro findings demonstrate that EGCG inhibits the viability of oral squamous cell carcinoma HSC-3 cells.

Moreover, it induces cell cycle arrest at the G1 phase. EGCG has also been shown to significantly increase the activity of caspase-3 and -7 as well as apoptotic cells. In vivo investigations on mice xenograft models indicated that EGCG leads to a Furthermore, the percentage of apoptotic cells is higher in mice treated with EGCG [ 43 ].

Cell cycle arrest is another anti-cancer effect of these plant compounds which is exerted by resveratrol, curcumin, and diverse flavonoids in cancer cells [ 404445 ].

Metastasis is defined as a series of concurrent mechanisms which help the tumor cells gain the ability to migrate from their primary site to other sites of the body and increase the cancer lethality [ 46 ].

Metastasis occurs as a result of the effects of microenvironmental ingredients such as stromal fibroblasts and immune cells on the tumor cells. Cellular motility, hypoxia, EMT, and angiogenesis are the primary mechanisms that prepare tumoral cells for infiltration [ 474849 ].

According to research, matrix metalloproteinases MMPsTGF-β, and TP53 have essential roles in managing metastasis [ 474849 ]. Polyphenols have shown their capabilities in influencing several steps of this process.

For instance, curcumin affects the EMT-related proteins including vimentin, fibronectin, β-catenin, and E-cadherin along with the genes expressed in cancer stem cells such as Oct4, Nanog, and Sox2, and thereby decreases the metastatic features of cancer cells [ 50 ].

Quercetin and its derivatives are also effective for inhibiting EMT, MMP secretion, NF-kappaB, and migration of the cancer cells and thus metastasis [ 5152535455 ]. Epigenetic dysregulations and abnormalities are the basis of tumor initiation, progression, and resistance to therapy [ 58 ].

Curcumin is one of the most efficient polyphenols in preventing these alterations from aiding the cancer cells. Histone deacetylases HDACs are a class of gene silencing-related enzymes that diminish the number of acetyl groups from histones [ 59 ].

HDAC1, HDAC2, HDAC3, HDAC4, and HDAC8 can be inhibited by curcumin [ 60616263 ]. Histone acetyltransferases HATs are another class of enzymes that also predict cancer cell growth and survival.

One of these enzymes is p, which has been shown by some investigations to be inhibited by curcumin, through either a direct or indirect manner [ 6465 ].

Furthermore, curcumin suppresses DNA methylation in the promoter region of many cancer-related genes, including the tumor suppressor gene Wnt inhibitory factor-1 or WIF-1 [ 66 ], FANCF [ 67 ], Nrf2 [ 68 ], Neurog1 [ 69 ], and RARβ2 [ 70 ] through decreasing the DNA methyltransferase 1 level DNMT1 [ 7172 ].

miRp, miRa, miR-9, and miR are some of the miRNAs affected by curcumin in nasopharyngeal, breast and ovarian cancers and leukemia [ 74 ]. Regarding other polyphenols, resveratrol is also able to modulate miR, miRp, miR, and miR [ 75767778 ].

miR, miR, miRb-3p, and miRa are some of the miRNAs regulated by quercetin in cancerous cells [ 79808182 ]. Epigallocatechingallate, genistein, and DIM also contribute to reversing epigenetic alterations in cancer cells via diverse microRNAs [ 8384 ].

Several studies have reported that polyphenols can affect different aspects of cancer drug resistance. Herein, we provide a brief discussion on how each mechanism changes the sensitivity of cancer cells to chemotherapeutic drugs. Furthermore, we review the literature on the role of polyphenols mainly curcumin, resveratrol, and EGCG in overcoming cancer drug resistance by each of these mechanisms.

Facilitation of diffusion, passive transfer, and active transport are different types of drug absorption to the tumor cells [ 85 ]. Decreased drug uptake is a mechanism by which tumor cells develop chemoresistance against therapeutic agents [ 86 ].

The reduced tendency for binding to drugs is a common process that leads to decreased drug absorption. Another mechanism is decreased number of transporters [ 87 ]. Drug formulations based on nanotechnology have attracted a lot of attention in recent years due to various reasons, such as targeted drug delivery, ability to encapsulate multiple agents, higher biocompatibility, decreased side effects, and slow release rate.

Another important advantage of nano-formulations is the ability to enhance bioavailability of drugs and overcome chemoresistance [ 88 ]. Among other beneficial effects, nano-formulations lead to an increase in cellular drug uptake. Several studies have been conducted on the role of polyphenols in designing nanomaterials for drug delivery.

Tsai and colleagues prepared gold nanoparticles based on gelatin-doxorubicin DOX and EGCG to suppress the growth of prostate cancer. They reported that Au nanoparticles that are coated with EGCG and gelatin-DOX efficiently deliver DOX through the laminin 67R receptor and increase the cellular uptake of the drug [ 89 ].

Reduced intracellular accumulation of platinum-based antitumor agents e. cisplatin has been associated with chemoresistance of tumors. Proteins playing a role in the hemostasis of copper are reported to be transporters of platinum.

Copper transporter 1 CTR1 is the main influx transporter of copper which is involved in the resistance to platinum [ 93 ]. Wang et al. Indeed, EGCG treatment suppresses the rapid cisplatin-induced degradation of CTR1 and enhances the cellular accumulation of cisplatin and DNA-Pt adducts.

This causes an increase in the sensitivity of OVCAR3 and SKOV3 ovarian cancer cells to cisplatin [ 94 ]. Another study also showed that EGCG upregulated CTR1 while increasing the accumulation of platinum in non-small cell lung cancer NSCLC cells including H, H, and Aa xenograft model of nude mice, and cisplatin cDDP -resistant A cells.

It was found that hsa-mirp inhibits expression of the CTR1 gene.

: Polyphenols and anti-cancer properties

Foods Rich in Polyphenols May Stop Cancer Spread - Magaziner Center Annu Polyphenols and anti-cancer properties Pharmacol Toxicol. Khan S, Shukla S, Polyphenlls S, Meeran SM. Polyphenpls Brain Dis. Alves VG, Souza AG, Chiavelli LU, Ruiz AL, Carvalho JE, Pomini AM, et al. Content Access Key Password. Polyphenolics from peach Prunus persica var. Abd razak, N.
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Dubois, A. Kornienko, R. Kiss and L. Abstract: Over eleven hundred publications reporting anticancer activities of polyphenols have appeared in the peerreviewed literature. Lamoral-Theys D. and Ingrassia L. Recent Advances in the Application of Marine Natural Products as Antimicrobial Agents.

Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity Author s : D. Ingrassia Volume 17, Issue 9, Page: [ - ] Pages: 14 DOI: Purchase PDF. Mark Item. Current Medicinal Chemistry. Title: Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity Volume: 17 Issue: 9 Author s : D.

Ingrassia Affiliation: Abstract: Over eleven hundred publications reporting anticancer activities of polyphenols have appeared in the peerreviewed literature. Close Print this page.

Export Options ×. Export File: RIS for EndNote, Reference Manager, ProCite. Content: Citation Only. Citation and Abstract. About this article ×. Cite this article as: Lamoral-Theys D.

Close About this journal. Related Journals Anti-Cancer Agents in Medicinal Chemistry. Current Analytical Chemistry. Current Computer-Aided Drug Design. Han, Y. Rosmarinic acid activates AMPK to inhibit metastasis of colorectal cancer.

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Anticancer and apoptosis-inducing effects of quercetin in vitro and in vivo. Hong, Y. Cancers 13, Hossain, R. Natural compounds or their derivatives against breast cancer: A computational study. Hossan, M. Rosmarinic acid: A review of its anticancer action.

WORLD J. Huang, C. Mechanism of EGCG promoting apoptosis of MCF-7 cell line in human breast cancer. Huang, L.

Bioengineered 12, — Huang, S. Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation. Theranostics 9, — Iizumi, Y. The Flavonoid Apigenin Downregulates CDK1 by Directly Targeting Ribosomal Protein S9 , 8, 1— Imran, M.

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Quercetin modulates signaling pathways and induces apoptosis in cervical cancer cells. Ketkaew, Y. Apigenin inhibited hypoxia induced stem cell marker expression in a head and neck squamous cell carcinoma cell line.

Oral Biol. Khan, K. Prunetin signals via G-protein-coupled receptor, GPR30 GPER1 : Stimulation of adenylyl cyclase and cAMP-mediated activation of MAPK signaling induces Runx2 expression in osteoblasts to promote bone regeneration.

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Lee, J. Curcumin-induced autophagy augments its antitumor effect against A human glioblastoma cells. Genistein as a potential anticancer agent against ovarian cancer.

Lee, K. Lee, Y. Inhibition of glutamine utilization sensitizes lung cancer cells to apigenin-induced apoptosis resulting from metabolic and oxidative stress.

Apigenin-induced apoptosis is enhanced by inhibition of autophagy formation in HCT human colon cancer cells. Li, H. Epigallocatechingallate induces apoptosis, inhibits proliferation and decreases invasion of glioma cell.

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Metabolic consequences of LDHA inhibition by epigallocatechin gallate and oxamate in MIA PaCa-2 pancreatic cancer cells. Metabolomics 11, 71— Luo, H.

EGCG decreases the expression of HIF-1α and VEGF and cell growth in MCF-7 breast cancer cells. ON, official J. Balkan Union Oncol. Luo, K. Tea polyphenol EGCG inhibited colorectal-cancer-cell proliferation and migration via downregulation of STAT3.

Mahmoud, M. Rosmarinic acid suppresses inflammation, angiogenesis, and improves paclitaxel induced apoptosis in a breast cancer model via NF3 κB-pcaspase-3 pathways modulation.

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Daidzein in soy could kill breast cancer cells. A January study 6 suggested daidzen could block or impair the spread of leukemia cells. Genistein in soy could disrupt DNA methylation in prostate cancer cells, renal carcinoma, and esophageal cell carcinoma.

Epigallocatechingallate could disrupt breast cancer and skin cancer cell lines. It is also being studied for its beneficial effects in leukemia and prostate cancer. An October study in the Journal of Cancer 7 suggests that Epigallocatechingallate was effective in shutting down cancer communications and pathways in lung cancer spread.

An October study 8 found protective effects of EGCG on endometrial, breast, and ovarian cancers. Ginseng could act to disrupt reactive oxygen species oxidation in brain cancer. A January study suggested that the ginseng leaf peptide significantly suppressed tumor growth and induced the tumor cells death.

Further the ginseng leaf peptide would be a potential anti-colon cancer candidate. Lycopene in tomatoes could disrupt DNA methylation in breast cancer cells. Phenethyl isothiocyanate in broccoli, cabbage, Brussels sprouts, and cauliflower could disrupt prostate cancer lines.

Resveratrol in red grapes, cranberries, blueberries, and nuts could disrupt colon, gastric, and lung cancer lines. Lemon peel extract. Another December study 12 suggested polyphenols could exert benefit against skin cancer. Chemopreventive effects of polyphenols are mediated by several signaling pathways against skin carcinogenesis and metastasis, implying the importance of polyphenols to open up new horizons in development of anti-skin cancer therapeutic strategies.

Tannic acid found in herbal teas. In a November study 13 , researchers found the antitumor and antioxidant effects of Tannic acid may be a promising treatment for glioblastoma based on animal research.

Patients receiving chemotherapy or radiotherapy routinely experience several side effects including toxicity, non-targeted damage of tissues, hair loss, neurotoxicity, multidrug resistance MDR , nausea, anemia and neutropenia.

Phytochemicals can interfere with almost every stage of carcinogenesis to prevent cancer development. Polyphenols have been found to be promising agents against cervical cancer.

In August , further research published in the journal International journal of molecular sciences 15 suggested:. All these studies are trying to find new chemopreventive agents with less toxicity but high effectiveness both in vitro and in vivo.

The bigger picture illustrates that polyphenols have great potential in cervical cancer prevention, with strong effects on gene modulation. Based on reports, over 10, flavonoids have been detected and categorized into several subclasses, including flavonols, anthocyanins, flavanones, flavones, isoflavones and chalcones.

It seems that the anticancer effect of flavonoids is mainly due to their antioxidant and anti inflammatory activities, and their potential to modulate molecular targets and signaling pathways involved in cell survival, proliferation, differentiation, migration, angiogenesis and hormone activities.

In the medical publication Cancer Letters , 17 doctors supported using polyphenols as mitochondria-targeted anticancer drugs. They noted that that mitochondria are the respiratory and energy centers of the cell where signaling pathways converge to give messages to the cells. One of those messages, as we discussed above, programs the death of cancer cells apoptosis.

From August , researchers publishing in the journal Biomolecules. Research in phytochemistry, nutrigenomics, and nutrigenetics has provided strong evidence that certain phytonutrients are able to modulate gene expression at transcriptional and post-transcriptional levels simply the gene expression levels of cancer.

Such phytonutrients may also be beneficial to prevent and treat breast cancer. Overall, these phytonutrients are found to inhibit breast cancer cell proliferation, differentiation, invasion, metastasis, angiogenesis, and induce apoptotic cell death by targeting various molecular pathways.

They also alter epigenetic mechanisms and enhance the chemosensitivity and radiosensitivity of cancer cells. An August paper in the journal Molecules 19 offers cancer patients these suggestions on the beneficial aspects of polyphenols used against the more harmful aspects of radiotherapy.

Top bar navigation Zhou B, Huang J, Zuo Y, Li B, Guo Q, Cui B, et al. Nieman KM, Romero IL, Van Houten B, Lengyel E. Therefore, in this study we identified the effects of PRSE on a number of cancer cell lines in vitro to identify any anti-cancer potential of the anti-oxidant supplement. miRp, miRa, miR-9, and miR are some of the miRNAs affected by curcumin in nasopharyngeal, breast and ovarian cancers and leukemia [ 74 ]. Naturally derived plant polyphenols have been demonstrated to inhibit metastasis initiation and progression by targeting both, cancer cells and cancer microenvironment. PLoS ONE 16 3 : e Powdered turmeric underground stems rhizomes have been used for more than years for treating broad range of conditions related to inflammation, allergies, parasitic infections, respiratory diseases, diabetes, neurodegenerative diseases and many others.
Can Polyphenols in Fruit Kill Cancer Cells?

Treatment of curcumin on human mammary epithelial and MCF-7 breast cancer cells reported a substantial decline in telomerase activity in a concentration-dependent manner associated with the downregulation of hTERT Tomeh et al.

The growth of oral mucosal epithelial cell lines and squamous cell carcinoma was inhibited by curcumin with the least consequence on normal oral epithelial cells. Curcumin reduced the efficiency of the eIF4F translational complex of mucosal cells via suppressing phosphorylation of eIF4G and eIF4B, combined with a decrease in total levels of eIF4E and Mnk1.

Curcumin triggers pestablished cell demise in basal cell carcinoma and breast cancer. However, in neuroblastoma, mammary epithelial carcinoma, and colon cancer, curcumin remedy unexpectedly via upregulated p53 expression, triggered nuclear translocation of p53, accompanied by p21 and Bax expression induction Allegra et al.

Curcumin in tumor tissue enhances the p53 molecule expression, modulates the pathway responsible for apoptosis in ovarian cancer as well as induces the p53 expression in nasopharyngeal carcinoma by mediating serine phosphorylation of p53 Sultana et al.

Kocaadam and Şanlier, examined the antitumor property of curcumin in various head and neck squamous carcinoma cell lines, CCL23 laryngeal , CAL27, UM-SCC14A, and UMSCC1 oral. Curcumin decreased the expression of NF-κB and controlled the expression of gene products, phospho-IκB-α, as well as inhibition of nuclear localization Kocaadam and Şanlier, In-vivo studies on mice tormented by colorectal cancer showed a better reaction to radiation remedy in aggregation with curcumin owing to its assets to target nuclear factor NF-κB Tomeh et al.

Silibinin induces autophagy upregulation of protein which was associated with microtubule formation Bai et al. Silibinin reduced tumor growth by downregulating extracellular signal-regulated kinase and Akt in human ovarian cells Cho et al.

Silibinin triggered autophagic cell death in breast cancer cells; the usage of mitochondrial potential became a result of ROS formation and ATP depletion, causing stimulation of expression of Bcl-2 adenovirus E1B kDa-interacting protein 3 Jiang et al.

Together, apoptosis and autophagy were strongly induced by silibinin through the interference of various pathways, up- and downregulation of the expression of caspase-3, Atg5, Atg7, Bcl-2, COX-2, HIF-1α, VEGF, MMP-2, 9, respectively Sameri et al.

In human hepatocellular carcinoma HCC , silibinin powerfully repressed the growth of HepG2 and Hep3B cell lines and showed relatively more potent cytotoxicity in Hep3B cells, causing apoptosis induction.

In HepG2, silibinin caused G1and G2-M phase arrest in Hep3B cells. A study conducted by Mateen et al. The cell growth was affected with silibinin treatment, and the cell cycle was reported to arrest at the G1 phase in a dose and time-dependent manner. Silibinin decreased kinase expression in all of the cell lines; however, no impact was found on CDK4 activity in H cells, with the concomitant reduction in retinoblastoma protein phosphorylation.

Silibinin strongly caused a decline in cell viability and death in MCF-7 cells related to expanded p53 expression Noh et al. Kaur et al. Results concluded that silibinin treatment in SW inhibited cell growth, prompted cell death, and reduced nuclear-cytoplasmic β-catenin; however, no longer in wild type, depicting its effect on the β-catenin pathway along with related biological responses.

Anticancer properties of silibinin investigated on CT26 mouse colon cell lines showed a reduction in proliferation, cell survival, angiogenesis, and migration. In Hep3B cells, silibinin reduces the protein concentrations of G2-M regulators with the inhibition of CDK-2, CDK-4, and CDC2 activity in HCC cells Varghese et al.

Cho et al. Silibinin, when given orally to A cells, shrinks the tumor volume, decreases Kipositive cells, increases transferase-mediated dUTP nick end labelling -positive cells, caspase-3 activation, p-ERK, and p-Akt inhibition.

Apigenin triggers cell cycle arrest at various proliferation laps, regulates intrinsic apoptotic pathways, and promotes different anti-inflammatory pathways Iizumi et al. Apigenin enhances the expression of anti-oxidant enzymes plus induces the inhibition of metastasis and angiogenesis Rezai-Zadeh et al.

Cancer cell proliferation is inhibited using apigenin through modulation of the cell cycle and blockage at checkpoints, i. Autophagy is induced through AMPK activation, which is triggered by apigenin, and the mTOR signaling pathway is also inhibited Sung et al.

Zhang et al. Higher PIG3 mRNA and protein expression due to apigenin processing indicated the involvement of PIG3 in apigenin-induced apoptosis in both KYSE and OE33 cells. The increase in activity of caspase-3 and -9 fragments recommended that PIG3 induction was mediated through apigenin which further caused esophageal cancer cell apoptosis via interfering with the mitochondrial pathway.

Masuelli et al. Apigenin treatment causes arrest of cell growth and induces apoptosis in many tumors by the modulation of diverse signaling pathways.

The authors also analyzed the interactions between apigenin and TRAIL in NSCLC cells. Results demonstrated apigenin and TRAIL produced a synergistic effect for the induction of apoptosis of NSCLC cells by upregulating death receptors-4, and -5 in a pdose-dependent fashion. Additionally, the pro-apoptotic proteins were upregulated, while the anti-apoptotic proteins, viz.

Bcl-xl and Bcl-2 were reported to be downregulated. Apigenin inhibited the activation of NF-κB, AKT, and ERK. In the mouse xenograft model, the combined treatment of apigenin and TRAIL entirely inhibited tumor proliferation as compared to the treatment of apigenin or TRAIL alone.

In total, apigenin enhanced antitumor activity in NSCLC cells which was induced by TRAIL through the inhibition of several pro-survival regulators. Luteolin inhibits the progression of cancerous cells, protects from carcinogenic stimuli, activates cell division blocks, and helps in the initiation of cell death via activating numerous signaling pathways.

Luteolin also reverses the epithelial-mesenchymal transition EMT by altering a mechanism that involves cytoskeleton contraction resulting in a change in the expression of epithelial biomarker E-cadherin in addition to a decrease in expression of the mesenchymal biomarkers.

In addition, luteolin elevates the intracellular concentration of ROS via the stimulating ER stress, which is lethal as well as mitochondrial dysfunction in glioblastoma cells Imran et al. Modulation of ROS levels, topoisomerase I and II, P13K, NF-kappaB and AP-I activity reduction, and p53 stabilization are mechanisms contributing to the anti-tumor activity of luteolin Lopez-Lazaro, Luteolin inhibits specific critical cancer, which is followed by the activation of various signaling pathways like mTOR and MAPK.

Programmed cell death is mediated through the cell cycle arrest. Luteolin arrests the G2 phase in non-small-cell lung cancer cells by the inhibition of the cyclin A expression plus CDC2 phosphorylation Ganai et al. In vitro studies on luteolin have revealed that luteolin inhibits breast cancer cell proliferation, is stimulated by IGF-1, arrests cell cycle development, plus induces cell death in a time-and dose-dependent manner Table 1.

In colon cancer, luteolin exhibits a withdrawing effect on nitric oxide synthase iNOS and COX-2 expressions and a suppressing one on MMP-2 and -9 expressions. Recent research has discovered that treatment with dimethylhydrazine induced renal bleeding in addition to colon polyps in rats with the enhancement in COX-2 and oxidative stress.

Luteolin treatment declined the concentrations of iNOS and COX-2 Abdel hadi et al. Luteolin treatment 15 μM, 24 h to human pancreatic cancer cells significantly declined nuclear GSK-3β and NF-κB p65 expression Bothe et al. The chemopreventive plus chemotherapeutic actions of luteolin against prostate cancer were demonstrated in the vastly persistent DuIII prostate cancer cells.

The study reported that luteolin decreased the growth of these cells and suppressed cancer cell intrusion. Johnson et al. In prostate fibroblastoma, luteolin caused inhibition of myofibroblast phenotypes and extracellular matrix contraction, which was induced by TGF-β; suppression of TGF-β signaling involving activation of AKT and ERK; suppressed activation of RhoA Johnson and Mejia, Table 1.

A recent study by Chakrabarti and Ray investigated the consequence of taking two different luteolin concentrations, viz. Luteolin in oral cancers affected the phosphorylation of ataxia-telangiectasia in conjunction with pathways of DNA repair. Luteolin reduced the growth of the SCC-4 cells and multiplied the death of tumor cells by interfering with the expression of some cyclins, cyclin-established kinase CDKs Wang F.

In head and neck squamous cell carcinoma, luteolin inhibited the tumor expansion plus histone acetylation, promoted arrest of the cell cycle, declined the movement of cells as well as altered gene expression, and upregulation of p53 induced plus miRNA systems Tu et al.

Luteolin played an influential part in human NSCLC cell line A against tumor cell propagation by inducing cell death along with suppression of movement of cells.

Apoptosis induction involves numerous steps in cells, viz. Caspases activation, alteration of MEK phosphorylation, Bcl-2 family proteins expression and downstream of kinase ERK, along with Akt phosphorylation Figure 2. Luteolin also lowered the mitochondrial membrane potential and enhanced the regulatory protein of the cell cycle in addition to the increase in the concentrations of apoptosis-related proteins.

Oral administration of luteolin appreciably declined the concentrations of tumor markers as well as expressions of MMP-2 and -9 Naso et al. In a xenograft mouse model, at a specific dose, luteolin reduced the pro-inflammatory cytokines and TNF-α stages in PC3 cells similarly to decreased weight and extent of tumors, affected the cell capability, triggered cell death, and downregulated the ERK, AKT, mTOR, MMPs expressions Han et al.

In another study, in a xenograft model in mice with NSCLC cells, luteolin and Infra-Red radiation co-treatment activated apoptotic cell death, and declined the expression of B-cell lymphoma 2 Bcl-2 along with caspase-complex activation.

Also, luteolin inhibited the progression of xenograft mouse models of esophageal squamous cell carcinoma Wu et al. Genistein possesses antitumor activities by the modulation of multiple signaling pathways, i. Genistein at higher concentration results in apoptosis mediated by inhibition of various proteins associated with primary tumor growth, i.

However, when genistein is given at a lower concentration via diet inhibits the transforming growth factor TGF pathway, which affects pro-metastatic actions such as cancer cell detachment and invasion Pavese et al.

Genistein induces endoplasmic reticulum ER stress by upregulation of glucose-regulated protein 78 GRP78 and CHOP expression. ER stress inhibitor also enhances genistein-induced cell death Yang F.

Genistein in HO cells changed the protein levels, which are related to the checkpoint pathway, resulting in the inhibition of cancer cell propagation Ouyang et al. Pretreatment with genistein by Solomon et al.

A recent study Yang F. Additionally, genistein also played an important part in triggering ER stress in HeLa cells mediated through the upregulation of glucose-regulated protein 78 and CHOP expression.

Genistein helps in the initiation of cell death in several hepatocellular carcinoma cells HCCs. Genistein exhibits potential anti-invasive and anti-metastatic activities against O-tetra decanoyl phorbolacetate-mediated metastasis which proceeds through downregulation of MMP-9 and NF-kB, and activator protein 1 transcription factors occurring via inhibition of MAPK Spagnuolo et al.

Genistein triggered apoptosis in the low-invasive MCF-7 and the high-attack in breast cancer cell lines 10— mM in a dose-dependent approach Spagnuolo et al.

Genistein triggered the ROS generation, thus, favoring cell death. Apoptosis induction by genistein is linked with the upregulation of cytosolic cytochrome c, with the downregulation of Bcl-2 in HepG2 cells Zhang et al. Genistein significantly inhibits the propagation of hepatocellular carcinoma and induces death of the cell in a concentration and time-dependent manner.

Genistein administration in ovariectomized rats increased uterine weight. An antagonistic effect of genistein on the estradiol increases uterine epithelial height Diel et al.

A protective effect of genistein against the progression of endometrial cancer along with atypical endometrial hyperplasia in mice was observed by the modulation of the expression of genes known to be linked with estrogen plus cytokines Lee et al.

Genistein significantly suppressed the attack of Bel 7, cells and altered the cell cycle, cell death, and angiogenesis in the renal parenchyma of nude mice with a xenograft transplant. Protocatechuic acid PCA exerts pro-apoptotic and anti-proliferative properties in different tissues.

Anti-tumor property of PCA involves the stimulation of c-Jun N-terminal kinase, p38 subgroups of the mitogen, which are further activated by the protein kinase MAPK family Khan et al. PCA blocks the retinone-induced apoptotic death of cells.

PCA influences the activity of cyclooxygenase COX inducible isoenzyme as well as nitric oxide synthase along with regulating proteins of the cell cycle, or inflammatory cytokines, comprising the part of oncogenesis Kakkar and Bais, Additionally, PCA reduced interleukins IL -6 and IL-8 in cancer cell lines Yin et al.

Metastasis mouse models in vivo were analyzed to study the effect of PCA on cancer cell attacks. The study concluded that PCA at non-cytotoxic concentrations inhibited cell migration and invasion. PCA treatment caused decreased expression of MMP-2 subsequently, a rise in MMP tissue inhibitor.

In colorectal cancer, the anticancer effect of RA causes the inhibition of COX-2 activation by repression of binding of activator protein-1 AP-1 and c-Fos inducing agents Hossan et al. The anti-metastatic effect of RA occurs via the AMPK phosphorylation, and colorectal cancer proliferation is slowed down, which further proceeds by the initiation of cell cycle arrest and apoptosis, followed by inhibition of expression of MMP-2 and MMP In conclusion, RA effects on EMT and MMPs expressions result in AMPK activation Han Z.

In leukemia, RA suppresses the activation of NF -k B-dependent anti-apoptotic proteins via phosphorylation inhibition, I kappa-B-alpha degradation, and p50 and p65 nuclear translocation Moon et al. The effects of RA on pancreatic tumor progression and its primary molecular mechanisms were explored by Han et al.

Authors concluded that RA considerably suppressed vital cellular functions in pancreatic tumor cells, finally inducing cell death in pancreatic cells. Further, RA significantly up-regulated and knocked down the expression of miR in pancreatic cancer cells, accompanied by the suppressive effects of RA on cell growth and EMT, and prohibited increased impact of RA on cell apoptosis in pancreatic tumor cells.

Results revealed that A cells treated with RA had decreased cell viability, propagation, invasive abilities, melanin content, and decreased expression of MMP-2 and MMP-9 proteins as compared to normal cells. RA increased the expression of pro-apoptotic proteins and suppressed Bcl-2 expression Huang et al.

Han Z. RA suppressed the CRC cells propagation, brought about cell cycle arrest, and hence, initiated apoptosis. RA mediated EMT through the growing the expression of an epithelial marker, E-cadherin, and lowering the expression of the mesenchymal markers and N-cadherin Figure 2.

In human leukemia U cells, RA was reported to trigger apoptosis which was in turn induced by TNF-α and generation of ROS.

RA inhibited NF-kB activation via phosphorylation inhibition, followed by the degradation of IκBαand nuclear translocation of p50 and p65, which is associated with NF-kB-dependent anti-apoptotic proteins suppression Hossan et al. Mice treated with oral RA suppressed tumor induction NF-κB, TNF-α, VEGF serum, and VEGF receptors.

RA induced apoptosis by restoring the expressions of Bcl-2, Bax, and caspase In Ehrlich solid tumor mice, RA, in combination with paclitaxel, significantly decreased the growth of the tumor with enhancement in levels of apoptotic markers Mahmoud et al.

In the swiss albino xenograft model, RA administration suppressed tumor formation, positively altered the antioxidant level, and stabilized the 7,dimethyl-benz a anthracene DMBA -induced alterations in the apoptotic markers Sharmila and Manoharan, The apoptosis effect of CA occurs via the increase in p53 and Bax protein expression with a decrease in Bcl-2 expression followed by activation of the caspase-3 pathway Changizi et al.

The BH3-protein Bcl-2 binding component 3 BBC3 is upregulated by CA, which causes mitochondrial death Jiang et al. CA inhibits the migration and invasive capacity of tumor cells, modulates mTOR2-related pathways, and reduces the phosphorylation of p-protein kinase C alpha PKCα , Akt, along with declined expression of Rictor and F-actin factors responsible for cell growth and organization of actin cytoskeleton.

In human hepatoma cells HCC , CA dose-dependently inhibits the activity of cell lines, i. CA alters the NF-κB signaling pathway and turns on the mitochondrial cell death of HCC through the upregulation of BBC3 Jiang et al.

Results demonstrated that CA effectively inhibited the increase of tumor cells. A study conducted by Changizi et al. Highest CA concentration up-and down-regulated Bax and Bcl-2, respectively, in 4T1 treated cells. Further, outcomes showed growth in the expression of P53 and caspase-3 for the duration of remedy in CA-handled 4T1 cells.

The anti-cancer effect of CA was evaluated in another study by Huang et al. In vivo , CA administration to mice bearing tumor cell-implanted xenografts inhibited the growth of the tumor.

CA antitumor effect was evaluated in a recent study Zeng et al. Authors discovered that CA noticeably slowed down the tumor growth with the prolongation of the survival rate of tumor-bearing mice.

Eupatorin showed an antitumor effect on human breast cancer cells and mediated CYP1- metabolism. The cytotoxic effect of eupatorin was investigated on the human breast carcinoma cell line as well as another cell line that was extracted from normal mammary tissue, MCFA.

Together, the presence of CYP1 family metabolism resulted in the flavone eupatorin selective activation in breast cancer cells but not in normal breast cells Androutsopoulos et al.

Razak et al. Cytotoxic consequences of eupatorin have been located on both cells; however, they remained non-poisonous to the ordinary cells of MCFa in a time- and dose-structured approach. However, eupatorin was reported to be mild cytotoxic on both cells after 24 h of treatment. In another study Pavlopoulou et al.

Eupatorin blocks cells at the G2-M phase and triggers cell death, activating a couple of caspases cytochrome- c release and breakdown of poly ADP-ribose polymerase in human leukaemia cells. Cell death via eupatorin is mediated via every apoptotic pathway and ROS mechanism.

Eupatorin down- and up-regulated cyclin D1 and B1 after 3 and 12 h of eupatorin treatment, respectively. Eupatorin lowered p53, p21, and Bax protein concentrations via initiation of the breakdown of caspase-3, -7, and poly ADP-ribose polymerase.

Eupatorin-triggered p21 and Bax expressions which were p53 and Egrpathways dependent, respectively. Most polyphenols are present in foods in the form of esters, glycosides and polymers that cannot be absorbed in their native form in the human gastrointestinal tract Sharifi-Rad et al.

Thus, before absorption of the molecules must be hydrolyzed by saliva, intestinal enzymes or need to be metabolized by the colonic microflora. Thus, the structural integrity and proper functioning of the digestive tract are essential for the optimal absorption of polyphenols.

The variability of the biological activity of polyphenols beyond the particularities of the human body also depends on the biological properties of the classes and subclasses of polyphenols Rudrapal et al.

For the anticancer effect, polyphenols can also be consumed in the form of natural supplements. In the case of approved natural supplements, they must be administered according to the recommendations made by the manufacturer, which can be found on the product packaging Tsoukalas et al.

Therefore, future translational studies are needed to determine the effective therapeutic dose in humans and the route of administration.

A therapeutic limitation is represented by the possibility of polyphenols interfering with the absorption of nutrients or drugs. More research needs to be done to better understand these potential interactions. To increase therapeutic efficacy, nanotechnologies have been tried to increase the absorption and reduced bioavailability of some polyphenols, and numerous studies have confirmed this benefit.

Food supplements with polyphenols do not endanger health, but there are uncertainties about the side effects of polyphenol supplements Rana et al. Therefore, new studies are needed in the future to overcome the biopharmaceutical problems of polyphenols in cancer.

In the attention to experimental evidence stated and mentioned withinside the review, it is miles glaring that polyphenols display more capability than other compounds by blocking more than one target in pathways and mechanisms associated with cancer progression.

Various in-vitro studies suggest that the polyphenols modulate Nrf 2 and NF-kB activation in cells and also influence the MAPK and PI3K function in the cells, thereby establishing a prominent role in cancer cell progression. In connection, the possibility of combining conventional drugs with polyphenols in individual or combination offers valuable advantages for developing more anti-cancer therapies with greater efficacy.

Although, there is no doubt about the role of oxidation in the occurrence of mutations in DNA and the increased risk of cancer, the isolated action of a particular polyphenol or polyphenolic compounds, in general, is unlikely to have a distant effect on the gastrointestinal tract - for example, in the mammary gland or lungs.

While data on the beneficial effects of polyphenolic compounds as anticancer agents, it has been observed that all these benefits depend not only on the food content of polyphenols, but especially on their bioavailability in the gastrointestinal tract, and their ability to be absorbed into the circulatory system to reach the cells where they manifest their protective effect.

Nevertheless, the usage of dietary polyphenols as whole foods can be a promising aspect of cancer prevention. Conceptualization and design were performed by JS-R, AS, DC, and WC; validation, investigation, data curation, and writing were performed by ES, DA, JS-R, PS, CH, and PD; review and editing were performed by PD, AS, WC, DC, and JS-R.

All the authors contributed equally, read and approved the final manuscript. All authors have read and agreed to the published version of the manuscript. Part of this study was funded by Région Centre-Val de Loire grant number INNO-COSM.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Abd razak, N.

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Kim, Y. Resveratrol inhibits cell proliferation and induces apoptosis of human breast carcinoma MCF-7 cells. Kitic, D. Anticancer potential and other pharmacological properties of prunus armeniaca L. Within the subclass of stilbenes, RES has been found in several edible natural products such as grapes, peanuts, berries and rhubarb Prostate cancer PC represents the second most commonly diagnosed cancer among males worldwide Countries following a Mediterranean-type dietary pattern Italy, Greece, Spain, Malta and some regions of France have been documented to have a lower incidence and mortality rate due to PC than northern European regions.

In a population-based case-control study conducted in Southern Italy, a total of patients with PC and controls were examined; the controls had a significantly higher adherence to the Mediterranean diet, following correction for confounding factors as age, body mass index, cigarette smoke, alcohol intake and physical activity The lowest age-standardized incidences of PC worldwide are registered in South Central Asia compared to westernized countries; lifestyle choices, including diet are considered to be involved in the risk of developing PC, as known risk factors such as age, race and family history cannot explain this geographical variability in incidence.

In fact, the risk of developing PC rapidly increases as much as fold in Asian immigrants to the United States who reduce their intake of soy, tea, fish, fruits and vegetables, while introducing more red meat and fat Therefore, dietary components such as vegetables, tomato sauce, fish and vegetable fat are associated with a lower risk of PC progression.

In particular, dietary factors that can influence the onset of PC are high intake of alcohol, dairy products, animal fat and meat; lycopene also has a tendency towards a favorable effect on PC incidence.

On the other hand, the intake of long-chain omega-3 polyunsaturated fatty acids does not seem to be associated with lower cancer incidence Vitamin D could also play an important role, as both low and high concentrations are associated with an increased risk In light of these considerations, scientific interest in the potential chemopreventive role in PC of various phytochemicals present in food is increasing.

The mechanisms through which they exert their anticancer activity include the inhibition of proliferation, the induction of apoptosis and arrest of the cell cycle. Moreover, they can modulate signaling pathways and influence epigenetic alterations, such as DNA methylation and expression patterns of microRNAs miRNAs.

In particular, some polyphenols lycopene, EGCG, CUR act through the downregulation of different signal transduction pathways.

Also sulphoraphane seems to exert antitumor effect through several mechanisms, such as anti-inflammatory, anti-angiogenetic and anti-metastatic activities Fig. Polyphenols act on the epigenetic mechanism by inhibiting the methyltransferase activities of HDAC, HAT and DNA which are deregulated in cancer cells.

Epidemiological studies have indicated that these plant bioactives exhibit multimodal effects on PC cells, and foods such as cruciferous and alliaceous vegetables, tomatoes, red wine, green tea, turmeric and pomegranate have all been linked to a reduced risk of developing PC. For example, red wine and grapes contain RES, which has various biological effects, such as anti-inflammatory, antioxidant and anticancer.

RES inhibits the in vitro dehydrotestosterone-induced progression of PC, interfering with the AR and CXCR4 pathway. CXCR4 as a chemokine receptor has been found to be upregulated in cancer metastases and has been used as a prognostic marker in various types of cancer, including leukemia, breast cancer BC and PC: RES treatment reduced CXCR4, AR, p-PI3K and p-AKT expression Green tea polyphenols containing EGCG have also been shown to exhibit numerous noteworthy biological activities, including anticancer properties.

In particular recent studies on PC have demonstrated that epigenetic mechanisms could represent the main actors in the regulation of matrix metalloproteinases MMP and their tissue inhibitor TIMP associated with the progression of PC.

In addition, clinical trials performed on patients undergoing prostatectomy and consuming mg EGCG for up to 6 weeks, compared to matched controls, demonstrate an increase in plasma TIMP-3 levels. Colorectal cancer CRC is the third most common type of cancer worldwide with a high incidence and mortality CRC is recognized as a multifactorial disease that is dependent on environmental variables and individual intrinsic factors.

In particular, eating habits have been linked to changes in the intestinal microbiota which could also contribute to the pathophysiology underlying CRC and its metabolic and psychological complications. The intestinal microbiota has a well-defined role in the body's homeostasis, in fact several highly prevalent gastrointestinal diseases have been associated with imbalances in microbiota composition dysbiosis and in particular the association with the onset of cancer has been suggested Among the bioactive compounds of the diet, polyphenols exert favorable effects on the intestinal microbiota, on free radicals and on inflammation Polyphenols are biotransformed by the intestinal microbiota and finally metabolized into relatively simple aromatic carboxylic acids, commonly termed phenolic acids These bioavailable metabolites can be even more bioactive than their precursors.

The modification of the composition of intestinal microbiota can significantly influence the bioavailability of polyphenols. In fact, human intestinal microbiota exhibits important hydrolytic activity, therefore when polyphenols reach the colon, their bioavailability can be significantly increased.

In addition, polyphenols can decompose into smaller phenolic acids for easy absorption by the intestinal mucosa. EGCG can be methylated through catechol- O -methyltransferase and can exert an inhibitory effect on DNA methyltransferase DNMT.

DNMT inhibition prevents hypermethylation of newly formed DNA strands, leading to a reversal process of silenced genes. EGCG may also suppress DNMT action by activating genes silenced by tumor cells by methylation In fact, AKT1 can be a key regulator of EMT in colon cancer cells and serve as a potential therapeutic target for this disease Djulis, a cereal crop rich in polyphenols and dietary fiber, can also prevent CRC.

Indeed Lee et al carried out a study on rats showing that polyphenols can protect rats from oxidative stress and regulate proteins related to anti-apoptosis, proapoptosis and proliferation to prevent CRC progression. Therefore, djulis may prove to be a promising CRC chemopreventive product in the future Inflammation-induced carcinogenesis has been shown to be associated with oxidative stress, genomic instability, immune effectors, cytokine dysregulation and the modulation of the NF-κB signaling pathway.

Foods such as strawberries and black raspberries have been shown to play a synergistic role in multiple molecular events, including the suppression of cytokine release, the reduction of oxidative stress, the reduction of genomic instability and the inhibition of NF-κB and related pathways A study carried out by Hu et al demonstrated a synergistic action of ginkgetin and RES in preventing VEGF-mediated angiogenesis in several experimental models, suggesting that this combination may play a role in anti-tumor treatment.

The reduced formation of sub-intestinal vessels was shown in zebrafish embryos and microvascular sprouting in rat aortic ring; the reduced phosphorylation of VEGFR2, Akt, eNOS and Erk, as well as the expression of matrix metalloproteinases MMPs was found in human umbilical vein endothelial cells HUVECs.

The combination of ginkgetin and RES was also effective on HT colon cancer xenograft nude mice and relieved the 5-fluorouracil-induced inflammatory response by suppressing expression levels of COX-2 and inflammatory cytokines The risk of developing BC is affected by non-modifiable factors, including age and genotype, as well as modifiable factors, such as smoking, alcohol, nutrition and occupational exposure It has been observed that obesity, a sedentary lifestyle and unhealthy diet are known to increase the mortality rate of BC survivors.

As the same risk factors are common to cardiovascular diseases, the risk of cardiovascular diseases is also higher among BC survivors. Consequently, the implementation of a healthy diet rich in unrefined cereal, fresh fruit and vegetables could also indirectly improve the outcome of BC survivors by reducing body weight.

The nutrients present in a typical Mediterranean diet have shown a positive impact on the biomarkers of inflammation, DNA damage, oxidative stress and genetic alterations, all factors that can influence BC outcomes. In addition, several studies have reported that a high adherence to MD is associated with a lower risk of the incidence of BC in post-menopausal women A prospective cohort study conducted in the Mediterranean included 10, middle-aged, Spanish female university graduates and revealed an inverse association between the total polyphenol intake and the risk of BC for post-menopausal women One of the polyphenols studied for its inhibitory effects on BC is carnosol.

An in vivo study demonstrated that this compound can reduce the proliferation of BC cell lines MDA-MB and can significantly inhibit invasion and metastasis both in vitro and in vivo ; in particular, it has been shown that carnosol exerts its effect against BC through the downregulation of MMP-9 activity and expression, and by the inhibition of the STAT3 signaling pathway through the ROS-dependent proteasome degradation of the STAT3 protein The antioxidant properties of RES, a natural component of plants such as peanuts, cocoa, grapes, berries and red wine, are attributed to its polyphenolic stilbene structure.

RES and its analogues have been classified as phytoestrogens able to bind estrogen receptor, and the results of investigations in ER-positive subtypes strongly suggest their use in hormone anticancer therapy.

In fact, the majority of authors agree on the ability of RES to modulate ERα and p53 expression in ER-positive BC: It inhibits the expression of major cell cycle-related genes, through the downregulation of ERα mRNA transcription. Recently, a membrane receptor site for RES on an integrin has been revealed in both ER-positive and ER-negative BC subtypes: Upon binding of RES with this receptor, the pdependent induction of apoptosis occurs While the potential effects against BC of RES and other polyphenols such as curcumin CUR , genistein, quercetin and silibinin have been widely investigated, interest towards the potential anticancer activity of luteolin is more recent.

The mechanisms considered to be responsible for the cancer preventive activity of luteolin are reduced DNA alterations, antioxidant, anti-inflammatory and antiestrogenic action. Moreover, pro-apoptotic e. Luteolin inhibits BC cell survival, proliferation and migration and reduces angiogenesis, by modulating multiple signaling pathways and miRNAs EGCG and oleuropein OLE have been suggested as potential supplements against BC.

EGCG also induced apoptosis by inhibiting miR expression and increasing PARP and pro-caspase expression Oleuropein OLE , a natural polyphenol, has also shown potential apoptotic and anti-invasive effects on MCF-7 cells.

In fact, OLE reduced neoplastic cell invasiveness and viability and at the same time induced apoptosis in MCF-7 cancer cells 48 ; in particular, OLE acts on cancer control by epigenetic mechanism, such as the inhibition of histone deacetylase HDAC Finally, an in vitro study reported the anti-proliferative and cytotoxic effects of a polyphenol complex catechin and lysine, in BC cell lines.

In particular, it was shown that this complex acts by interfering with glucose uptake and lactate production by tumor cells. Nonetheless, epidemiological studies on flavonoids and BC have some limitations: Study design, a low sample size, variable doses of flavonoid intake and BC subtype are the most common Lung cancer LC is the second most common type of cancer among both sexes, with a high mortality rate worldwide The consumption of fruit, vegetables and natural products is considered useful in the prevention and fight against LC.

Some natural polyphenols have potential anticancer activities owing to their anti-proliferative, anti-migratory, anti-metastasis, anti-angiogenic and pro-apoptotic properties. A recent comprehensive review summarized preclinical studies investigating the molecular mechanisms of natural polyphenols or analogs with a potential role in LC.

RES, CUR and EGCG emerged as the most studied compounds Lately, research has made immense progress in the comprehension of the mechanisms through which RES inhibits cell proliferation, induces apoptosis and cell cycle arrest, and suppresses invasion and metastasis.

In particular, RES has been shown to induce apoptosis through multiple signaling pathways, including the kinases, AKT, STAT3, PKC, p38, JNK, ERK, AMPK and PFK; various cyclins A, D, E and CDK also act as cell cycle regulators. Multiple growth and transcription factors are also involved, as VEGF, FGF, TGFβ, EGFR, AhR, Nrf2, NF-κB and p The majority of these pathways have been identified to play a role in the pro-apoptotic effects of CUR and EGCG.

CUR also has been shown to exert an anticancer effect in LC through epigenetic alterations and the regulation of miRNA expression Although the induction of apoptosis appears to be the main mechanism underlying the antitumor activities of polyphenols in LC, there is evidence of other mechanisms being involved in their inhibitory effects on lung tumor survival and progression.

RES has been shown to lead to a significant reduction and imbalance in the pools of deoxyribonucleosides triphosphates dNTP , which suppress subsequent DNA synthesis. Furthermore, the inhibition of DNA synthesis blocks the progression through the S phase in A cells, which can partially contribute to the cytotoxic effect of RES In vivo and in vitro studies have demonstrated that EGCG, a polyphenol present in green tea, inhibits the proliferation and migration and induces apoptosis in LC A and H cells.

These effects are partially achieved through inhibition of the NF-κB signaling pathway. Furthermore, the concomitant administration of EGCG and BAY has a synergistic effect and may serve as a new therapeutic strategy for LC.

Dieckol is a polyphenolic substance extracted from brown algae. This suggests that dieckol may be a potent natural anticancer drug for the treatment of NSCLC These data confirm the potential complementary role of RES, CUR and EGCG in cancer treatment to enhance the efficacy of existing therapies, reducing side-effects.

Polyphenols, including EGCG, CUR and RES, are known to exert an antioxidant effect; however, under certain conditions, they can be genotoxic for tumor cells. A study conducted by Almeida et al 57 evaluated the antitumor activity of RES and its possible mechanisms of action in bladder cancer cells with a different state of the TP53 gene.

This gene responds to stress signals inducing cell cycle arrest, apoptosis, senescence and DNA repair; its mutations are the most common alterations in bladder cancer cells and are correlated with poor prognosis and recurrence. Its antitumor activity was evaluated in different bladder tumor cells RT4, grade 1, TP53 wild type; grade 2; Tgrade 3, TP53 mutated.

RES decreased cell proliferation and induced DNA damage in all neoplastic cell lines. However, TP53 wild-type cells were more resistant, while they were more prone to apoptosis, accompanied by AKT, mTOR, and SRC downregulation as well as modulation of the DNMT1 gene.

An in vitro study conducted on BFTC cells, a human urinary bladder transitional cell carcinoma TCC cell, treated with EGCG, identified differentially expressed genes and 22 candidate genes with potential miRNA interactions.

These genes were mainly involved in the biogenesis of nicotinamide adenine dinucleotide NAD , in the inflammatory response and in the oxidation-reduction metabolism CUR is capable of suppressing the growth of a variety of cancer cells, including those of bladder cancer. CUR could be considered a promising candidate in bladder cancer therapy as it modulates various signaling pathways such as PI3K, Akt, mTOR and VEGF involved in the progression and malignancy of bladder cancer Skin is considered the protective barrier of the organism, shielding it from harmful substances, mechanical damage, pathological invasion and radiation.

Skin cancer SC is considered to be the most common type of cancer worldwide; this is the result of several mutations in cancer-related genes, including proto-oncogenes and tumor suppressors in skin cells, which cause an imbalance in cell homeostasis and excessive skin proliferation.

The initiation of skin tumors can be attributed to various factors, although excessive exposure to UV radiation is considered the main risk factor for SC. The main classification of SC is between melanoma and non-melanoma. Non-melanoma skin cancer NMSC in turn is distinguished into basal cell carcinoma BCC and squamous cell carcinoma SCC originated from epidermal keratinocytes.

The inhibition of cellular proliferation, invasion and metastasis would occur by modulating the expression of inflammatory and cytokine genes such as IL-6, IL-1, GM-CSF and TNF-α, IL-2, GM-CSF and INF-γ and IL in melanoma models The treatment of melanoma remains a challenging issue, due to its aggressive metastatic ability and resistance to current therapeutic approaches.

Though no clinical studies are yet available assessing the efficacy of the most active polyphenols in SC, epidemiological evidence indicates that the poorly soluble polyphenols, such as CUR, RES, EGCG, coumarin and quercetin, exert anticancer effects.

In their review, Heenatigala Palliyage et al suggested that poorly soluble polyphenols, such as CUR, RES, quercetin, coumarin and EGCG may have significant benefits in the treatment of melanoma thanks to their antioxidant, anti-inflammatory, antiproliferative and chemoprotective properties.

The well-known limitations to their use, i. Rodríguez-Luna et al 62 proposed the combination of the carotenoid fucoxanthin and the polyphenol rosmarinic acid RA as a natural promising tool in prevention of UVB-induced skin alterations as photo-aging, skin inflammation and its derivation to pre-cancerous lesions and skin carcinomas.

RA is a phenolic ester traditionally isolated from some terrestrial plants as Rosmarinus officinalis L. or Melissa officinalis L. and also abundantly found in Zostera marina seagrass beds. RA has been widely studied due to its remarkable biological and pharmacological activities, including anti-microbial, antioxidant and anti-inflammatory properties.

The authors of that study demonstrated that the combination of fucoxanthin and RA improved their antioxidant and anti-inflammatory profiles by reducing UVB-induced apoptosis and the consequent ROS production.

This association also downregulated inflammasome components, such as NLRP3, ASC and caspase-1 and interleukin IL -1 production. Moreover, Nrf2 and HO-1 antioxidant genes expression increased in UVB-exposed pre-treated HaCaT cells. The study conducted by Shin et al analyzed the effects of quercetin on skin aging.

In particular, quercetin has been shown to suppress UV-induced matrix metalloproteinase-1 MMP-1 and cyclooxygenase-2 COX-2 expression by preventing UV-mediated collagen degradation in human skin tissues; inhibit the activator of protein-1 AP-1 induced by UV rays and on NF-κB; attenuate UV-ray phosphorylation of extracellular signal-regulated kinase ERK , terminal kinases C-Jun N JNK , protein kinase B Akt and signal transducer and activator of transcription 3 STAT3 ; and to directly inhibit the kinase activity of the protein kinase Cδ PKCδ and JAK2 Pancreatic cancer is one of the most severe neoplasms due to a very poor prognosis, as in the majority of patients it is usually diagnosed at an advanced stage.

Current chemotherapeutic agents administered to patients with metastasis pancreatic cancer are not able to significantly improve life expectancy. For this reason, novel therapeutic strategies are required to prevent or target metastatic disease aiming to improve the patient's outcome.

Wei et al studied EGCG as a potentially safe and effective agent for use with gemcitabine in blocking the migration and invasion of pancreatic cancer, in part by inhibiting the Akt and EMT pathways.

Since Akt signaling plays an important role in pancreatic cancer cell growth, downregulation of this kinase may partly explain the reduction in cell growth observed in EGCG-treated tumors.

EGCG has effectively reduced pancreatic cancer cell growth in vitro and in vivo , otherwise there is little evidence of a beneficial effect of EGCG on cancer metastases the effectiveness of chemotherapy agents is low and the disease has an unfavorable prognosis with frequent recurrences and high mortality.

Though the in vitro anti-leukemic effect of polyphenols has been studied for decades, there are only few in vivo studies. RES has pleiotropic benefits due to its antioxidant and anti-inflammatory properties; recent findings suggest that it may have great potential in adjuvant therapy for leukemia.

RES can act as an autophagy modulator and apoptosis inducer in MOLT-4 and HL human leukemia cells It has also been shown to reduce the therapeutic doses of drugs, such as barasertib and everolimus, minimizing their side-effects on both leukemic and normal lymphocytes Recent findings suggest that CUR, in addition to its antioxidant and anti-inflammatory effects, may be a promising candidate for acute myeloid leukemia therapy A recent study provided in vivo evidence confirming its effect on the apoptosis and invasion of human acute leukemia SHI-1 cells, through activation of JNK and p38 and inhibition of ERK and NF-κB signals.

Furthermore, CUR may also downregulate the expression of MMP9 and MMP2 as well as vimentin, leading to suppression of the metastatic potency of SHI-1 EGCG exerts potent antitumor activity in hematological malignancies, including several types of leukemia.

There is a rich body of evidence suggesting that a diet rich in fruits and vegetables, mostly owing to the contribution of natural polyphenols, can reduce the incidence of specific cancers. Among the most extensively studied polyphenols are RES, EGCG and CUR.

Many of the effects attributed to these compounds are linked to their antioxidant and anti-inflammatory properties; however, the multiple mechanisms involved include the modulation of molecular events and signaling pathways associated with cell survival, proliferation, differentiation, migration, angiogenesis, hormonal activities, detoxification enzymes and immune responses Table II Future research directions can potentially expand upon the use of dietary-based polyphenols as whole foods, whole-food extracts or purified compounds, especially in combinations, as a potent and effective method in cancer prevention and adjuvant therapy.

Notwithstanding their promising role in cancer prevention and treatment, polyphenols often have a poor bioavailability when administered as pure active principles, representing an important limit to their use. Possible interactions with other natural compounds present in the diet can also influence their efficacy.

However, the bioavailability and thus efficacy of these compounds can be improved by the administration in combination with other phytochemicals, with anti-cancer drugs or in polyphenol-loaded nanotechnology-based delivery systems Particular attention should be paid to the safety of polyphenols.

It should be noted that some isoflavones, such as genistein and daidzein, seem to have hormone-related adverse effects on cancer.

Therefore, the use of these polyphenols in the treatment of cancer should be prudent. Research interest on the effects of dietary polyphenols on the intestinal microbiota and the relative mechanisms of action has only recently spread.

Dietary polyphenols seem to affect gut microbiota thanks to a bi-directional relation. On the one hand polyphenols can modulate the composition of microbiota; on the other hand, the microbiota is able to metabolize them into bioactive compounds.

However, it seems clear that correct eating habits, typical of the Mediterranean diet, characterized by a high intake of polyphenols, play an important role in the maintenance of intestinal functions Recently, significant steps forward have been made in the understanding of the alterations driving to cancer development and progression at a cellular, molecular and genetic level.

Relevant advances have been achieved also in the comprehension of the molecular mechanisms explaining the chemopreventive properties of specific polyphenols 45 , Nonetheless, evidence from human studies is still inadequate and trials often resulted inconclusive or discordant.

The main weaknesses of the studies conducted so far are the imprecise concentration of polyphenols in the tested foods or drinks, poor awareness of their kinetics and of the actual contribution of single compounds to their effect. Therefore, further clinical studies are warranted to support the use of polyphenols in the prevention and treatment of cancer.

GB, CC and CF substantially contributed to the conception and design of the study, revising it critically and providing final approval. MP, FG and SC were involved in the drafting, correction and revising the manuscript.

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Polyphenols constitute an important group of natural products that are traditionally Antioxidant-rich foods for digestive health with Polyphenos Antioxidant-rich foods for digestive health range of bioactivities. These are Polhphenols found PPolyphenols low Joint health awareness in natural propefties and Antioxidant-rich foods for digestive health anti-csncer available in nutraceuticals or dietary Polyphenol. A group znd polyphenols that include apigenin, quercetin, curcumin, resveratrol, EGCG, Polyphenlls kaempferol have Polypnenols Antioxidant-rich foods for digestive health to regulate signaling pathways that are anti-cabcer for cancer development, progression, and metastasis. Here, Hunger control solutions describe novel mechanistic insights on the effect of this group of polyphenols on key elements of the signaling pathways impacting cancer. We describe the protein modifications induced by these polyphenols and their effect on the central elements of several signaling pathways including PI3K, Akt, mTOR, RAS, and MAPK and particularly those affecting the tumor suppressor p53 protein. Modifications of p53 induced by these polyphenols regulate p53 gene expression and protein levels and posttranslational modifications such as phosphorylation, acetylation, and ubiquitination that influence stability, subcellular location, activation of new transcriptional targets, and the role of p53 in response to DNA damage, apoptosis control, cell- cycle regulation, senescence, and cell fate. Thus, deep understanding of the effects that polyphenols have on these key players in cancer-driving signaling pathways will certainly lead to better designed targeted therapies, with less toxicity for cancer treatment.

Author: Kejinn

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