Polyphenols and anti-cancer properties -
Transformed cells acquire new properties that can have a significant impact on local structures or the whole organism. Cells that proliferate acquire new properties e.
According to the WHO, cases will increase from 14 million to 27 million by , with a global fatality rate of Cancer is a complicated phenotype with an infinite replicative capacity unaffected by growth cues Zlatian et al.
The capability of cancer cells to avoid cell death activation, persistent angiogenesis, tissue invasion, and metastasis is unrivalled Docea et al. Considering this, metastasis is one of the primary causes of cancer-related mortality Javed et al.
However, a big part of cancer-related fatalities can be mitigated or averted by avoiding risk factors and following evidence-based preventative interventions Hossain et al.
Several medications and therapies such as chemotherapy and radiation have been used to treat cancer Rizvi et al. However, these treatments and drugs have adverse effects, such as developing drug resistance in patients over time and non-specific toxicity to normal cells Sharifi-Rad et al. As a result, developing a treatment that can achieve an objective measure of efficacy is critical; in this regard, plant-based drugs with established efficacy, fewer side effects, and safety are crucial Sharifi-Rad et al.
The polyphenols, either in individuals or in groups, can be used to design treatment or combined therapy with distinct molecular mechanisms, ultimately resulting in greater efficacy Azmi et al. Apart from their anti-cancer properties, polyphenols can also be used in conjunction with chemotherapy and radiotherapy Asensi et al.
This updated review deals with different anti-cancer potential activities viz. This review will be a valuable resource for developing secondary metabolite-based anti-cancer therapy.
FIGURE 1. Chemical structures of most representative polyphenols employed as anticancer agents. In the current comprehensive review, the anticancer properties of the polyphenols presented according to their molecular mechanisms of action were analyzed. In vitro and in vivo experimental pharmacological studies analyzed were processed to select the best data on the antitumor, anticancer, signaling and molecular anticancer mechanisms of polyphenols.
The most important obtained data were summarized in tables and figures. Quercetin exhibits multifactorial anti-tumor activity by decreasing cancer risk, growth, as well as the escalation of cancerous cells.
Quercetin represses tumor growth of a variety of cancer cell lines, including breast, colorectal, head, lung, ovarian, melanoma, and leukemia, in a dose-dependent manner Hashemzaei et al. TABLE 1. Anticancer perspectives of polyphenols along with their mechanism of action and signaling pathway.
Many experimental pharmacological studies have revealed that quercetin exerts the anti-tumor effect by changing the cell cycle, metastasis progression, angiogenesis, cell proliferation inhibition, and promotion of apoptosis, thus, affecting autophagy Tang et al. Additionally, the anti-tumor activity of quercetin involves the regulation of epigenetics in tumor cells, which further regulate mRNA expression, and DNA methylation.
Therefore, it increases the bioavailability of the drug to the tumor cell by the inhibition of BCRP, MRP1, and P-gp P-glycoprotein Kedhari Sundaram et al.
Anti-tumor property of quercetin is well depicted by its ability to interfere in various cellular signal pathways and inhibits enzymes responsible for carcinogens activation Rauf et al.
Moreover, quercetin-mediated apoptosis results from the induction of stress proteins, microtubule disruption, and cytochrome c release from mitochondria, followed by caspases activation Panthi et al.
Quercetin reduces the propagation of cancer cells via the inhibition of intracellular signaling, i. Quercetin induces apoptosis of cancer cells by modulating the modulation of survival signaling pathways Akt, NF- k B or regulatory molecules, which are linked to cell death Nguyen et al.
Various in-vitro and xenograft models have shown the inhibitory role of quercetin in the growth of cancers which are revealed in apoptosis promotion, inhibition of proliferation, angiogenesis, and metastasis, making it a potential antitumor agent Panthi et al.
Quercetin possesses its antitumor activity in a dose varied from 3 to 50 µM on numerous cell lines, i. The ability to trigger apoptosis of quercetin in cancerous cells makes this molecule an appealing preference for various cancer therapies Figure 2.
Quercetin arrests the cell cycle and induces apoptosis in conjunction with p53 phosphorylation, which stabilizes p53 at mRNA and protein levels in HepG2 cells. In HCT colon carcinoma cells, apoptosis of the tumor cells is caused by p53 to the quercetin-mediated expression of NAG-1 Gibellini et al.
FIGURE 2. Potential molecular targets and signaling pathways for the antitumor effect of polyphenols. H lung carcinoma cell line was discovered to have extra liable to cytotoxicity compared to the A lung carcinoma line Gibellini et al.
Quercetin exerted significant inhibition of cell proliferation and induction of apoptosis in human renal cell adenocarcinoma cells via the survivin mRNA inhibition, protein expression, and caspase 3 activation Reyes-Farias and Carrasco-Pozo, The proteasomal degradation of survivin takes place by quercetin, which in flip increases the concentration of cyclin B1 and p53 proteins, thereby enhancing surviving and p21 protein expression and inhibiting apoptosis Gibellini et al.
In prostate cancer cells, quercetin complements the TNF-associated apoptosis-inducing ligand TRAIL , which in turn causes apoptosis through induction of the expression of the death receptor DR The upregulation of DR-5 and downregulation of β-FLIP make contributions to the recuperation of TRAIL sensitivity which further inhibits hepatocellular carcinoma cells by the use of quercetin.
The superior TRAIL-caused apoptosis using quercetin takes vicinity via inhibiting the expression of the ERK-MSK1 pathway Gibellini et al.
In a recent study, the expansion of ovarian cancer cells was inhibited by quercetin by a mechanism related to TGF-β1 Shafabakhsh and Asemi, The effect of quercetin on tumor growth was analyzed in-vivo by angiogenesis and metastasis. Prostate tumor inhibition by quercetin in vivo in a mouse model is upregulated by the expression of Thrombospondin-1, which inhibits tumor propagation Yang F.
et al. Zhao et al. The cell death by EGCG is initiated by the intrinsic pathways in various cancers Table 1. Induction of apoptosis takes place through some pathways which incorporate intrinsic and extrinsic pathways, regulatory proteins, the strain on the endoplasmic reticulum through the activation of caspase-mediated pathways, death receptors, downregulation of several anti-apoptotic proteins, upregulation of Bad, and Bax pro-apoptotic proteins in human adrenal cancers cells Wu et al.
In cyclins, EGCG stops cyclin D1 and turns on p21, which in addition consists of ERK, IKK, and PI3K signaling pathways in which colorectal cancer cells are being inhibited from proliferating Rady et al. In cervical cancer, EGCG prevented the spread, invasion, and migration of HeLa cells via down-and upregulation of MMP-9 and TIMP-1 genes, respectively Sharma et al.
In colorectal-cancer-cell, EGCG activates caspase-3 for apoptosis, PARP, downregulation of STAT3 and phosphorylated STAT3 p-STAT3 , decreased Bcl-2 MCL-1, vimentin, along with the increase in E-cadherin Luo et al.
EGCG set up its important function for inhibition of glioma and showed Mitogen-activated protein kinase pathway MAPK involvement in apoptosis and proliferation Figure 2. EGCG treatment with TRAIL induces rapid apoptosis which could be a striking approach for treating several gliomas Li et al.
EGCG possesses an anti-tumor effect on various cancer cells in-vitro, including adrenal and breast. Cervical, colorectal, gastric, liver, lung, ovarian, prostate, and skin cancer cells Gan et al. Huang et al. The comparison of expression of P53 in the EGCG-combined with the si-P53 group revealed the enhanced expression of the former in the combination of EGCG than that of the si-P53 group.
Luo et al. Moreover, expression of HIF-1α protein in addition to vascular endothelial growth factor declined in cancer cells in a dose-dependent approach on pre-treatment with progressing concentrations of EGCG.
In ovarian cancer cell growth, EGCG was reported to show inhibition of growth in all cell lines in a dose-dependent manner; thereby, apoptosis and cell cycle arrest was triggered Kim et al. Wu et al. Another study suggested that the pro-EGCG remedy affected tumor angiogenesis in endometrial cancers.
Pro-EGCG contributes to the tumor angiogenesis inhibition in xenograft animal models which takes place through downregulation of vascular endothelial factor A, and HIF-1 α.
Pro-EGCG remedy reduced vascular endothelial factor A secretion from endometrial cancer cells. In EGCG-treated endometrial adenocarcinoma, the expressions of the sex hormones estrogen and progesterone receptor were decreased along with the decrease in MAPK signals and phospho-Akt.
An interesting study to assess the characteristic of EGCG effects on the metabolism of pancreatic adenocarcinoma cells was undertaken. Results found that the adenocarcinoma cells treated with catechin enormously suppressed lactate production and anaerobic glycolysis in addition to glucose consumption.
A pioneering examination confirmed the blended better antitumor reaction of curcumin plus EGCG on prostate cancer cells, which in any other case had been immune to chemotherapy, and apoptosis inducers.
The co-remedy of EGCG and curcumin enhanced the protein expressions of p However, their expression was unchanged on treatment with each compound alone Eom et al.
An in-vitro look on bladder cancer cells showed that EGCG prompted morphological modifications and inhibition in a dose- and time-established fashion.
In addition, EGCG-treated with bladder tumor cells found sub-G1 populations similarly to activation of caspase-3 and In-vivo findings tested that EGCG brought about cell arrest in the G1 phase, and apoptosis was induced via ROS generation Lu et al. Sur et al. Findings revealed that both the compounds in combination limited the hepatocellular carcinoma development at the 30th week after the carcinogen had been given, depicting their potential chemopreventive action in the continuous treated group than in the post-treated group.
EGCG has a defensive effect on the growth, liver, and pulmonary metastases of colon cancers in nude mice by the activation of the Nrf2-UGT1A signal pathway Almatroodi et al. A phase I study on the safety and effectiveness of EGCG mouthwash was performed, which was given in addition to radiation in head and neck cancer episodes.
The assigned dose of EGCG mouthwash was directed in a standard 3 plus 3 dose-escalation design. EGCG administration decreased oral mucosal injury in patients Zhu et al.
Curcumin activates the formation of ROS, enhances intracellular calcium levels, and changes cell membrane potential, which further activates apoptotic pathways in tumor cells Liu and Ho, Curcumin disrupts the maintained stability of the mitochondrial membrane, inflicting the elevated suppression of the Bcl-2 and Bcl-xL apoptotic protein expression Tomeh et al.
Overall, the anti-tumor activity of curcumin in the cell causes an increase in growth suppressor factors, decreases associated proliferative pathways, and Wnt-βcatenin, acts on angiogenesis VEGF , and enhances apoptosis Allegra et al.
Curcumin has anti-cancer properties against breast cancer on Her2-positive cell lines SKBR3 and BT , having a lower inhibitory concentration IC 50 for curcumin compared to triple-negative cell lines. The decrease in IC 50 is directly proportional to the expression of ER rather than Her2.
ER-negative cell lines, i. When treated with curcumin, the malignant colorectal cells reduce M 1 G levels without any significant change in COX-2 protein levels. 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. For mouse antibodies we used ILAPC Cat. Cells were analysed by flow cytometry using the BD FACSCanto II. Statistical analysis was performed with the GraphPad Prism software V9.
Flow cytometry analysis was performed using the BD FACSDiva software v8. In western society, cancer is the leading cause of death affecting 1 in 3 individuals and constitutes a major threat to public health.
Amongst the many potential contributors to the complexity of the disease are genetic, environmental and behavioral factors.
Physical inactivity and poor diet play a major role in cancer development [ 26 — 29 ]. Polyphenols, found in common dietary foods, have been shown to have anti-cancer properties and are powerful therapeutics against cancer.
Polyphenols have an array of anti-cancer properties including inhibition of gene expression, angiogenesis, metastasis and reduction of cell proliferation [ 30 ].
The mechanism of action have been well established for some of the best studied polyphenols i. resveratrol, kaempferol, quercetin , and their anti-proliferative effects is due to anti-VEGFmediated anti-angiogenic properties [ 31 ].
Here, we show anti-proliferative effects on cancer cell lines in the presence of PRSE, rich in polyphenols, and elucidate some mechanistic attributes to their anti-proliferative properties.
Polyphenols from an array of food sources such as honey, virgin argan oil, green tea, blackberries and pomegranate juice have been shown to have anti- proliferative, pro-apoptotic, anti-angiogenic, anti-oxidant effects to cancer cell lines [ 32 — 35 ].
Commercial sugar cane bagasse cultivated in Brazil containing high levels of phenolic compounds are cytotoxic to cancer cell lines and inhibits cell growth [ 36 ].
Isolation of phenolics from sugar cane bagasse showed that luteolin, p-courmaric acid and protocatechuic acid had anti-proliferative effects [ 37 ]. Culturing a number of mouse and human cancer cell lines in the presence of PRSE showed anti-proliferative activity.
Anti-proliferative effects were not noted in T human normal colon epithelial cell line at all PRSE doses tested. However, anti-proliferative effects in a dose-dependent manner were evident in the human colon cancer cell line LIM and the 2 mouse colon cancer cell lines, MC38 and CT PRSE had no anti-proliferative effect to the human colon cancer cell line HT Absorbance was measured at each time point at nm.
PRSE had no anti-proliferative effect on the human breast cancer cell line ZR As U cells are non-adherent cells, they pelleted in the U-bottom wells prior to imaging, so pellet size is representative of cell number Fig 2.
Scale bars represent um, with images at 10x magnification. Cytokines are known to play pivotal roles in cancer initiation, progression and pathogenesis.
These cytokines may be secreted by immune cells or by the cancer cells themselves. Changes to cytokines secreted by cancer cell lines were assessed in the presence and absence of PRSE. Cells were isolated and analysed by flow cytometry for the expression of intracellular TNF-α, VEGF-1, and lysates were prepared from the same samples for analysis of NF-κB expression by ELISA.
Supernatants were also collected and analysed for cytokine secretion using the 8- or 9-plex bioplex cytokine bead array kit. Cultured supernatants were used in the bioplex assay for the determination of secreted cytokines IL-1, IL-2, IL-4, IL-6, IL-8, IL, TNF-α, IFN-γ.
All cytokines were detected and secreted in the cultured supernatants of the human cancer cell lines, A lung cancer , LIM colon cancer and SKOV-3 ovarian cancer , however, the only cytokines which showed significant differences between PRSE treated yellow bars and untreated blue bars were IL-4 and IL-8 Fig 3.
Although IL-4 is known as an anti-inflammatory cytokine and induces Th2 type immune responses, it has been shown to have paradoxical roles in cancer. IL-4 has been shown to possess anti-tumor activity by inhibiting cell growth and inducing apoptosis, whilst other studies have shown IL-4 to stimulate tumor cell growth and proliferation [ 38 ].
In fact, IL-4 has been shown to enhance proliferation of human pancreatic cancer cells via MAPK, Akt-1 and Stat-3 pathways [ 39 ]. IL-4 has also been shown to enhance proliferation of breast cancer cells and blocking IL-4 compromises breast cancer cell proliferation, invasion and growth.
In thyroid cancer tissue, high levels of endogenous IL-4 are noted which contributes to cancer cell survival. Culturing human colon cancer cell line LIM in the presence of PRSE decreased the secretion of IL-4, and may contribute to PRSE reducing LIM cell proliferation. IL-8 is a pro-inflammatory cytokine and involved in chemotaxis.
Expression of IL-8 by cancer cells aids angiogenesis, increases proliferation and survival of cancer cells and promotes tumor escape from immune cells [ 40 ].
In addition, expression of IL-8 by cancer cells is associated with poor prognosis in cancer patients. PRSE decreased the secretion of IL-8 by human lung cancer cell line, A, suggesting that PRSE exerts anti-cancer effects via downregulation of IL IFN-γ plays an important role in promoting innate and adaptive immune responses [ 41 ].
IFN-γ in cancer cells has been shown to be anti-proliferative and provide protection against tumor development. In mouse colon cancer cell line CT26 and mouse melanoma cell line B16, no significant changes of cytokines IL-1β, IL-2, IL-4, IL-5, IL-6, IL, GM-CSF and TNF-α were noted in the presence of PRSE or ibuprofen.
However, there was a significant increase in IFN-γ production by the mouse colon cancer cell line CT26 in the presence of PRSE increase from Exogeneous IFN-γ was previously shown to have strong anti-proliferative activity in 15 different cancer cell lines [ 42 ].
TNF-α plays dual functions in cancer cells, where in some cases it induces apoptosis and necrosis, and in others it promotes tumor growth. However, there is strong evidence that TNF-α is pro-tumorigenic, promoting progression and metastasis of cancer cells [ 43 ].
In fact, targeting transmembrane TNF-α with an anti-TNF-α monoclonal antibody, suppresses growth of breast cancer cells [ 43 ]. In our analysis of intracellular cytokine expression in cancer cell lines, only one positive sample was found, albeit weakly; TNF-α expression in mouse CT26 colon cancer cells which was reduced by PRSE.
PRSE decreased intracellular expression of TNF-α by It is possible that one of the anti-proliferative mechanisms of PRSE may be due to the decreased TNF-α expression.
Vascular endothelial growth factor VEGF-1 is a signal protein expressed by cells that initiates angiogenesis development of new blood vessels. Cancer cells express VEGF in order to help receive adequate blood supply to support their rapid growth. Cancer patients have overall reduced survival if their tumor is shown to overexpress VEGF-1 [ 44 ].
PRSE was shown to decrease VEGF-1 expression by This has also been shown in other polyphenol rich food sources such as, extra virgin olive oil, red wine and green tea [ 45 — 47 ]. NF-κB controls gene transcription, thereby regulating cytokine production and cell survival. It is involved in cancer development, and in many solid tumors, increased expression of NF-κB is noted.
Activation of NF-κB is a result of an inflammatory microenvironment during cancer progression. We therefore determined the effects of PRSE on NF-κB expression by cancer cell lines A, B16, CT26, LIM, SKOV Ibuprofen was used as a control, however, it did not prove to be a good positive control for decreased NF-κB expression in all cancer cell lines.
There was no decrease in NF-κB expression in A human lung cancer or LIM human colon cancer cell lines. Some other plant polyphenols have also been shown to decrease NF-κB expression such as those present in green tea [ 17 ].
Annexin-V is a calcium-dependent phospholipid-binding protein, which binds to phosphatidylserine PS exposed on apoptotic cells. Annexin-V stains cells early in apoptosis, whereas propidium iodide PI stains apoptotic cells at a much later-stage cell death.
Human ovarian cancer cell line, SKOV Thus, in this cell line, PRSE increases the proportion of cells undergoing cell death. Human colon cancer cell line LIM PRSE increased the percentage of cells undergoing apoptosis from 0.
Mouse colon cancer cell line MC Hence, PRSE has no effect on cell death, but induces apoptosis to a proportion of MC38 cells. Mouse melanoma cell line, B There were no significant effects of PRSE on apoptosis of human lung cancer cell line A and mouse colon cancer cell line CT In this study we demonstrate an anti-cancer effect of PRSE in a number of different cell lines.
The data shown in our study will contribute towards understanding the efficacy and activity of nutraceuticals extracted from sugarcane, and further detailed mechanism studies, such as next generation sequencing and bioinformatics are warranted to understand the full spectrum of PRSE actions and pathways activated and downregulated in the presence of PRSE.
The authors would like to thank the support from the Institute for Health and Sport and the Immunology and Translational Group within the Mechanisms and Interventions in Health and Disease Program, Victoria University, Melbourne Australia.
JF was supported by University of Melbourne postgraduate scholarship. Browse Subject Areas? Inoue M, et al. Regular consumption of green tea and the risk of breast cancer recurrence: follow-up study from the hospital-based epidemiologic research program at Aichi Cancer center HERPACC , Japan.
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Editor-in-Chief: Atta-ur-RahmanFRS Polyphenols and anti-cancer properties Life Fellow Kings College University of Cambridge Polyphenosl UK. ISSN Anti-csncer : ISSN Online : X. Page: [ - ] Pages: DOI: Polyphenols are a group of water-soluble organic compounds, mainly of natural origin. The compounds having about aromatic rings and more than 12 phenolic hydroxyl groups are classified as polyphenols. Metrics details. Chemotherapeutic anti-caner are used to treat advanced xnti-cancer of cancer or propertiez Best energy supplements. However, cancers proeprties develop resistance Food insecurity solutions drugs, leading to Polyphenols and anti-cancer properties of treatment and recurrence of the Safe weight management. Polyphenols are a Best energy supplements of organic compounds with more than 10, members which have a three-membered flavan ring system in common. These natural compounds are known for their beneficial properties, such as free radical scavenging, decreasing oxidative stress, and modulating inflammation. Herein, we discuss the role of polyphenols mainly curcumin, resveratrol, and epigallocatechin gallate [EGCG] in different aspects of cancer drug resistance. Increasing drug uptake by tumor cells, decreasing drug metabolism by enzymes e.Polyphenols and anti-cancer properties -
Chemotherapeutic drugs are used to treat advanced stages of cancer or following surgery. However, cancers often develop resistance against drugs, leading to failure of treatment and recurrence of the disease. Polyphenols are a family of organic compounds with more than 10, members which have a three-membered flavan ring system in common.
These natural compounds are known for their beneficial properties, such as free radical scavenging, decreasing oxidative stress, and modulating inflammation. Herein, we discuss the role of polyphenols mainly curcumin, resveratrol, and epigallocatechin gallate [EGCG] in different aspects of cancer drug resistance.
Increasing drug uptake by tumor cells, decreasing drug metabolism by enzymes e. cytochromes and glutathione-S-transferases , and reducing drug efflux are some of the mechanisms by which polyphenols increase the sensitivity of cancer cells to chemotherapeutic agents.
Polyphenols also affect other targets for overcoming chemoresistance in cancer cells, including cell death i. autophagy and apoptosis , EMT, ROS, DNA repair processes, cancer stem cells, and epigenetics e. Localized solid tumors are often treated with surgery in their early stages.
Advances made in the field of antitumor agents have led to a significant increase in patients' life quality and disease-free survival [ 2 ].
Despite the importance of chemotherapeutic drugs, there are significant drawbacks in using them to treat cancer, such as solubility and instability of drugs, nonspecific drug delivery, and adverse effects due to systemic toxicity [ 3 ].
Furthermore, recurrence and relapse of cancer occur in some patients even after a favorable response at the beginning of the treatment. Indeed, acquired drug resistance has become an important challenge that results in the failure of cancer treatment [ 2 ].
Both acquired and intrinsic processes can lead to chemoresistance in cancer cells [ 4 ]. Acquired drug resistance indicates a newly developed resistance against a therapeutic approach 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 that are responsible for heterogeneity.
There are various cell generations within one tumor, 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 response [ 6 , 7 , 8 ].
Increased drug efflux, changes in the target of drugs, apoptosis, and repair signaling pathways are other mechanisms involved in the resistance of cancer cells to chemotherapeutic drugs [ 4 , 9 ].
Polyphenols are a large family of 10, plant compounds that are known for their common structural features including the three-membered flavan ring system and multiple phenol units [ 10 , 11 ]. These natural compounds are mostly found in fruits, green and black tea, coffee, red wine, cocoa, and seeds [ 12 ].
These beneficial organic agents are categorized into several subclasses including catechins, flavonoids which contain flavonols, flavanols, and flavones , anthocyanins, catechins, isoflavones, chalcones, curcuminoids, and phenolic acids structures are shown in Fig. Schematic representation of different structures of polyphenols.
These agents have a three-membered flavan ring system in common. The idea of using polyphenols for treating cancer patients is not new. Early studies considering the anti-cancer effects of different polyphenols were conducted in the late twentieth century and our knowledge on these advantageous agents has been widely improved since then [ 14 , 15 ].
What makes these agents greatly beneficial and interesting is that they attack cancer cells in a variety of ways and confront many cancer hallmarks summarized in Fig. Some of the anti-cancer effects of polyphenols including epigenetic, anti-metastatic, pro-apoptotic, and anti-oxidant impacts.
The anti-oxidant impacts of polyphenols are possible through either scavenging free radicals or building a barrier against their generation Fig. The main free radicals that exist in our cells and cause oxidative stress are reactive oxygen species ROS and reactive nitrogen species RNS [ 16 ].
This occurrence stabilizes free radicals and prevents them from damaging the cellular components [ 17 ]. It seems that the B ring of polyphenols plays the most important role in scavenging hydroxyl, peroxyl, and 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 NOS , xanthine oxidase XO , and peroxidase are some of these enzymes, whose activity can be altered when certain interactions occur between them and polyphenols [ 19 , 20 ].
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 [ 25 , 26 , 27 , 28 ].
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 [ 37 , 38 , 39 , 40 , 41 , 42 ].
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 [ 40 , 44 , 45 ].
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 [ 47 , 48 , 49 ]. According to research, matrix metalloproteinases MMPs , TGF-β, and TP53 have essential roles in managing metastasis [ 47 , 48 , 49 ].
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 [ 51 , 52 , 53 , 54 , 55 ].
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 [ 60 , 61 , 62 , 63 ]. 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 [ 64 , 65 ]. 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 [ 71 , 72 ].
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 [ 75 , 76 , 77 , 78 ]. miR, miR, miRb-3p, and miRa are some of the miRNAs regulated by quercetin in cancerous cells [ 79 , 80 , 81 , 82 ].
Epigallocatechingallate, genistein, and DIM also contribute to reversing epigenetic alterations in cancer cells via diverse microRNAs [ 83 , 84 ]. 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 A , a xenograft model of nude mice, and cisplatin cDDP -resistant A cells.
It was found that hsa-mirp inhibits expression of the CTR1 gene. Meanwhile, lncRNA nuclear enriched abundant transcript 1 NEAT1 increases the expression of NEAT1. Indeed, NEAT1 is suggested to increase EGCG-induced CTR1 through sponging hsa-mirp. Therefore, EGCG enhances the sensitivity of NSCLC cells to cisplatin both in vitro and in vivo [ 95 ].
MRP1 regulates both absorption and disposition of various xenobiotic and endogenous substrates, such as drugs, across different physiological barriers [ 96 ]. Treating this chemoresistant cell line with resveratrol leads to a reduction in MRP1 expression.
Furthermore, the absorption of the MRP1 substrate 5 6 -carboxyfluorescein diacetate is reported to be enhanced by resveratrol.
Therefore, it is suggested that resveratrol may enhance DOX cellular absorption by reducing the gene expression of MRP1 [ 97 ].
The main cause of multi-drug resistance in cancer cells is the increased efflux of antitumor agents through drug transporters which are embedded in the membrane [ 98 ]. P-gp is a pump involved in drug efflux and is associated with multi-drug resistance [ ]. Didox is a polyhydroxyphenol that serves as a chemo-sensitizer.
In HCT colorectal cancer cells, the combination of didox and resveratrol with DOX leads to the reduction of DOX IC 50 from 0. Both didox and resveratrol significantly increase DOX intracellular entrapment by preventing the efflux effect of p-gp [ ]. EGCG is shown to modulate p-gp function and enhance the intracellular entrapment of DOX in drug-resistant KB-A1 cells.
Indeed, combination of 50 μM of EGCG with 10 μM DOX for 4 h increases the DOX intracellular concentration by 2. Furthermore, in vitro studies and xenograft models confirmed that EGCG enhances the antitumor activities of DOX in drug-resistant tumors [ ].
Liang et al. Meanwhile, lower doses of the mentioned compounds with DOX lead to significant suppression of HCC cell proliferation in vitro as well as growth of hepatoma in a mouse xenograft model compared to administration of either agent alone. Using EGCG or ECG in combination with DOX increases the intracellular accumulation of DOX, suggesting that catechins suppress the activity of the P-gp efflux pump.
Furthermore, this combinational treatment enhanced the intracellular retention of a P-gp substrate, rhodamine , while reducing the expression of mRNA of HIF-1α and MDR1 [ ]. Therefore, the repair of DNA damage can be inhibited by suppressing this signaling pathway, which, in turn, increases the sensitivity to radio- and chemotherapy [ ].
Resveratrol exerts this potentiating effect by suppressing the activity of p-gp and lowering mRNA and protein levels of p-gp. Through active drug efflux, MRP5 causes drug resistance against gemcitabine and 5-fluorouracil 5-FU.
Curcumin is shown to increase the sensitivity of MRP5 over-expressing HEK, PANC-1, and MiaPaCa-2 cells to 5-FU. Therefore, it is suggested that curcumin can act as an inhibitor of MRP5 while reversing multidrug resistance in pancreatic cancer [ ]. It is observed that curcumin treatment leads to an increase in DOX intracellular accumulation.
The mentioned effect is negatively associated with the activity of ATP binding cassette subfamily B member 4 ABCB4. Treating cells overexpressing ABCB4 with DOX and curcumin reduces DOX efflux.
In addition, ABCB4 ATPase activity is suppressed by curcumin without any changes in its protein expression Evidence has indicated that following treatment with antitumor agents, some cell-protective gene products are induced.
In phase I and phase II of drug metabolism, some enzymes are involved which are useful for the detoxification from harmful endogenous and exogenous compounds. In phase I of drug metabolism, different cytochrome isoforms are involved, including CYP1A2, CYP1A6, CYP1B1, CYP2B6, and CYP2C19 [ ].
Curcumin treatment also significantly increases the bioactivity of tamoxifen. It is suggested that curcumin may suppress the cytochrome-mediated metabolism of tamoxifen to 4-hydroxyfamoxifen, an active metabolite of tamoxifen, as evidenced by the reduced metabolite-parent AUC ratio.
Therefore, curcumin-mediated enhanced bioavailability of tamoxifen is probably mediated by the suppression of tamoxifen metabolism in the liver and the small intestine [ ]. Gamma-glutamyl transferases GGTs , thiopurine methyltransferases TPMTs , glutathione- S -transferases GSTs , dihydropyrimidine dehydrogenases DPDs , and uridine diphospho-glucuronosyltransferases UGTs are enzymes playing roles in phase II of drug metabolism.
The altered expression of these enzymes may cause multidrug resistance in cancer cells [ , ]. Curcumin is shown to reduce the activity of gamma-glutamyl transpeptidase GGTP in ZR mammary cells which are resistant to oxidative damage [ ].
Studies have reported that a moderate reduction in the levels of glutathione can enhance the sensitivity of tumor cells to chemotherapeutic agents [ ]. GSTs are observed to be overexpressed in different cancers e. cancers of breast, liver, and lung and lead to drug resistance [ , , ].
Therefore, suppressing GST is suggested to help overcome cancer resistance to chemotherapeutic drugs. Derivatives of flavonoids e. baicalin, phloretin, baicalein, and phloridzin are reported to be related to the suppression of GST functions [ ].
Curcumin and ellagic acid are capable of inhibiting GSTs M, M, A, A, and P while using 1-chloro-2,4 dinitrobenzene CDNB as a substrate [ ].
Curcumin analogs i. However, their inhibitory effects on GTS A, GTS M, and GST P are smaller compared to curcumin [ ]. Galangin is a flavonoid that suppresses the cellular activity of GST P at a concentration of 25 μM in GST P transfected MCF-7 breast cancer cells.
Quercetin, kaempferol, and eriodictyol are other flavonoids that moderately inhibit the activity of GST P Most flavonoids mainly quercetin and luteolin are shown to inhibit GS-X pump transport.
However, flavonoids without a C2—C3 double bond e. catechin and eriodictyol do not suppress the activity of the GS-X pump [ ]. Epigenetic modification indicates some reversible changes in the expression of genes without causing changes in the sequence of DNA [ ].
Mechanisms involved in epigenetics are capable of driving acquired cancer resistance against chemotherapeutic drugs. Epigenetic alterations occur at a high rate in tumors, leading to the diverse patterns of gene expression that cause drug resistance [ ].
Since drug resistance can be reversed and it shows rapid kinetics and absence of genetic mutations, epigenetic mechanisms may be involved in insensitivity to drugs [ ]. Epigenetic processes form different states of transcription which lead to a dynamic heterogeneous nature in the population of tumor cells [ ].
As already mentioned, there are a number of mechanisms leading to epigenetic alterations, among which the role of miRNAs in the development of drug resistance in cancer is greatly investigated [ , , ].
Therefore, targeting epigenetic changes and miRNAs with polyphenols may be a potential approach to overcome cancer drug resistance. DNA methylation by resveratrol has been explored by a very limited number of studies.
Zadi Heydarabad and colleagues showed that DNA methylation of BAX and BCL2 genes in a T-cell acute lymphoblastic leukemia cell line, CCRF-CEM, can be detected after resveratrol treatment by a methylation-specific polymerase chain reaction technique.
They suggested that this observation might explain the effect of resveratrol in sensitizing ALL cells to apoptosis [ ]. In another study, the effect of resveratrol on retinoic acid resistance in the anaplastic thyroid cancer cell line THJT and the human medulloblastoma UW cell line showed that resveratrol not only demethylates the cellular retinoic acid binding protein 2 CRABP2 promotor but also decreases the amounts of some DNA methyltransferases such as DNMT1, 3A, and 3B [ ].
Despite these studies, Zadi Heydarabad et al. From another point of view, resveratrol induces apoptosis and enhances chemosensitivity to Adriamycin in MCF-7 breast cancer cells. It has been shown that the mentioned effects of resveratrol are inhibited by modulation of miRp, which is a critical suppressor.
Moreover, modulation of miRNA by inhibitors or mimics of miRp demonstrate that miRp is involved in the regulation of CDKs i. CDK2, CDK4, and CDK6 and anti-apoptotic factors e. BCL-2 following resveratrol treatment [ 77 ].
Quercetin with a concentration of 5 μM improves the sensitivity of osteosarcoma B cells to cisplatin. Furthermore, it upregulates miR expression while downregulating the expression of KRAS, which is the miR target.
Moreover, knockdown of miR is shown to hinder quercetin-induced increased sensitivity to cisplatin. In the U MG glioblastoma cell line, curcumin increases expression of miRa and enhances temozolomide-induced apoptosis.
However, miRa inhibits the enhanced anti-tumor action of temozolomide which is induced by curcumin. Meanwhile, upregulation of miRa inhibits the activation of NF-κB and increases apoptosis in cells treated with temozolomide [ ].
According to evidence, curcumin is one of the most important polyphenols in regulating epigenetic alterations of cancerous cells [ 73 , 74 ]; nonetheless, its efficacy in sensitizing tumoral cells to chemotherapeutic drugs is still controversial.
In an in vitro study on the SiHa cell line, Roy and Mukherjee found that curcumin increases the effect of cisplatin on cervical cancer cells through several mechanisms including inhibition of histone deacetylase 1 HDAC1 [ ]. Royt et al. also confirmed that histone deacetylase can be decreased after curcumin treatment in the MCF-7 ER positive cell line [ ].
Despite the small number of studies on DNA methylation and histone modification after curcumin treatment, the role of this agent in microRNA regulation has been intensively studied. Resistance to cisplatin in the Acp ovarian cancer cell line can be reduced indirectly by curcumin: demethylation in the promoter region of MEG3 occurs after curcumin usage, which leads to the down-regulation of miR This microRNA is able to establish chemoresistance through increasing the capability of extracellular vesicles [ ].
Decreased resistance to is also observed after treating Adr-resistant MCF-7 cells with curcumin-encapsulated liposomes [ ]. Curcumin decreases the resistance to Adriamycin via altering the expression of some microRNAs including miRbp [ ].
Overcoming Adriamycin-resistance has also been examined in human acute myeloid leukemia cells HL [ ]. microRNAa is another microRNA whose down-regulation can result in lower resistance to 5-fluorouracil in SW colon cancer cells [ ]. Curcuminoids 2. The metastasis-associated gene 1 MTA1 gene is reduced in these cells due to the up-regulation of microRNAc by curcumin in vitro [ ].
Similar to cell growth and division, a key component of homeostasis is programmed cell death. Apoptosis, necrosis, and autophagy are three types of programmed cell death that are involved in development [ ].
Several studies have been conducted on the underlying mechanisms of apoptosis in the past two decades. These investigations demonstrate that apoptosis involves different signaling pathways which are associated with survival pathways and change the phenotype of cells, such as drug resistance [ ].
Apoptosis is a programmed cell death that removes aged and damaged cells from the body. In cancer, apoptotic signaling is dysregulated.
Indeed, anti-apoptotic pathways are activated in cancer cells, which results in uncontrolled proliferation of cells, leading to drug resistance and tumor recurrence [ ]. Autophagy is a mechanism of homeostatic cellular recycling which is involved in the response to therapeutic and metabolic stresses.
By autophagy, the body tries to maintain or restore the homeostasis of metabolism via catabolic lysis [ ]. Evidence has shown that cancer therapeutic approaches are capable of inducing autophagy.
Meanwhile, autophagy is demonstrated to enhance the survival of tumor cells and lead to therapy resistance in some cases [ ]. Gefitinib is an epidermal growth factor receptor EGFR tyrosine kinase inhibitor TKI which is used for treating patients with NSCLC. However, cases with wild-type mutations of KRAS and EGFR are resistant to this therapeutic agent.
Curcumin is shown to increase the anti-tumor effects of gefitinib against the H and H gefitinib-resistant NSCLC cell lines. Treating these cells with the combination of curcumin and gefitinib leads to the induction of autophagy and autophagy-mediated apoptosis.
Pharmacological inhibitors of autophagy, 3-MA, or Bad A1 are also shown to reverse the synergistic effect of curcumin and gefitinib [ ]. Resveratrol exerts anti-tumor effects against human oral cancer CAR cells while showing low toxicity in normal oral cells. As evidenced by acridine orange AO and monodansylcadaverine MDC staining, resveratrol treatment leads to the formation of autophagic vacuoles and acidic vesicular organelles.
Furthermore, resveratrol induces expression of autophagy-related genes at the mRNA level, including Beclin-1, Atg5, Atg12, and LC3-II. It also leads to apoptosis as evidenced by DNA condensation or DNA fragmentation. Resveratrol-induced cleavage of caspase-3 and -9 as well as apoptosis is reduced by Z-VAD-FMK, a pan-caspase inhibitor.
Moreover, inhibitors of PI3K class III and AMPK 3-MA and compound c, respectively lead to inhibition of autophagic vesicle formation and protein levels of LC3-II [ ].
As evidenced by fluorescence staining and cytometry, quercetin induces apoptosis in these cells. Apoptosis is paralleled by mitochondrial cytochrome c release to the cytosol, reduced mitochondrial membrane potential, Akt dephosphorylation, upregulation of caspase-3 and Bax as well as downregulation of p-Bad and Bcl Notably, constitutive activation of Akt hinders quercetin-mediated Akt and Bad dephosphorylation as well as degradation of poly ADP-ribose polymerase PARP [ ].
Quercetin treatment enhances the apoptosis of tumor cells. Indeed, it increases the expression of Bclassociated death promotor, Bclinteracting mediator of cell death, and Bclassociated X protein. Also, it reduces the potential of mitochondrial membrane potential as well as expression of Bcl-2 while activating caspase-3, -8, and -9 [ ].
In cisplatin-resistant oral cancer CAR cells, EGCG induces apoptosis and autophagy. EGCG increases the protein levels of cleaved caspase-3 and -9 as well as their activities.
Additionally, it enhances the protein levels of Bax, Beclin-1, LC3B-II, Atg5, Atg7, and Atg Meanwhile, it decreases the Bcl-2 expression, STAT3 phosphorylation of Tyr, and Ser phosphorylated AKT. The expression of multidrug resistance 1 MDR1 is also suppressed by EGCG at gene and protein levels [ ] Table 1.
DNA damage response DDR is a collection of mechanisms involved in detecting DNA damage and signaling it, which lead to either DNA repair processes or cell death pathways [ , ]. DDR plays a protective role for the human genome against damage through removing errors and inhibiting mutation insurgence under physiological conditions.
However, DNA repair systems work in favor of tumor cells following treatment with DNA damaging agents, causing failure in treatment [ ]. Moreover, in vivo examination of this agent in 20 female athymic mice showed that EGCG octaacetate, an EGCG prodrug, improves the efficacy of platinum-based chemotherapy [ ].
Thymidine phosphorylase is an enzyme in the pyrimidine salvage pathway which hinders DNA damage-induced cell death in cancer cells [ ]. Curcumin treatment reduced the expression of thymidine phosphorylase at mRNA and protein levels in non-small-cell lung cancer.
A similar study also indicated that demethoxycurcumin is able to decrease the resistance to cisplatin by means of downregulating ERCC1 in non-small cell lung cancer both in vitro and in vivo [ ].
Cisplatin exerts its antitumor effects through the formation of intra- and inter-strand cross-links of DNA, leading to blockade of DNA replication. Furthermore, curcumin decreases the cisplatin-induced mono-ubiquitination of FANCD1 and formation of nuclear foci.
BRCA1 and RAD51 are two proteins leading to homologous recombination HR and thereby repair of double-strand DNA breaks [ ]. Resveratrol enhances the antitumor effects of cisplatin in MCF-7 and chemo-resistant MCF-7 MCF-7R breast cancer cells.
Data demonstrated that resveratrol at a concentration of μM reduces the protein levels of Rad51 and transcript levels of components of the HR initiation complex. It has been observed that following 48 h of DNA damage induced by cisplatin, Rad51 protein levels are increased. However, resveratrol suppresses the upregulation of Rad Also, resveratrol sustains the phosphorylation of histone H2AX at serine , implying the inhibitory effect of resveratrol on the repair of double-strand breaks DSBs [ ].
Investigations on almost all types of cancer have revealed that CSCs are responsible for decreasing the tumor response to both chemo- and radiotherapy [ , , , , , , , , , , , ].
It seems that slowing down the cell cycle, having anti-apoptotic machinery, a high capacity for repairing DNA damage, the potency of establishing a proper environment for cancer growth, and stemness features are the main reasons why CSCs provide resistance to our common therapies [ , , , ].
Overall, targeting CSCs is a suitable approach for decreasing tumor resistance and increasing the efficacy of our common therapies. Considering polyphenols for targeting this population of cells has recently given a new insight for treating resistant cancers. A line of research conducted on curcumin showed the anti-CSC characteristics of this agent in colon [ ], pancreatic [ ], liver [ ], breast [ 50 ], and brain [ ] cancers.
Curcumin treatment administered for cancerous cells of the colon resulted in lower levels of CSC markers such as CD44, CD, and CD24 and lower ability of CSCs to form a sphere [ ]. Additionally, curcumin triggers apoptosis in CSCs either administered alone or with irinotecan CPT and thereby decreases resistance to this chemotherapeutic drug [ ].
Decreasing the stemness features of CSCs through inhibiting the enhancer of zeste homolog-2 EZH2 subunit of polycomb repressive complex 2 PRC2 is also attributed to curcumin [ , ]. Inhibiting a long non-coding RNA named PVT1 is how curcumin sensitizes pancreatic cancer cells to gemcitabine [ ].
Other than that, stemness-related genes including Nanog, Sox2, and Oct4 are also prone to be affected by curcumin [ 50 ]. Another mechanism by which curcumin decreases chemoresistance is its ability to decrease antiapoptotic protein levels and increase proapoptotic protein levels in CSCs [ ].
The former proteins include Bcl-2 and Bcl-w and the latter ones include Bax, Bak, Bad, Bik, and Bim. In this way, the resistance of breast cancer to mitomycin C can be diminished [ ]. Nanomedicine can also be effective in treating brain cancer with curcumin [ ].
Curcumin-loaded nanoparticles grafted with anti-aldehyde dehydrogenase not only increased the permeability of curcumin through the brain-blood barrier but also provided a steady release of this polyphenol [ ].
An in vivo study conducted by Zhou et al. Epigallocatechingallate is another member of the polyphenol family which is also able to reverse some of CSC characteristics including renewal and migration in nasopharyngeal cancer cells [ ]. Baicalin is a flavone whose role in EMT has been investigated on an osteosarcoma cell line: it can inhibit the EMT-inducing transcription factors Snail1 and Slug and thereby reduce the anoikis-related resistance [ ].
An in vivo study conducted by Toden and colleagues also corroborated the anti-resistance effects of EGCG on cancer stem cells. They observed that 5FU sensitivity could be achieved when EGCG suppressed colorectal cancer stem cells through affecting the Notch signaling pathway and increasing the levels of tumor suppressive microRNAs [ ].
Through altering the hemostasis of redox, cancer cells enhance chemoresistance. Different processes are involved in chemoresistance mediated by redox which includes increased progression of the cell cycle, autophagy mediated by endoplasmic reticulum stress, increased numbers of cancer stem-like cells, and enhanced conversion to metastasis [ ].
ROS exert several functions in cancer cells, such as regulating proliferation, apoptosis, and survival. Compared to normal and non-multidrug-resistant cancer cells, ROS levels and the activity of antioxidant enzymes are increased in cancer cells that are resistant to chemotherapeutic agents.
Therefore, changes in ROS levels may have a greater impact on multidrug-resistant cancer cells. Studies have shown that agents modulating the generation of ROS are potentially useful for treating patients with multidrug-resistant cancer [ ].
The thioredoxin Trx system has three key members which are NADPH, Trx, and thioredoxin reductase TrxR. This system, which is involved in the regulation of redox, has been shown to play a role in the development and progression of cancer.
Indeed, high expression levels of Trx and TrxR in cancer cells lead to drug resistance [ ]. Ai and colleagues have designed 21 ligustrazine-curcumin hybrids 10a-u and reported that compound 10d suppresses the proliferation in both drug-resistant and drug-sensitive lung cancer cells.
In another study by Zhou et al. an analog of curcumin, 1E,4Z,6E hydroxy 4-hydroxymethoxyphenyl 5-methylfuranyl hepta-1,4,6-trienone 2a , suppressed the growth of cisplatin-resistant lung cancer A59 cells. Nuclear factor erythroid 2-related factor 2 NRF2 is a transcription factor that is traditionally found to regulate the protective mechanisms against oxidative stress [ ].
Recent investigations have shown that this transcription factor is also involved in the development and progression of cancers as well as chemoresistance [ , , , , , ]. Therefore, NRF2 is reported to be a potential candidate in overcoming cancer chemoresistance [ ]. Zhang et al.
Curcumin also chemosensitizes head and neck squamous carcinoma cells to cisplatin in vitro through targeting Nrf-2 and pSTAT3 signaling pathways [ ].
In pancreatic cancer cells, resveratrol inhibits the nutrient-deprivation autophagy factor-1 NAF-1 via activating the Nrf2 pathway and accumulating intracellular ROS [ ]. Furthermore, combined treatment with EGCG and Nrf2 siRNA results in a synergic Nrf2 downregulation and reversal of tamoxifen resistance [ ].
The expression of androgen receptor AR is significantly associated with poor prognosis of glioblastoma patients [ ]. Moreover, AR leads to the development of resistance against temozolomide. The curcumin analog ALZ is able to induce ubiquitination of AR by FBXL2, resulting in its degradation.
ALZ suppresses the survival of both temozolomide-sensitive and -resistant glioblastoma cells in vitro and in vivo. Treating glioblastoma cells with ALZ also leads to lipid peroxidation, ROS accumulation, and inhibition of glutathione peroxidase GPX 4, which are indicators of ferroptosis.
Regarding the in vivo effect of this treatment, Chen and colleagues transplanted temozolomide-sensitive or -resistant glioblastoma U87MG cells into mouse brain. They observed that ALZ suppressed the proliferation of tumor cells as well as increasing their survival [ ] Table 2.
Epithelial to mesenchymal transition or EMT is a dedifferentiation process whose target is to prepare epithelial cells for migration and metastasis [ ]. Diverse molecular alterations cause the transformation of polar epithelial cells into multipolar and motile mesenchymal cells [ ]; therefore, epithelial genes containing E-cadherin, ZO-1, and occludin should be decreased in cells undergoing EMT while mesenchymal genes containing N-cadherin, vimentin, and fibronectin ought to be increased [ ].
Similar to every other cellular process, signaling pathways have a pivotal role in EMT; these pathways encompass transforming growth factor beta TGFβ , Wnt, Notch and Hedgehog [ ]. The mechanism by which EMT contributes to the resistance of several cancer types is mainly related to CSCs [ ]. This association was suggested due to the similarity of signaling pathways involved in EMT and CSCs.
To our knowledge, CSCs probably recall EMT by affecting the non-CSC cells of the tumor [ ]. The ATP-binding cassette ABC transporters seem to be greatly involved in CSC-induced EMT of tumor cells.
Investigations on resistant tumor cells undergoing EMT reveal the higher expression of these transporters [ ]. As well as CSCs, EMT is also susceptible to the ingredients of the tumor microenvironment including cancer-associated fibroblasts CAF and hypoxia [ , ].
For targeting EMT in cancer cells, curcumin is confirmed to be a suitable option. It decreases 5-fluorouracil-resistance by means of affecting the TET1-NKD2-WNT axis and thereby hindering EMT [ ].
In colorectal cancer cells, this effect aids the reduction of 5-fluorouracil resistance [ ]. Furthermore, in colorectal cancer calls, curcumin increases the markers of epithelial cells including E-cadherin when utilized with irinotecan [ ]. H19 is a long noncoding RNA with the role of establishing tamoxifen resistance in breast cancer cells, which can be impacted by curcumin [ ].
H19 overexpression is responsible for EMT in breast cancer cells, which can be reversed after curcumin treatment [ ]. In addition to curcumin, resveratrol might also be a suitable option for overcoming resistance through EMT inhibition [ ].
EMT inhibition is also possible by quercetin. Quercetin decreases the resistance to docetaxel in prostate cancer cells by affecting some mechanisms including EMT [ ]. NF-κB p65 inactivation is another mechanism that is used by epigallocatechingallate to inhibit EMT in nasopharyngeal cancer stem cells [ ].
EGCG, which is a green tea polyphenol, seems to be effective against CSCs of nasopharyngeal carcinoma and inhibits some of their features including EMT [ ]. Lin et al. Geraniin is another member of the polyphenol family which can be found in Phyllanthus amarus [ ].
Elevating the levels of E-cadherin and decreasing the levels of Snail are two effects of this agent on lung cancer cells. After using geraniin, anoikis resistance is decreased in these cells through inhibition of EMT [ ].
Our knowledge of the anti-cancer effects of polyphenols has remarkably expanded since the discovery of these beneficial agents, which is why the understanding of the underlying mechanisms by which they work is essential. Accumulative investigations have clarified how these natural compounds are able to inhibit cancer hallmarks such as proliferation, apoptosis, inflammation, etc.
But what if polyphenols have a more significant ability that would assist us through overcoming cancer? Resistance to the common therapies involving chemo- and radiotherapy is our most important difficulty in restricting the progression of cancer cells and decreasing the number of cancer-related deaths.
So far, only a few clinical trials have been performed on the role of polyphenols in overcoming cancer drug resistance. One of them is a phase II study of resveratrol SRT with bortezomib in patients with relapse of refractory multiple myeloma. This study has shown that this therapeutic approach has a low safety profile while showing minimal efficacy [ ].
This study, performed on 21 patients, shows that combined therapy with gemcitabine and 8 g of oral curcumin daily is a safe and feasible treatment for patients and further investigations should be carried out to define its efficacy [ ]. Taken together, the developments in our understanding of these agents have revealed the wide range of their effects against treatment resistance, but still, the lack of sufficient human research is holding us back from using polyphenols widely in clinical practice.
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Acta Histochem. Download references. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. Gerald J. Friedman Diabetes Institute at Lenox Hill Hospital, Northwell Health, New York, NY, , USA. Division of Endocrinology and Metabolism, Department of Medicine, Friedman Diabetes Institute at Lenox Hill Hospital, Northwell Health, E 59th Street, Suite 8B, Room , New York, NY, , USA.
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For more information prpperties PLOS Subject Areas, click anc. Plant polyphenols have an array of health benefits primarily Polyphejols Best energy supplements be related to their high Polyphenols and anti-cancer properties of anti-oxidants. These are commonly undervalued and knowledge of Polyphenlos biological properties xnd grown exponentially Hydrating and plumping Best energy supplements last decade. Polyphenol-rich sugarcane extract PRSEa natural extract Polyphenols and anti-cancer properties sugar cane, is marketed as high in anti-oxidants and polyphenols, but its anti-cancer activity has not been reported previously. We show that, PRSE exerts anti-cancer properties on a range of cancer cells including human LIM and mouse MC38, CT26 colon cancer cells lines; human lung cancer Ahuman ovarian cancer SKOV-3pro-monocytic human leukemia U and to mouse melanoma B16 cell lines; whereas no effects were noted on human breast ZR and human colon HT29 cancer cell lines, as well as to human normal colon epithelial cell line T Anti-proliferative effects were shown to be mediated via alteration in cytokines, VEGF-1 and NF-κB expression.
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