Nothing Special   »   [go: up one dir, main page]
Next Article in Journal
CLytA-DAAO, Free and Immobilized in Magnetic Nanoparticles, Induces Cell Death in Human Cancer Cells
Next Article in Special Issue
Antiproliferative Effect of Acridine Chalcone Is Mediated by Induction of Oxidative Stress
Previous Article in Journal
Preliminary Studies on the Application of Grape Seed Extract in the Dyeing and Functional Modification of Cotton Fabric
Previous Article in Special Issue
Efficacy of Jackfruit365™ Green Jackfruit Flour Fortified Diet on Pegfilgrastim to Prevent Chemotherapy-Induced Leukopenia, Irrespective of Tumor Type or Drugs Used—A Retrospective Study
You seem to have javascript disabled. Please note that many of the page functionalities won't work as expected without javascript enabled.
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomolecules
Volume 10
Issue 2
10.3390/biom10020221
biomolecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Therapeutic Potential of Plant Phenolic Acids in the Treatment of Cancer

by
Mariam Abotaleb
1,
Alena Liskova
2,
Peter Kubatka
3 and
Dietrich Büsselberg
1,*
1
Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, P.O. Box 24144, Qatar
2
Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
3
Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(2), 221; https://doi.org/10.3390/biom10020221
Submission received: 20 November 2019 / Revised: 26 January 2020 / Accepted: 28 January 2020 / Published: 3 February 2020
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
Browse Figures
Figure 1
<p>Molecular pathways targeted in cancer treatment.</p> "> Figure 2
<p>Biosynthesis of phenolic acids in plants via the shikimic acid pathway. Adapted from [<a href="#B3-biomolecules-10-00221" class="html-bibr">3</a>].</p> "> Figure 3
<p>(<b>a</b>) Benzoic acids: vanillic, gentisic, protocatechuic, gallic, and syringic acid; (<b>b</b>) Cinnamic acids: caffeic, ferulic, <span class="html-italic">p</span>-coumaric, and sinapic acid.</p> "> Figure 3 Cont.
<p>(<b>a</b>) Benzoic acids: vanillic, gentisic, protocatechuic, gallic, and syringic acid; (<b>b</b>) Cinnamic acids: caffeic, ferulic, <span class="html-italic">p</span>-coumaric, and sinapic acid.</p> "> Figure 4
<p>(<b>a</b>) Molecular targets of benzoic acids; vanillic, gallic, gentisic, protocatechuic and syringic in cancer treatment (<b>b</b>) Molecular targets of cinnamic acids; caffeic, ferulic, <span class="html-italic">p</span>-coumaric, and sinapic in cancer treatment.</p> ">
Versions Notes

Abstract

:
Globally, cancer is the second leading cause of death. Different conventional approaches to treat cancer include chemotherapy or radiotherapy. However, these are usually associated with various deleterious effects and numerous disadvantages in clinical practice. In addition, there are increasing concerns about drug resistance. In the continuous search for safer and more effective treatments, plant-derived natural compounds are of major interest. Plant phenolics are secondary metabolites that have gained importance as potential anti-cancer compounds. Phenolics display a great prospective as cytotoxic anti-cancer agents promoting apoptosis, reducing proliferation, and targeting various aspects of cancer (angiogenesis, growth and differentiation, and metastasis). Phenolic acids are a subclass of plant phenolics, furtherly divided into benzoic and cinnamic acids, that are associated with potent anticancer abilities in various in vitro and in vivo studies. Moreover, the therapeutic activities of phenolic acids are reinforced by their role as epigenetic regulators as well as supporters of adverse events or resistance associated with conventional anticancer therapy. Encapsulation of phyto-substances into nanocarrier systems is a challenging aspect concerning the efficiency of natural substances used in cancer treatment. A summary of phenolic acids and their effectiveness as well as phenolic-associated advances in cancer treatment will be discussed in this review.

1. Introduction

Cancer is defined as an irreversible impairment in cellular homeostasis. It is a multifactorial, heterogeneous metabolic disease. This impairment may be associated with internal sources such as loss/ reduced cellular functions; apoptosis, oxidative stress, mutations and hypoxia, or emerging from external origins listed as prolonged exposure to radiation, ultraviolet rays, pollution, in addition to smoking, and stress. Cancer progression is marked by six main hallmarks: (1) uncontrolled cell growth and differentiation, (2) replicative immortality, (3) promotion of angiogenesis, (4) increased proliferative signaling, (5) resistance in cell death and finally (6) metastatic invasion. Thus, targeting these molecular pathways attempting to repair the disturbed balance is required to control and treat of cancer (Figure 1) [1].
Phenolics are vital constituents in plants frequently found in fruits, vegetables, cereals, and legumes. In plants they function in wide range of processes such as pigmentation, growth, reproduction and resistance to pathogens or predators. They are classified into five main classes: coumarins, flavonoids, phenolic acids, stilbenes, and tannins [2,3]. Phenolics are secondary metabolites mainly produced in plants from shikimic acid via the phenylpropanoid pathway (Figure 2). They are also produced as a result of the breakdown of lignin and cell wall polymers in vascular plants and as by-products of the monolignol pathway [2,3].
Phenolic acids are additionally classified as benzoic acids (Figure 3a) or cinnamic acids (Figure 3b). The direct biosynthetic route of benzoic acids is unclear; however, they are usually produced from cinnamic acid and its derivatives. Frequently found examples are: p-hydroxybenzoic acids including vanillic, protocatechuic, syringic, and gallic acid, in addition to gentisic acid, derived from catabolism of tyrosine [3,4], while cinnamic acids are ortho-oxygenated then subsequently methylenated, leading to the formation of the majority of hydroxycinnamic acids such as ferulic, p-coumaric, caffeic, and sinapic acid. Phenolic acids are found in free forms or conjugated with esters, ethers and a variety of other molecules (simple sugars, organic acids and plant polymers) [2,3,5,6]. Key structural motifs required for the anticancer activity of phenolic compounds include the aromatic ring, unsaturated substituted chains and the number and position of free hydroxyl groups [3]. This review aims to concentrate on the potential of phenolic acids as cytotoxic agents in terms of mechanism of action and therapeutics.

2. Therapeutic Effects of Phenolics in Preclinical Cancer Research

Phenolics are popular for their potency as medicinal compounds in treatment of various diseases such as diabetes, cardiovascular and neurodegenerative diseases, as well as cancer. Their antidiabetic property is mediated through the modulation of glucose metabolism [2]. Their potency as anticancer compounds is primarily attributed to their antioxidant activity; being strong radical scavengers, metal chelators, modifiers of endogenous defense mechanisms as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx), enhancers of glutathione (GSH) redox status, and regulators of diverse proteins and transcriptional factors such as nuclear factor erythroid related factor (NRF2) [2,7]. Moreover, their anticarcinogenic effects is associated with their ability to inhibit cell proliferation (extracellular signal-regulated kinase (Erk)1/2, D-type cyclins, and cyclin-dependent kinases (CDKs)), angiogenic factors (vascular endothelial growth factor (VEGF) and MIC-1), oncogenic signaling cascades (phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt)), inducing apoptosis, and preventing cellular migration and metastasis [2,5].

2.1. BenzoicAacids

2.1.1. Vanillic Acid

Vanillic acid (4-hydroxy-3-methoxybenzoic acid, VA) is produced from ferulic acid in a reaction that involves vanillin as an intermediate [8,9]. It is a major active compound isolated from Angelica sinensis and green tea [8]. VA acts as a chemo-protectant and contributes in the prevention of benzo(a)pyrene-induced lung cancer in Swiss albino mice was indicated by its free-radical scavenging antioxidant activity [10]. VA also demonstrated antioxidant and anti-lipid peroxidative abilities in the DMBA-induced hamster buccal pouch carcinogenesis. Interestingly, administration of VA led to the restoration of levels of lipid peroxidation by-products and abnormalities in antioxidative status which were found to be altered after administration of DMBA alone [11]. In cancer treatment; the potential anticancer effectiveness of whole plant or isolated plant extracts containing several natural compounds as well was tested. Interestingly, transformed root extract of Leonurus sibiricus is rich in various polyphenolic compounds including VA as well as gentisic acid,4-hydroxybenzoic acid, 1,3-dicaffeoylquinic acid, and α-resorcylic acid, demonstrated an ability to inhibit proliferation and to induce apoptosis in glioma cells with these effects mediated via generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, enhancement of S and G2/M cell cycle phases, and changes in mRNA levels of apoptotic factors including Bax, Bcl-2, p53, Caspase-3, -8 and -9 [12]. In HCT116 colorectal cancer cells, isolated VA inhibited angiogenesis and proliferation and led to cell cycle arrest at G1 phase by inhibiting the expression of hypoxia inducing factor (HIF-1) protein synthesis in a dose dependent manner (30 µM) without affecting its degradation or its mRNA expression. Thus, this inhibitory effect depends on the inhibition of mTOR/p70S6K/4E-BP1 and Raf/MEK/ERK pathways [8]. The in vitro antioxidant capacity of VA was demonstrated through the reduced DNA damage, induced by H2O2 in human lymphocytes at concentrations of 0.17–67.2 μg/mL [9]. While, in rat models of N-methyl-N’-nitro-N-nitrosoguanidine (MNNG)-induced endometrial carcinoma treatment (100 mg/kg body weight) showed high antioxidant potency, their action involved increasing the levels of cellular antioxidants; SOD, CAT, GPx, GSH, and vitamins C and E in plasma and uterus, as well as reducing oxidative damage by decreasing the levels of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and cytochrome p450. The same study additionally, demonstrated the reduction of cancer progression and metastasis by down regulation of the expression of oncogene cyclin D1 and matrix metalloproteinases (MMP) -2, -9 [13].

2.1.2. Gentisic Acid

Gentisic acid (2,5-dihydroxybenzoic acid, GeA) is a biosynthetic derivative of salicylic acid and a byproduct of tyrosine catabolism found in citric fruits, grapes, artichokes, sesame, and olives. It has antioxidant and anti-inflammatory effects and is also used in the treatment of cardiovascular diseases [14,15]. The potent antioxidant effects of GeA could be direct as it is a free radical scavenging molecule or indirect by acting as an agonist of NRF2 which regulates the synthesis of antioxidant molecules [14]. The anticancer effectiveness of Vaccinium myrtillus whole extract on HCT-116 cells, demonstrated to be an effective antioxidant. It is worth mentioning that GeA is considered to be one of the most abundant polyphenols found in this extract along with quercetin and kaempferol [16].
Importantly, the administration of GeA at clinically available doses led to the blockage of growth, DNA synthesis, and colony formation in C6 glioma in vitro. Considering in vivo model, GeA enhanced the survival of Ehrlich breast ascites carcinoma-bearing mice. Regarding the growth of Ehrlich solid tumors (EST) affected by GeA alone or by sodium selenite, GeA reduced their growth and did not modify antineoplastic effects of selenium which initially decreased EST. However, GeA led to the blockage of the selenite’s tumor stimulation at later stage. Lastly, GeA attenuated side effects of doxorubicin including myofibrillary and endothelial damage as well as hyalinization necrosis [17]. Additionally, GeA has an indirect role in controlling brain glioblastoma as it blocks the OAT3 and solute carrier-22A8 responsible for brain efflux of anticancer drugs, leading to accumulation of chemotherapeutic agents in brain hence, reducing the tumor growth. Moreover, GeA and its isomers regulate cell cycle progression by blocking CDK 1 enzymatic activity [14].

2.1.3. Protocatechuic Acid

Protocatechuic acid (3,4-dihydroxybenzoic acid, PCA) is found in plum, star anise, melissa, rosemary, cinnamon, sudan mallow, St. John’s wort, berries, cauliflower, and lentils. It has a wide range of biological and pharmacological activities including antioxidant, antibacterial, anticancer, antiulcer, antidiabetic, antifibrotic, antiviral, anti-inflammatory, analgesic, cardiac, antiaging, hepatoprotective, neurological, and nephroprotective efficacy [5]. In cancer, PCA promoted cell death in HepG2 cell lines by stimulating the JNK and p38-MAPK [18,19]. Moreover, PCA exerted apoptotic and antiproliferative effects in HL-60 leukemia and human gastric adenocarcinoma (AGS) cells which were manifested by increased DNA fragmentation and Bax expression, reduced Bcl-2 protein expression, induction of RB phosphorylation, and activation of Fas/FasL pathway [19]. PCA also induced mitochondrial apoptotic cell death in PC12 cells through loss of mitochondrial membrane potential and induction of ROS [19]. In addition, treatment of three ovarian cell lines (SKOV-3, OVCAR-3, and A2780) with PCA showed a significant reduction in viability and colony formation, the mechanism was illustrated to be through the induction of apoptosis, autophagy and cell cycle arrest at G2/M phase, concluded by the activation of Poly-(ADP-Ribose)-Polymerase (PARP), upregulation of caspase-3 and Bax, as well as a downregulation of Bcl-2. PCA administration also led to upregulation of autophagy-related protein LC3-II and induction of GFP-LC3 puncta formation. An inhibitory efficacy of PCA on OVCAR-3 cells may be associated with increased glutathione levels and decreased intracellular ROS [20]. Furthermore, PCA was effective in penetrating cancer cells inducing lactate dehydrogenase leakage and disrupting the mitochondrial membrane potential by decreasing Na+/K+-ATPase activity in various cell lines including MCF-7, A549, HepG2, HeLa, and LNCaP cells. Additionally, antimetastatic potential of PCA in human gastric carcinoma AGS cells was mediated via the inhibition of MMP-2 secretion [21]. Moreover, PCA at 25 µM showed potent anti-angiogenic activities in in vitro study using HUVECs as it blocked cellular proliferation, migration, invasion and increased ROS generation thus inhibited VEGFR2-dependant Akt/MMP2 and ERK pathways [22]. In human gastric carcinoma AGS cells antimetastatic effect was mediated via the inhibition of MMP-2 secretion [21]. Additionally, the antimetastatic effects of PCA were evaluated in AGS cells used in wound healing model and Boyden chamber assay in vitro and in metastasis in vivo model of B16/F10 melanoma cells injected in mice. Essentially, antimigratory and antiinvasive abilities of PCA were found to be associated with decreased expression MMP-2 via the down-regulation of the Ras/Akt/ nuclear factor-kappa (NF- κB) pathway by targeting RhoB activation. Additionally, an inhibition of metastasis of B16/F10 melanoma cells to the liver as a result of PCA administration was also observed [23].
In cancer therapy the protective effect of PCA was also demonstrated in reducing nephrotoxicity in the cisplatin-treated rats in a dose dependent manner, such that PCA co-treatment at doses of 10 and20 mg/kg body weight resulted in remarkable improvement in the histological appearance and reduction in tubular cell damage, reduction of elevated levels of pro-caspase-3 induced by cisplatin in rat kidneys [24]. In nanomedicine and drug delivery it is associated with improvements in the therapy efficacy, reduction of side effects and prolonged bioavailability. Therefore, graphene oxide–polyethylene glycol (GO-PEG) nanocarrier system was designed for the PCA. Due to the overexpression of folate receptor on majority of cancer tissues, folic acid coating (FA) was employed in this nanocarrier to target cancer cells (GO-PEG-PCA-FA). Importantly, GO-PEG-PCA-FA nanocarrier system was demonstrated to be more effective anti-cancer agent when compared with free PCA as well as uncoated delivery system against colon cancer HT-29 and HEP-G2 cells. Moreover, in vitro release of PCA was found to be highly sustained and extended [25]. Similarly, the effectiveness of PCA intercalated in the nanocarrier zinc-aluminium-layered double hydroxide (PCA-ZnAl) system against diethylnitrosamine/phenobarbital-induced hepatocellular carcinoma was evaluated in BALB/c mice. Intercalated PCA is more thermally stable and its release from the carrier system is sustained and controlled. Actually, both PCA and doxorubicin remarkably reversed tumor marker expression as well as lung and kidney structures and weight gain. However, PCA-ZnAl group was associated with better or similar improvements in comparison with doxorubicin treatment or the administration of plain nanocomposites [26].

2.1.4. Gallic Acid

Gallic acid (3,4,5-trihydroxybenzoic acid, GA) is extracted from chestnut green chicory, blackberry, raspberry, walnuts, chocolate, wine, green tea, and vinegar either in free form or as a part of hydrolysable tannins. It has strong anti-microbial, anti-inflammatory, and anticancer activities. Its anticancer activities are mainly exerted by preventing cellular proliferation, promotion and generation of reactive oxygen species (ROS) and cell cycle arrest in G2/M phase [5,27]. Aqueous extract from Rhus verniciflua (RVSE) upregulated p53 and p21 and thus induced apoptosis in sub-G1 phase in MCF-7 breast cancer cells. Importantly, high-performance liquid chromatography of RVSE revealed only the presence of GA, hence, an antiproliferative efficacy on MCF-7 cells may be attributed to the effects of GA [28].
At low concentrations (5 μM) GA selectively inhibited the growth and in vitro angiogenesis of two ovarian cancer cell lines OVCAR-3 and A2780/CP70 in a concentration-dependent manner. GA inhibited VEGF secretion through suppression of Akt phosphorylation and HIF-1α expression and promotion of PTEN expression [29]. In glioblastoma multiforme (GBM) T98G cell lines GA antiproliferative effect was associated with epigenetic alterations in miRNAs initiating apoptotic cell death at low concentrations [30]. Additionally, GA decreased IL-6 protein level resulting in suppressing pAkt signaling by blocking pSTAT3, pERK1/2, consequently leading to the reduction of the survival, proliferation, and invasion in PC3 cells [31]. While the epidermal growth factor receptor (EGFR)-dependent anti-proliferative and apoptotic effects of GA in malignant mesothelioma (SPC212) cells were demonstrated to be dually concentration- and time-dependent. Importantly, the activation and upregulation of ERK1/2, EGFR, Akt proteins and the expression of p21 gene along with the downregulation of Cyclin D and Bcl-2 genes were demonstrated by GA, in EGF-induced SPC212 cells leading to a transitory G1 arrest and triggering of mitochondrial and p38MAPK mediated apoptosis [32]. The proapoptotic effect of GA in DBTRG-05MG cells was shown by altering calcium ion homeostasis from the endoplasmic reticulum in a dose dependent manner, evoking mitochondrial apoptotic pathways involving ROS production [33]. Similarly in, cervical cancer cells HeLa and human umbilical vein endothelial cells (HUVEC), GA led to apoptotic cell death via the induction of ROS and GSH accompanied by the loss of mitochondrial membrane potential [34]. The ROS-dependent pro-apoptotic effects of GA were also demonstrated in declined viability of HCT-15 colon cancer or LNCaP prostate cancer cells [27]. The beneficial effects of GA in triple-negative breast cancer (TNBC) were suggested by the study that revealed an ability of GA to induce G1 phase arrest and apoptosis via p38 mitogen-activated protein kinase/p21/p27 axis in MDA-MB-231 cells [35]. Moreover, GA was associated with p53-involved upregulation of Fas, FasL, and DR5 and apoptosis in AGS cells [36]. In addition, epigenome-protecting abilities of GA were also observed in tobacco-associated cancers. GA reduced nuclear and cytoplasmatic DNA methyltransferases in H1299 cells [37]. GA was also found to be a potent inhibitor of HDAC8 and class IIa/b HDAC activity [38].In addition, GA demonstrated anti-invasive effects in human nasopharyngeal carcinoma cells NPC-BM1 through the inhibition of p38 MAPK signaling pathway, this was due to suppressed transcription of MMP-1 by down-regulation of Ets1 and c-Jun, c-fos of the AP-1 [39]. In case of AGS cells, GA up-regulated of RhoB and the down-regulated Akt/small GTPase signals and NF- κB activity inhibited cell migration [40]. In addition to its role in suppressing the invasion and migration of PC-3 prostate cancer cells through down-regulation of MMP-2 and MMP-9 [27]. Furthermore, an ability of GA to inhibit viability of lung carcinoma A549 cells was related to the GA upregulating voltage dependent anion-selective channel protein 1 [41]. In addition, the anticancer and auxiliary effects of GA were observed in NSCLC A549 cells treated with cisplatin. GA inhibited the proliferation and induced the apoptosis in a dual manner, which was associated with upregulated Bax and downregulated Bcl-2 and modulated the JAK/STAT3 signaling [42].
In therapeutics a post-fermentation oolong tea extract (PFOTE) GA-enriched using Aspergillus sojae was associated with further enhanced demethylation abilities. PFOTE also increased sensitivity to cisplatin and showed stronger antiproliferative abilities when compared with oolong tea extract [37]. Furthermore, an ability of GA to potentiate side effects of conventional chemotherapeutic drugs was evaluated in HeLa cervical cancer cells. Interestingly, the combination of GA and Paclitaxel was associated with lower side effects and thus may represent a replacement of Paclitaxel/Carboplatin combination which is currently one of the most commonly used drugs in the therapy of cervical cancer [43]. Similarly, the potential of GA at 50 and 100 µM as a co-adjuvant to Paclitaxel was demonstrated by its ability to sensitize Paclitaxel-resistant ovarian cancer cells (A2780AD) via inactivation of ERK which was associated with an increase in ROS [44]. Additionally, in multidrug resistant small cell lung cancer SCLC H446, GA showed promotive effects to cisplatin, as shown by it changed morphology, inhibited the growth and induced apoptosis generated of ROS, disruption of MMP, downregulation of XIAP expression, and upregulation of Bax, Apaf-1, DIABLO and p53 expression [45]. Similarly, as in case of GeA, iron oxide magnetite nanoparticles coated with polyethylene glycol and loaded with GA (Fe₃O₄-PEG-GA) were found to be more effective against human lung A549, breast MCF-7, and colon HT-29 cells when compared with free GA [46]. Moreover, encapsulation of GA into PLGA-CS-PEG nanocomposite was also associated with increase in its bioavailability and antitumor efficacy in rats [47].

2.1.5. Syringic Acid

Syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid, SyA) is an abundant phenolic compound present in dates, olives, pumpkin, grapes, spices, acai, red wine, palm and honey [5,7,48]. It has higher potency than p-hydroxybenzoic acid due to the free radical scavenging activity attributed to the presence of two methoxy moieties at positions 3 and 5 [7]. Apparently, non-melanoma skin cancer is related to excessive UV exposure. The study focusing on an association between SA and UVB-induced signaling and skin cancer revealed that chemo-preventive potential in vitro and in vivo was mediated mainly via an ability of SA to inhibit Nox/PTP-κ/EGFR axis. Specifically, the protective efficacy of SyA in human epidermal keratinocytes HaCaT cells is based on the ability to inhibit UVB-induced COX-2, MMP-1, prostaglandin E2 expression, activator protein-1 activity, phosphorylation of mitogen-activated protein kinases and Akt, EGFR as well as ROS formation. Moreover, SyA along with the administration of antioxidant N-acetyl-L-cysteine constrained the action of UVB-induced NADPH oxidase activity. In vivo, SyA pretreatment led to the dose-dependent suppression of UVB-induced skin cancer incidence in mice [48]. Menyanthes trifoliate root extracts containing terpenoids and polyphenols including SyA led to induction of apoptosis mediated via G2/M phase cell cycle arrest and alterations in the expression of Bax, Bcl-2, cas-3 nad p53 as well as the decrease in the mitochondrial membrane potential in IV glioma cells [49]. Additionally, Manuka honey (MH) is considered as the source of various phenolic compounds such as GA and SyA. MH treatment led to the cell cycle arrest at S phase in HCT-116 cells and at G2/M phase in the LoVo cells. Moreover, MH caused promoted apoptosis via increase in p53, cleaved-PARP, caspase-3, activation of extrinsic and intrinsic apoptotic pathways as well as suppression of p-Akt and increase in expression of p-p38MAPK and endoplasmic stress markers [50]. Similarly, isolated SyA induced apoptosis via mitochondrial pathway by elevating the expression of caspases 3 and 9, cytochrome c, Apaf-1, Bax, and p53 in contrast to the downregulation of Bcl-2 gene expression and caused liberation of ROS in HepG2 cells [51].
SyA also showed high potency in treatment of DMBA-induced hamster buccal pouch carcinogenesis (HBPC) in a dose dependent manner. Results showed that anti-lipid peroxidative, antioxidant, anti-cell proliferative, and apoptosis-inducing properties of SyA were mediated by down-regulation of TBARS, LOOH, enzymatic (SOD, CAT and Gpx) and non-enzymatic antioxidants (vitamin E and GSH) and reduction of the expression of PCNA, Cyclin D1, and mutant p53 [52]. Moreover, SyA was found to repress cell surface glycoconjugate abnormalities induced by 7,12-dimethylbenz(a)anthracene and to restore expression of cytokeratin in the plasma and buccal mucosa of golden Syrian hamster buccal pouch carcinogenesis. Results suggested that SyA possess membrane stabilizing effects during neoplastic changes with its efficacy mediated probably via inhibition of the abnormal GPs separation and regulation of glycosyltransferase activity [53]. It also exhibits antimitogenic and chemo sensitizing activity in human colorectal cancer SW1116 and SW837 cell lines by time-dependent induction of cell-cycle arrest at S/G2-M, G1/G2-M and S/G2-M phase and apoptosis, inhibition of cell migration and NF- κB, and DNA binding. Cell cycle arrest and apoptosis are elucidated by increased S-phase, downregulated cell cycle proteins CDK4, CDK6 and cyclins B, C, E1, H and upregulated p19, p21Cip1/Waf1 and p27kip1 expression. Moreover, apoptosis is also induced by the upregulation of expression of the proapoptotic genes (Bax, Bak, Bad, Bid, Bim, Apaf1, AIF Smac, caspases-2, 3, 6, 7, 8 and 9) [54].

2.2. Cinnamic Acids

Hydroxycinnamic acids are synthesized in various plants and fruits such as coffee beans, tea, berries, tomatoes, citrus, grapes, spinach, beetroots, artichokes, potatoes, and cereals. They display anticancer, antiatherogenic, antimalarial, antifungal, antimicrobial, and antioxidant activities [2]. Cinnamic acids esters are considered to be the most potent class when compared to methoxylated or hydroxylated forms [3].

2.2.1. Caffeic Acid

Caffeic acid (3,4-dihydroxycinnamic acid, CA) is found as ester form in wheat, quinoa, triticale, barley, corn, oat, rye, rice, thyme, oregano millet, sage, and sorghum [2,5]. CA and its derivatives are well known for their antibacterial, anti-mutagenic, anti-inflammatory, and anti-carcinogenic properties, which could be linked to its antioxidant activity [55]. Their antioxidant effects are mediated by modulating signaling pathways such as NF- κB, MAPK, and Akt. Moreover, they induce cell cycle arrest and enhance apoptosis in neck, tongue, and mouth carcinomas [5]. In Ht-29 cell lines, both CA and 5-caffeoylquinic acid reduced cell viability via promotion of specific cell cycle alterations (increased cellular population at G0/G1, decrease in G2/M cells) and induced apoptosis in a time- and dose-dependent manner [3,56]. Interestingly, the antioxidant activity of CA could be related to its iron-chelating property through the formation of iron-CA complexes inhibiting Fenton-induced oxidative damage by preventing the formation of free hydroxyl radicals [55]. CA was also noted for its antioxidant effects by suppressing the production of ROS -SOD-, and prevention of cancer progression and migration by decreasing cell adhesion by reduced attachment to extracellular matrix (ECM) in human lung A549 and colon adenocarcinoma HT29-D4 cells [3,57]. Moreover, an evaluation of CA antitumor efficacy was performed on human cutaneous melanoma SK-Mel-28 cell line. Interestingly, CA exhibited an important role in the prevention of tumor progression via decrease in cell viability and induction of apoptosis. Moreover, CA treatment led to the cell cycle modulation, inhibition of colony formation, and changes in the expression of caspases [58]. Importantly, CA attenuated cancer stem cells-like properties via inhibition of TGFβ-SMAD2 signaling pathway mediated by microRNA-148a in vitro as well as in vivo mouse models [59]. Generally speaking, caffeic acid phenethyl ester (CAPE) is a component of honeybee propolis. Both CA and CAPE are considered to possess cell cycle inhibitory and proapoptotic properties in cancer cells [60]. Moreover, CAPE induced apoptosis in human multiple myeloma cells through oxidative stress with these effects mediated via activation of caspase-3 and PARP cleavage and decrease in intracellular antioxidant level [61]. Additionally, CAPE inhibited cancer progression through inactivation of NF-κB signaling in ovarian SKOV-3 cells [62] and attenuated proliferation and invasion of nasopharyngeal cancer cells via upregulation of NDRG1 expression through MAPK pathway and inhibition of STAT3 phosphorylation [63]. Actually, comparison of anticancer effects of CA and CAPE revealed dose and time-dependent ability of CAPE to be more potent in treating breast cancer cells with the mechanisms of its action mediated by inducing apoptosis, cell cycle arrest in MDA-MB-231 cells [60] and reducing the migration of MCF-7 [64]. Additionally, proapoptotic and anti-metastatic effects of pineapple vinegar (PV) were evaluated in mouse mammary gland cells in vitro and in vivo. PV rich in GA and CA was prepared in the process of double fermentation. Interestingly, 70 % of cell population underwent apoptosis and 30 % inhibited wound closure of 4T1 cells in response to the administration of PV. Therefore, anti-cancer efficacy of pineapple vinegar may be associated with the presence of phenolic acids, especially GA and CA in high content [65]. Moreover, methanol extracts of Anchusa azurea Mill, with CA as one of the four most abundant compounds, was found to induce programmed cell death in cancer cell line via activation of capsase-3/7 and -9 as well as modulation of cytoskeleton dynamics [66]. Interestingly, when combined with cisplatin; CA increased its therapeutic potential, the combinatory treatment led to the inhibition of cell growth of HeLa and CaSki cell lines which may be explained by the synergistic growth inhibition. Moreover, the combination of CA and cisplatin was also associated with increase in the expression of caspase-3, -7 and -9 [67].

2.2.2. Ferulic Acid

Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA) is one of the most abundant phenolic acids in plants. It is a byproduct derived from metabolizing phenylalanine and tyrosine found in wheat, buckwheat, rice, corn, oats, rye, orange, corn, herbs, spices, sorghum, millet, quinoa, and barley [2]. A wide range of therapeutic activities of FA is demonstrated in several diseases including diabetes, neurodegenerative, cancer and cardiovascular diseases [27]. Still, FA which is known antioxidant at lower concentrations, may act as a pro-oxidant leading to oxidative DNA breakage and ROS generation at higher concentrations (50 µM) or in the presence of chelator metal ions such as copper (25 µM) [27,68]. In prostate cancer PC-3 and LNCaP cell lines, FA inhibited cell proliferation, invasion and induced apoptosis at 300 μM and 500 μM, respectively [27,69]. Moreover, FA showed cytotoxic effects in the colorectal cancer Caco-2 cell line by elongating S/G2 phase and reducing G1 phase. Additionally, FA also exerted antioxidant effects by suppressing the production of superoxide anion and preventing cancer migration by reducing cell adhesion in adenocarcinoma lung A549 and colon HT29-D4 [3,57]. FA also showed protective effects to DNA damage induced by H2O2 and UV at 2 μg/mL [70]. Moreover, FA demonstrated ex vivo and in vivo inhibition of endothelial cell tube formation, proliferation and migration in response to basic fibroblast growth factor 1 (FGF-1). The suppression of melanoma growth and angiogenesis was carried out through FGFR1-mediated PI3K-Akt signaling pathway [71]. In addition, the anticancer efficacy of FA occurs by affecting colony formation, cell cycle, apoptotic and invasive and behavior of MIA PaCa-2 cells by increasing in the expression of Bax, p53, PTEN, caspases-3 and -9 and associated with decrease in the expression of CDK 4/6, cyclin D1 and Bcl-2 [72]. Furthermore, FA inhibited proliferation and induced apoptosis in 143B and MG63 osteosarcoma cells dose-dependently leading to G0/G1 phase arrest and apoptosis by down-regulating the expression of CDK 2, 4 and 6, upregulating Bax, downregulating Bcl-2, subsequently enhancing caspase-3 activity. It also inhibited PI3K/Akt activation in both cell lines [73,74]. FA role in suppressing metastasis was regulated by the reversal of epithelial-mesenchymal transition in vitro in MDA-MB-231 moreover, the inhibition of cell invasion through reducing MMP-9 mRNA expression [75].
In addition, FA suppressed invasion, migration, and colony formation leading to cell cycle arrest, apoptosis, invasion, migration, and colony formation in TT human thyroid cancer cell line as was demonstrated by decrease in expression of novel gene URG4/URGCP, CCND1, CDK4, and 6, Bcl-2, MMP2, and MMP9 and significant increase in the expression of p53, PARP, PUMA, NOXA, Bax, Bid, caspases-3 and -9 [76]. Moreover, the derivative of FA; FXS-3 inhibited metastasis and proliferation in human lung cancer A549 cells. Specifically, the administration of FXS-3 led to the apoptosis, G0/G1 arrest, increase in Bax/Bcl-2 ratio, MMP-2 inhibition and regulation of ERK/p38, JNK, AKT/mTOR and MEK/ERK signaling. Next, FXS-3 also suppressed metastasis and proliferation in A549 xenograft-bearing mouse and tail vein injection of A549 cells induced pulmonary tumor metastasis model. These results suggested FXS-3 to be a promising anticancer agent [77]. Furthermore, FA and 4-vinylguaiacol inhibited EGF-induced proliferation of breast cancer cells in vitro as well as synthesis of new DNA; therefore, it may potentially represent a structure for small molecule agents targeting EGFR [78].
In therapeutics the modulatory effect of FA on resistant ChR8-5 cells and tumor xenografts was mediated by FA synergistically enhancing doxorubicin-induced apoptotic signaling in the drug resistant cells. Also, NF-κB translocation was associated with the modulation of PI3K/Akt/signaling pathway [79]. It has limited applicability owing to its poor solubility;, FA is therefore, encapsulated into cyclodextrin nano sponges improved its solubility and in vitro cytotoxicity thus, representing a suitable delivery system with enhanced antiproliferative activity in MCF-7 and 4T1 breast cancer cell lines when compared with free FA [78]. Actually, the conjugation of nanoparticle with phytochemicals may represent a new approach in combinatorial chemotherapy as was demonstrated by the use of ZnO nanoparticle-FA conjugate in Huh-7, hepG2 cells and diethylnitrosamine-induced hepatocellular cancer on Wistar albino rat model [80]. Moreover, polyFE (chemically modified FE) loading doxorubicin nanoparticles maintained effective delivery of the drug in the acidic tumor microenvironment in vitro and reduced toxicity of free doxorubicin in vivo [81].

2.2.3. p-Coumaric Acid

p-Coumaric acid (4-hydroxycinnamic acid, p-CA) is extracted from wheat, barley oat, corn, rye, quinoa, rice, millet, honey sorghum barley grains and buckwheat [2]. The inhibitory effect of p-CA was demonstrated in colon cancer cell lines HT 29 and HCT-15 by inducing mitochondrial mediated apoptosis through increasing the ROS levels, changing the mitochondrial membrane potential and inhibiting the cell cycle at sub G1 phase [3]. In Rosa canina extract p-CA demonstrated selective cytotoxic efficacy in human lung A549 and prostate PC-3 cells in comparison with normal fibroblast. The extract was also associated with arrest of the cell cycle at G1 phase and induction of apoptosis mediated through MMP reduction and increase in caspase activity [82].
Isolated p-CA demonstrated also chemo protectant effects in stomach cancers by reducing the formation of carcinogenic nitrosamines. In addition, p-CA exhibited excellent free radical scavenging and NF- κB modulatory activities [83]. Furthermore, p-CA administration led to the inhibition of glucose related protein 78, which is often deregulated in colon cancer, and activation of unfolded protein response-mediated apoptosis in in vitro and in vivo models of colon cancer. p-CA was also associated with a decrease in the expression of IL-6, COX-2, TNF-α, PGE2, p-p65 and p-IκBα and thus reduced inflammation [84]. The study evaluating protective efficacy of p-CA against 1,2 dimethylhydrazine (DMH)-induced colonic preneoplasia in rats demonstrated significant ability of p-CA to suppress DMH-associated preneoplastic lesion. Moreover, p-CA also exerted strong antioxidant response and detoxification mechanism and thus protected the colon against genotoxic insult with 100mg/kg body weight to be the most optimal dosage [85]. Similarly, p-CA supplementation in DMH-administered rats of short-term preclinical model of colon cancer led to the decrease in the expression of colonic proteins (cyclin B1, mdm2, cdc2) that control cell cycle as well as early response genes (c-fos, c-jun, c-myc) maintaining proliferation. Moreover, p-CA induced apoptosis via modulation of Bax/Bcl-2 ratio and improvement of detoxification potential [86]. Remarkably, the study evaluating reversal effects of bound polyphenol of inner shell (BPIS) from foxtail millet bran revealed that the fraction of molecular weight (MW) < 200 of BPIS, with FA and p-CA as main components, reversed multidrug resistance in HCT-8/Fu cells. The mechanism of its action was mediated via inhibition of proliferation, apoptosis induction, increase in accumulation of Rh-123 and decrease in the expression of multidrug resistance protein (MRP-1), p-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) [87].

2.2.4. Sinapic Acid

Sinapic acid (4-hydroxy-3,5-dimethoxycinnamic acid, SA) existing as free or esterified form is found in cereal grains, rye, wheat triticale, barley, oat, rye, rice, rapeseed, kale, white cabbage, turnip, broccoli, citrus fruits, and various herbs such as sage and thyme [2]. It exerts an antioxidant potential by acting as a free radical scavenging agent and increasing the activities of enzymatic and non-enzymatic antioxidants including SOD, CAT, and GSH [21]. Dimethyl sulfoxide extract of Dianthus carmelitarum with SA as one of the two most abundant phenolic compounds exerted selective cytotoxic effect on human colon cancer WiDr cells when compared with normal colon cells. It was also associated with S phase cell cycle arrest and induction of apoptosis mediated via reduced MMP [88]. Interestingly, the production of many phenolic constituents was associated with marine-derived fungus Penicillium brevicompactum treated with nicotinamide and sodium butyrate. Nicotinamide treatment-based resulted in the isolation and identification of nine compounds including SyA and SA which exerted free radical scavenging as well as antiproliferative abilities against HepG2 cell line [89]. Regarding anticancer activities of pure SA in human prostate cancer cells, it was associated with increase in the expression of Bax, caspase-3, -8, FAS, tissue inhibitor of metalloproteinase (TIMP-1), cytochrome c, and cadherin (CDH) 1 in PC-3 cells as well as increase in expression of caspase-3, -7, cytochrome c and Bax in LNCaP cells. However, it significantly decreased the expression of MMP-9 in PC-3 cells, while a decrease in the expressions of CDH2, MMP-2 and MMP-9 was observed in LNCaP [90]. Additionally, antiproliferative and HDAC inhibitory abilities of peanut phenolics including p-CA, FA, and SA were evaluated in MCF-7 and HeLa cells. Importantly, all of the compounds led to the dose-dependent inhibition of proliferation, concentration-dependent induction of apoptosis and indication of HDAC inhibition in both cell lines. Moreover, all of the mentioned compounds induced cell cycle arrest at G0/G1 phase in MCF-7 cells and S-phase arrest in HeLa cells induced by p-CA and FA [91].

3. Use of Phenolics in Clinical Research

The use of phenolics in clinical studies is not sufficiently represented in cancer research. Actually, we found hardly any association between phenolic acids and clinical cancer research. Regarding phenolic acids, the association between coffee intake and risk of breast cancer was evaluated in NIH-AARP Diet and Health Cohort Study conducted on 198 404 women. Despite that both of the main coffee constituents, caffeine and CA, were associated with suppression of mammary carcinogenesis in vivo and DNA methylation inhibition in vitro, no association between coffee intake and breast cancer was found in this large mostly postmenopausal prospective cohort [92]. Conceivably, topical antioxidant mixture of vitamin C, FA, and phloretin protected human skin against harmful UV irradiation, which suggests the complementary and synergistic effects of this mixture with sunscreen in human skin photoprotection [93]. Particularly, chemical analysis of black tea revealed high concentrations of GA [94]. Importantly, GA metabolites including 3MOGA were increased after consumption of five cups of black tea daily [95]. Actually, 3OMGA exhibits strong antiproliferative activity and the authors of the following study expected contribution of colonic phenolic breakdown products with tea health benefit in the digestive system. Therefore, a clinical trial evaluating an association between concentration of phenolic acids in plasma and urine of men consuming green or black tea and chemo-preventive abilities for colon cancer revealed that black tea-specific marker 3OMGA was increased after consumption of six cups of black tea when compared with water control [94].

4. Conclusions and Future Aspects

Phytochemicals are currently gaining great importance in both cancer prevention and treatment due to their antioxidant, antiproliferative, antiangiogenic, proapoptotic, and anticancer properties. The role of benzoic and cinnamic acids is summarized in Figure 4a,b, respectively, and Table 1 [96,97]. Therefore, phenolics are robust candidates in the treatment of various types of cancer. Above all, the significant antineoplastic potential of benzoic and cinnamic acids as isolated plant phytochemicals is relatively well studied in in vitro as well as in vivo preclinical cancer research studies involving diverse cancer types. The lack of preclinical research focusing on the therapeutic effectiveness of VA against cancer may be partially explained/compensated by the occurrence of evidence demonstrating VA as potent chemo-preventive agents which was demonstrated in carcinogen-induced animal models of carcinogenesis [10,11]. Actually, the anti-cancer effectiveness of selected phytochemicals can be supported by an amount of evidence suggesting an important role of whole plant foods. Due to the presence of mixture of phytochemicals, whole plant food is suggested to exert better anti-cancer abilities when compared with isolated phytochemicals [96,97,98]. Therapeutic potential of whole plant food was demonstrated by several studies including evaluation of administration of Vaccinium myrtillus extract with GeA as the most abundant polyphenol [16], as well as RVSE with identified presence of GA [28]. Additionally, positive results were related to various whole plants characterized by presence of SyA, CA, and p-CA including Menyanthes trifoliate root extracts [49]. Extracts of Anchusa azurea Mill [66], Rosa canina extract [82], or extract of Dianthus carmelitarum [88]. Unlike clutivars of common beans [99], black raspberries did not inhibit the growth of cancer cells, despite that PCA was detected in rat prostates [100]. Importantly, several above-mentioned phytochemicals exerted also an ability to improve effectiveness or reduce side effects of conventional anticancer therapy. GeA as well as GA attenuated side effects of doxorubicin [17] and paclitaxel [43]. Additionally, GA was found to sensitize paclitaxel resistant cancer cells [44] and CA increased therapeutic potential of cisplatin [67]. Moreover, we emphasize important role of phenolics as epigenetic regulators. GA was demonstrated to be a potent inhibitor of DNMT as well as HDAC [38]. Furthermore, an ability of CA to attenuate cancer stem cells-like properties was mediated by microRNA-148a [59]. Also peanut phenolics including p-CA, FA, and SA were indicated to inhibit HDAC [91]. Above all, natural products represent potential anti-cancer agents. However, the bioavailability and efficient use of natural compounds is limited by their physico-chemical properties [26]. The use of nanomedicine in the area of drug delivery is associated with improvements in therapy efficacy, reduction of side effects, and prolonged bioavailability. GO-PEG-PCA-FA nanocarrier system designed for the PCA was found to be more effective anticancer agent when compared with free PCA [25]. Similar results were obtained also in case of PCA-ZnAL [26]. As well as in Fe₃O₄-PEG-GA [46] and PLGA-CS-PEG used to encapsulate GA [47]. Encapsulation of FE into cyclodextrin nanosponges led to improved solubility and cytotoxicity [80]. Eventually, the potential of natural compounds in association with benefit of nanocomposites need to be further studied [26].
In conclusion phenolics are robust candidates in the treatment of various types of cancer, they act on various molecular targets, (proliferation, angiogenesis, growth and differentiation, metastasis and apoptosis). However, additional studies in vitro and in vivo are required to ensure their efficacy and asses side effects. Due to the obvious lack of clinical intervention, we consider it necessary to implement evaluation of anticancer potential of phytochemicals, either isolated or mixtures, also in clinical practice.

Author Contributions

The authors contributed as follows: Conceptualization, M.A. and D.B.; Literature Review and Resources, M.A.; Writing—Original Draft Preparation, M.A.; Writing—Review and Editing, M.A.; A.L.; P.K. and D.B.; Figure Preparation and Editing, M.A. and D.B.; Visualization, M.A. and D.B.; Supervision, D.B.; Project Administration, D.B.; Funding Acquisition, D.B. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by a National Priorities Research Program grant (NPRP 11S-1214-170101; awarded to Dietrich Büsselberg, June 2019-Current) from the Qatar National Research Fund (QNRF, a member of Qatar Foundation). The statements made herein are solely the responsibility of the authors. The publication of this article was funded by the Qatar National Library.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the article.

Abbreviations

Apoptosis Inducing FactorAIF
Apoptosis Protease Activating Factor-1Apaf-1
B-Cell Lymphoma 2Bcl-2
Bcl-2 Antagonist and KillerBak
Bcl-2 Associated Death PromoterBad
Bcl2-Associated X ProteinBax
Bcl-2-Like Protein 11Bim
BH3 Interacting-Domain Death AgonistBid
Breast cancer resistance proteinBCRP
CatalaseCAT
Cadherin CDH
C-Jun N-Terminal Kinase JNK
Cyclin Dependent Kinases CDKs
Epidermal Growth Factor ReceptorEGFR
Extracellular matrixECM
Extracellular signal-regulated kinaseERK
GlutathioneGSH
Glutathione PeroxidaseGPx
Hypoxia Inducing Factor HIF-1
Lipid HydroperoxidesLOOH
Macrophage Inhibitory Cytokine MIC-1
Matrix Metalloproteinases MMP
Mechanistic target of rapamycinmTOR
Mitogen-activated protein kinase MEK
Mitogen-Activated Protein KinaseMAPK
Multidrug resistance protein MRP
Nicotinamide Adenine Dinucleotide Phosphate HydrogenNADPH
Nicotinamide Adenine Dinucleotide Phosphate OxidasesNox
N-methyl-N’-nitro-N-nitrosoguanidineMNNG
Nuclear Factor Erythroid 2-Related Factor 2NRF2
Nuclear factor-kappa BNF- κB
Organic Anion Transporter-3 OAT3
P-glycoproteinP-gp
Phosphoinositide 3-KinasePI3K
Poly (ADP-Ribose) Polymerase PARP
Protein Kinase BAkt
Protein Tyrosine Phosphatase ReceptorPTP-κ
Reactive Oxygen Species ROS
Rhodamine-123
Second Mitochondrial Derived Activator of Caspase		Rh-123
Smac
Superoxide DismutaseSOD
Tissue inhibitor of metalloproteinaseTIMP-1
Thiobarbituric Acid Reactive SubstancesTBARS
Vascular Endothelial Growth FactorVEGF

References

  1. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [Green Version]
  2. Ls, R.; Nja, S. Anticancer Properties of Phenolic Acids in Colon Cancer – A Review. J. Nutr. Food Sci. 2016, 06, 10–4172. [Google Scholar] [CrossRef] [Green Version]
  3. Anantharaju, P.G.; Gowda, P.C.; Vimalambike, M.G.; Madhunapantula, S.V. An overview on the role of dietary phenolics for the treatment of cancers. Nutr. J. 2016, 15, 99. [Google Scholar] [CrossRef] [Green Version]
  4. Călinoiu, L.F.; Vodnar, D.C.J.N. Whole grains and phenolic acids: A review on bioactivity, functionality, health benefits and bioavailability. Nutrients 2018, 10, 1615. [Google Scholar] [CrossRef] [Green Version]
  5. Srinivasulu, C.; Ramgopal, M.; Ramanjaneyulu, G.; Anuradha, C.M.; Suresh Kumar, C. Syringic acid (SA) A Review of Its Occurrence, Biosynthesis, Pharmacological and Industrial Importance. Biomed. Pharmacother 2018, 108, 547–557. [Google Scholar] [CrossRef]
  6. Rahman, M.J.; Costa de Camargo, A.; Shahidi, F. Phenolic profiles and antioxidant activity of defatted camelina and sophia seeds. Food Chem. 2018, 240, 917–925. [Google Scholar] [CrossRef] [PubMed]
  7. Chander, M. Anticancer Efficacy of Some Plant Phenolics - A Recent Scenario. IJCMAS 2018, 7, 1746–1768. [Google Scholar] [CrossRef]
  8. Gong, J.; Zhou, S.; Yang, S. Vanillic Acid Suppresses HIF-1alpha Expression via Inhibition of mTOR/p70S6K/4E-BP1 and Raf/MEK/ERK Pathways in Human Colon Cancer HCT116 Cells. Int. J. Mol. Sci. 2019, 20, 465. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Taner, G.; Ozkan Vardar, D.; Aydin, S.; Aytac, Z.; Basaran, A.; Basaran, N. Use of in vitro assays to assess the potential cytotoxic, genotoxic and antigenotoxic effects of vanillic and cinnamic acid. Drug Chem. Toxicol. 2017, 40, 183–190. [Google Scholar] [CrossRef]
  10. Velli, S.K.; Sundaram, J.; Murugan, M.; Balaraman, G.; Thiruvengadam, D. Protective effect of vanillic acid against benzo(a)pyrene induced lung cancer in Swiss albino mice. J. Biochem. Mol. Toxicol. 2019, 33, e22382. [Google Scholar] [CrossRef]
  11. Anbalagan, V.; Raju, K.; Shanmugam, M. Assessment of Lipid Peroxidation and Antioxidant Status in Vanillic Acid Treated 7,12-Dimethylbenz[a]anthracene Induced Hamster Buccal Pouch Carcinogenesis. J. Clin. Diagn Res. 2017, 11, BF01¨CBF04. [Google Scholar] [CrossRef] [PubMed]
  12. Sitarek, P.; Skala, E.; Toma, M.; Wielanek, M.; Szemraj, J.; Skorski, T.; Bialas, A.J.; Sakowicz, T.; Kowalczyk, T.; Radek, M.; et al. Transformed Root Extract of Leonurus sibiricus Induces Apoptosis through Intrinsic and Extrinsic Pathways in Various Grades of Human Glioma Cells. Pathol. Oncol. Res. 2017, 23, 679–687. [Google Scholar] [CrossRef]
  13. Bhavani, P.; Subramanian, P.; Kanimozhi, S. Preventive Efficacy of Vanillic Acid on Regulation of Redox Homeostasis, Matrix Metalloproteinases and Cyclin D1 in Rats Bearing Endometrial Carcinoma. Indian J. Clin. Biochem. 2017, 32, 429–436. [Google Scholar] [CrossRef]
  14. Ozpinar, A.; Elmaci, İ.A.; Altinoz, M. Gentisic Acid, a Quinonoid Aspirin Metabolite in Cancer Prevention and Treatment. New Horizons in Management of Brain Tumors and Systemic Cancers. J. Cancer Res. Oncobiol. 2018, 1, 109. [Google Scholar]
  15. Cavalcante, F.M.L.; Almeida, I.V.; Dusman, E.; Mantovani, M.S.; Vicentini, V.E.P. Cytotoxicity, mutagenicity, and antimutagenicity of the gentisic acid on HTC cells. Drug Chem. Toxicol. 2018, 41, 155–161. [Google Scholar] [CrossRef] [PubMed]
  16. Demirel Sezer, E.; Oktay, L.M.; Karadadas, E.; Memmedov, H.; Selvi Gunel, N.; Sozmen, E. Assessing Anticancer Potential of Blueberry Flavonoids, Quercetin, Kaempferol, and Gentisic Acid, Through Oxidative Stress and Apoptosis Parameters on HCT-116 Cells. J. Med. Food 2019, 22, 1118–1126. [Google Scholar] [CrossRef] [PubMed]
  17. Altinoz, M.A.; Elmaci, I.; Cengiz, S.; Emekli-Alturfan, E.; Ozpinar, A. From epidemiology to treatment: Aspirin’s prevention of brain and breast-cancer and cardioprotection may associate with its metabolite gentisic acid. Chem. Biol. Interact. 2018, 291, 29–39. [Google Scholar] [CrossRef]
  18. Yip, E.C.; Chan, A.S.; Pang, H.; Tam, Y.K.; Wong, Y.H. Protocatechuic acid induces cell death in HepG2 hepatocellular carcinoma cells through a c-Jun N-terminal kinase-dependent mechanism. Cell Biol. Toxicol. 2006, 22, 293–302. [Google Scholar] [CrossRef] [Green Version]
  19. Semaming, Y.; Pannengpetch, P.; Chattipakorn, S.C.; Chattipakorn, N. Pharmacological properties of protocatechuic Acid and its potential roles as complementary medicine. Evid. Based Complement. Alternat. Med. 2015, 2015, 593902. [Google Scholar] [CrossRef] [Green Version]
  20. Xie, Z.; Guo, Z.; Wang, Y.; Lei, J.; Yu, J. Protocatechuic acid inhibits the growth of ovarian cancer cells by inducing apoptosis and autophagy. Phytother. Res. 2018, 32, 2256–2263. [Google Scholar] [CrossRef]
  21. Quinn, L.; Gray, S.G.; Meaney, S.; Finn, S.; Kenny, O.; Hayes, M. Sinapinic and protocatechuic acids found in rapeseed: Isolation, characterisation and potential benefits for human health as functional food ingredients. Irish J. Agric. Food Res. 2017, 56, 104–119. [Google Scholar] [CrossRef] [Green Version]
  22. Hu, J.; Lin, S.; Huang, J.J.; Cheung, P.C.K. Mechanistic Study of the In Vitro and In Vivo Inhibitory Effects of Protocatechuic Acid and Syringic Acid on VEGF-Induced Angiogenesis. J. Agric. Food Chem. 2018, 66, 6742–6751. [Google Scholar] [CrossRef] [PubMed]
  23. Lin, H.H.; Chen, J.H.; Chou, F.P.; Wang, C.J. Protocatechuic acid inhibits cancer cell metastasis involving the down-regulation of Ras/Akt/NF-kappaB pathway and MMP-2 production by targeting RhoB activation. Br. J. Pharmacol. 2011, 162, 237–254. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Yamabe, N.; Park, J.Y.; Lee, S.; Cho, E.-J.; Lee, S.; Kang, K.S.; Hwang, G.S.; Kim, S.-N.; Kim, H.Y.; Shibamoto, T. Protective effects of protocatechuic acid against cisplatin-induced renal damage in rats. J. Funct. Foods 2015, 19, 20–27. [Google Scholar] [CrossRef]
  25. Saifullah, B.; Buskaran, K.; Shaikh, R.B.; Barahuie, F.; Fakurazi, S.; Mohd Moklas, M.A.; Hussein, M.Z. Graphene Oxide(-)PEG(-)Protocatechuic Acid Nanocomposite Formulation with Improved Anticancer Properties. Nanomaterials 2018, 8, 820. [Google Scholar] [CrossRef] [Green Version]
  26. Gani, S.A.; Muhammad, S.A.; Kura, A.U.; Barahuie, F.; Hussein, M.Z.; Fakurazi, S. Effect of protocatechuic acid-layered double hydroxide nanoparticles on diethylnitrosamine/phenobarbital-induced hepatocellular carcinoma in mice. PLoS ONE 2019, 14, e0217009. [Google Scholar] [CrossRef]
  27. Zhou, Y.; Zheng, J.; Li, Y.; Xu, D.P.; Li, S.; Chen, Y.M.; Li, H.B. Natural Polyphenols for Prevention and Treatment of Cancer. Nutrients 2016, 8, 515. [Google Scholar] [CrossRef]
  28. Kim, M.S.; Lee, C.W.; Kim, J.H.; Lee, J.C.; An, W.G. Extract of Rhus verniciflua Stokes Induces p53-Mediated Apoptosis in MCF-7 Breast Cancer Cells. Evid. Based Complement. Alternat. Med. 2019, 2019, 9407340. [Google Scholar] [CrossRef] [Green Version]
  29. He, Z.; Chen, A.Y.; Rojanasakul, Y.; Rankin, G.O.; Chen, Y.C. Gallic acid, a phenolic compound, exerts anti-angiogenic effects via the PTEN/AKT/HIF-1alpha/VEGF signaling pathway in ovarian cancer cells. Oncol. Rep. 2016, 35, 291–297. [Google Scholar] [CrossRef]
  30. Paolini, A.; Curti, V.; Pasi, F.; Mazzini, G.; Nano, R.; Capelli, E. Gallic acid exerts a protective or an anti-proliferative effect on glioma T98G cells via dose-dependent epigenetic regulation mediated by miRNAs. Int. J. Oncol. 2015, 46, 1491–1497. [Google Scholar] [CrossRef] [Green Version]
  31. Heidarian, E.; Keloushadi, M.; Ghatreh-Samani, K.; Valipour, P. The reduction of IL-6 gene expression, pAKT, pERK1/2, pSTAT3 signaling pathways and invasion activity by gallic acid in prostate cancer PC3 cells. Biomed. Pharmacother. 2016, 84, 264–269. [Google Scholar] [CrossRef] [PubMed]
  32. Demiroglu-Zergeroglu, A.; Candemir, G.; Turhanlar, E.; Sagir, F.; Ayvali, N. EGFR-dependent signalling reduced and p38 dependent apoptosis required by Gallic acid in Malignant Mesothelioma cells. Biomed. Pharmacother. 2016, 84, 2000–2007. [Google Scholar] [CrossRef] [PubMed]
  33. Hsu, S.S.; Chou, C.T.; Liao, W.C.; Shieh, P.; Kuo, D.H.; Kuo, C.C.; Jan, C.R.; Liang, W.Z. The effect of gallic acid on cytotoxicity, Ca2+ homeostasis and ROS production in DBTRG-05MG human glioblastoma cells and CTX TNA2 rat astrocytes. Chem. Biol. Interact. 2016, 252, 61–73. [Google Scholar] [CrossRef] [PubMed]
  34. Park, W.H. Gallic acid induces HeLa cell death via increasing GSH depletion rather than ROS levels. Oncol. Rep. 2017, 37, 1277–1283. [Google Scholar] [CrossRef] [Green Version]
  35. Lee, H.L.; Lin, C.S.; Kao, S.H.; Chou, M.C. Gallic acid induces G1 phase arrest and apoptosis of triple-negative breast cancer cell MDA-MB-231 via p38 mitogen-activated protein kinase/p21/p27 axis. Anticancer Drugs 2017, 28, 1150–1156. [Google Scholar] [CrossRef]
  36. Tsai, C.L.; Chiu, Y.M.; Ho, T.Y.; Hsieh, C.T.; Shieh, D.C.; Lee, Y.J.; Tsay, G.J.; Wu, Y.Y. Gallic Acid Induces Apoptosis in Human Gastric Adenocarcinoma Cells. Anticancer Res. 2018, 38, 2057–2067. [Google Scholar]
  37. Weng, Y.-P.; Hung, P.-F.; Ku, W.-Y.; Chang, C.-Y.; Wu, B.-H.; Wu, M.-H.; Yao, J.-Y.; Yang, J.-R.; Lee, C.-H. The inhibitory activity of gallic acid against DNA methylation: Application of gallic acid on epigenetic therapy of human cancers. Oncotarget 2017, 9, 361–374. [Google Scholar] [CrossRef] [Green Version]
  38. Choi, S.Y.; Kee, H.J.; Jin, L.; Ryu, Y.; Sun, S.; Kim, G.R.; Jeong, M.H. Inhibition of class IIa histone deacetylase activity by gallic acid, sulforaphane, TMP269, and panobinostat. Biomed. Pharmacother. 2018, 101, 145–154. [Google Scholar] [CrossRef]
  39. Pang, J.S.; Yen, J.H.; Wu, H.T.; Huang, S.T. Gallic Acid Inhibited Matrix Invasion and AP-1/ETS-1-Mediated MMP-1 Transcription in Human Nasopharyngeal Carcinoma Cells. Int. J. Mol. Sci. 2017, 18, 1354. [Google Scholar] [CrossRef] [Green Version]
  40. Ho, H.H.; Chang, C.S.; Ho, W.C.; Liao, S.Y.; Lin, W.L.; Wang, C.J. Gallic acid inhibits gastric cancer cells metastasis and invasive growth via increased expression of RhoB, downregulation of AKT/small GTPase signals and inhibition of NF-kappaB activity. Toxicol. Appl. Pharmacol. 2013, 266, 76–85. [Google Scholar] [CrossRef]
  41. Aikebaier, M.; Amier, A.; Hureshitanmu, K.; Xuejun, L. VDAC1 Mediated Anticancer Activity of Gallic Acid in Human Lung Adenocarcinoma A549 Cells. Anti-Cancer Agents Med. Chem. 2018, 18, 255–262. [Google Scholar]
  42. Zhang, T.; Ma, L.; Wu, P.; Li, W.; Li, T.; Gu, R.; Dan, X.; Li, Z.; Fan, X.; Xiao, Z. Gallic acid has anticancer activity and enhances the anticancer effects of cisplatin in nonsmall cell lung cancer A549 cells via the JAK/STAT3 signaling pathway. Oncol. Rep. 2019, 41, 1779–1788. [Google Scholar] [PubMed] [Green Version]
  43. Aborehab, N.M.; Osama, N. Effect of Gallic acid in potentiating chemotherapeutic effect of Paclitaxel in HeLa cervical cancer cells. Cancer Cell Int. 2019, 19, 154. [Google Scholar] [CrossRef] [PubMed]
  44. Sanchez-Carranza, J.N.; Diaz, J.F.; Redondo-Horcajo, M.; Barasoain, I.; Alvarez, L.; Lastres, P.; Romero-Estrada, A.; Aller, P.; Gonzalez-Maya, L. Gallic acid sensitizes paclitaxel-resistant human ovarian carcinoma cells through an increase in reactive oxygen species and subsequent downregulation of ERK activation. Oncol. Rep. 2018, 39, 3007–3014. [Google Scholar] [PubMed]
  45. Wang, R.; Ma, L.; Weng, D.; Yao, J.; Liu, X.; Jin, F. Gallic acid induces apoptosis and enhances the anticancer effects of cisplatin in human small cell lung cancer H446 cell line via the ROS-dependent mitochondrial apoptotic pathway. Oncol. Rep. 2016, 35, 3075–3083. [Google Scholar] [CrossRef] [PubMed]
  46. Rosman, R.; Saifullah, B.; Maniam, S.; Dorniani, D.; Hussein, M.Z.; Fakurazi, S. Improved Anticancer Effect of Magnetite Nanocomposite Formulation of GALLIC Acid (Fe(3)O(4)-PEG-GA) Against Lung, Breast and Colon Cancer Cells. Nanomaterials 2018, 8, 83. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Ahmed, H.H.; Galal, A.F.; Shalby, A.B.; Abd-Rabou, A.A.; Mehaya, F.M. Improving Anti-Cancer Potentiality and Bioavailability of Gallic Acid by Designing Polymeric Nanocomposite Formulation. Asian Pac. J. Cancer Prev. 2018, 19, 3137–3146. [Google Scholar] [CrossRef] [Green Version]
  48. Ha, S.J.; Lee, J.; Park, J.; Kim, Y.H.; Lee, N.H.; Kim, Y.E.; Song, K.M.; Chang, P.S.; Jeong, C.H.; Jung, S.K. Syringic acid prevents skin carcinogenesis via regulation of NoX and EGFR signaling. Biochem. Pharmacol. 2018, 154, 435–445. [Google Scholar] [CrossRef]
  49. Kowalczyk, T.; Sitarek, P.; Skala, E.; Toma, M.; Wielanek, M.; Pytel, D.; Wieczfinska, J.; Szemraj, J.; Sliwinski, T. Induction of apoptosis by in vitro and in vivo plant extracts derived from Menyanthes trifoliata L. in human cancer cells. Cytotechnology 2019, 71, 165–180. [Google Scholar]
  50. Afrin, S.; Giampieri, F.; Gasparrini, M.; Forbes-Hernandez, T.Y.; Cianciosi, D.; Reboredo-Rodriguez, P.; Amici, A.; Quiles, J.L.; Battino, M. The inhibitory effect of Manuka honey on human colon cancer HCT-116 and LoVo cell growth. Part 1: The suppression of cell proliferation, promotion of apoptosis and arrest of the cell cycle. Food Funct. 2018, 9, 2145–2157. [Google Scholar] [CrossRef]
  51. Gheena, S.; Ezhilarasan, D. Syringic acid triggers reactive oxygen species-mediated cytotoxicity in HepG2 cells. Hum. Exp. Toxicol. 2019, 38, 694–702. [Google Scholar] [CrossRef] [PubMed]
  52. Velu, P.; Vinothkumar, V.; Babukumar, S.; Ramachandhiran, D. Chemopreventive effect of syringic acid on 7,12-dimethylbenz(a)anthracene induced hamster buccal pouch carcinogenesis. Toxicol. Mech. Methods 2017, 27, 631–640. [Google Scholar] [CrossRef] [PubMed]
  53. Periyannan, V.; Veerasamy, V. Syringic acid may attenuate the oral mucosal carcinogenesis via improving cell surface glycoconjugation and modifying cytokeratin expression. Toxicol. Rep. 2018, 5, 1098–1106. [Google Scholar] [CrossRef] [PubMed]
  54. Abaza, M.S.; Al-Attiyah, R.; Bhardwaj, R.; Abbadi, G.; Koyippally, M.; Afzal, M. Syringic acid from Tamarix aucheriana possesses antimitogenic and chemo-sensitizing activities in human colorectal cancer cells. Pharm. Biol. 2013, 51, 1110–1124. [Google Scholar] [CrossRef] [Green Version]
  55. Genaro-Mattos, T.C.; Mauricio, A.Q.; Rettori, D.; Alonso, A.; Hermes-Lima, M. Antioxidant Activity of Caffeic Acid against Iron-Induced Free Radical Generation--A Chemical Approach. PLoS ONE 2015, 10, e0129963. [Google Scholar]
  56. Murad, L.D.; Soares Nda, C.; Brand, C.; Monteiro, M.C.; Teodoro, A.J. Effects of caffeic and 5-caffeoylquinic acids on cell viability and cellular uptake in human colon adenocarcinoma cells. Nutr. Cancer 2015, 67, 532–542. [Google Scholar] [CrossRef]
  57. Nasr Bouzaiene, N.; Kilani Jaziri, S.; Kovacic, H.; Chekir-Ghedira, L.; Ghedira, K.; Luis, J. The effects of caffeic, coumaric and ferulic acids on proliferation, superoxide production, adhesion and migration of human tumor cells in vitro. Eur. J. Pharmacol. 2015, 766, 99–105. [Google Scholar] [CrossRef]
  58. Pelinson, L.P.; Assmann, C.E.; Palma, T.V.; da Cruz, I.B.M.; Pillat, M.M.; Manica, A.; Stefanello, N.; Weis, G.C.C.; de Oliveira Alves, A.; de Andrade, C.M.; et al. Antiproliferative and apoptotic effects of caffeic acid on SK-Mel-28 human melanoma cancer cells. Mol. Biol. Rep. 2019, 46, 2085–2092. [Google Scholar] [CrossRef]
  59. Li, Y.; Jiang, F.; Chen, L.; Yang, Y.; Cao, S.; Ye, Y.; Wang, X.; Mu, J.; Li, Z.; Li, L. Blockage of TGFbeta-SMAD2 by demethylation-activated miR-148a is involved in caffeic acid-induced inhibition of cancer stem cell-like properties in vitro and in vivo. FEBS Open Bio 2015, 5, 466–475. [Google Scholar] [CrossRef] [Green Version]
  60. Kabala-Dzik, A.; Rzepecka-Stojko, A.; Kubina, R.; Jastrzebska-Stojko, Z.; Stojko, R.; Wojtyczka, R.D.; Stojko, J. Comparison of Two Components of Propolis: Caffeic Acid (CA) and Caffeic Acid Phenethyl Ester (CAPE) Induce Apoptosis and Cell Cycle Arrest of Breast Cancer Cells MDA-MB-231. Molecules 2017, 22, 1554. [Google Scholar] [CrossRef] [Green Version]
  61. Marin, E.H.; Paek, H.; Li, M.; Ban, Y.; Karaga, M.K.; Shashidharamurthy, R.; Wang, X. Caffeic acid phenethyl ester exerts apoptotic and oxidative stress on human multiple myeloma cells. Invest. New Drugs 2019, 37, 837–848. [Google Scholar] [CrossRef] [PubMed]
  62. Liu, G.L.; Han, N.Z.; Liu, S.S. Caffeic acid phenethyl ester inhibits the progression of ovarian cancer by regulating NF-κB signaling. Biomed. Pharmacother. 2018, 99, 825–831. [Google Scholar] [CrossRef] [PubMed]
  63. Chiang, K.C.; Yang, S.W.; Chang, K.P.; Feng, T.H.; Chang, K.S.; Tsui, K.H.; Shin, Y.S.; Chen, C.C.; Chao, M.; Juang, H.H. Caffeic Acid Phenethyl Ester Induces N-myc Downstream Regulated Gene 1 to Inhibit Cell Proliferation and Invasion of Human Nasopharyngeal Cancer Cells. Int. J. Mol. Sci. 2018, 19, 1397. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Kabala-Dzik, A.; Rzepecka-Stojko, A.; Kubina, R.; Wojtyczka, R.D.; Buszman, E.; Stojko, J. Caffeic Acid Versus Caffeic Acid Phenethyl Ester in the Treatment of Breast Cancer MCF-7 Cells: Migration Rate Inhibition. Integr. Cancer Ther. 2018, 17, 1247–1259. [Google Scholar] [CrossRef] [PubMed]
  65. Mohamad, N.E.; Abu, N.; Yeap, S.K.; Lim, K.L.; Romli, M.F.; Sharifuddin, S.A.; Long, K.; Alitheen, N.B. Apoptosis and metastasis inhibitory potential of pineapple vinegar against mouse mammary gland cells in vitro and in vivo. Nutr. Metab. 2019, 16, 49. [Google Scholar] [CrossRef] [Green Version]
  66. Ceramella, J.; Loizzo, M.R.; Iacopetta, D.; Bonesi, M.; Sicari, V.; Pellicano, T.M.; Saturnino, C.; Malzert-Freon, A.; Tundis, R.; Sinicropi, M.S. Anchusa azurea Mill. (Boraginaceae) aerial parts methanol extract interfering with cytoskeleton organization induces programmed cancer cells death. Food Funct. 2019, 10, 4280–4290. [Google Scholar] [CrossRef]
  67. Koraneekit, A.; Limpaiboon, T.; Sangka, A.; Boonsiri, P.; Daduang, S.; Daduang, J. Synergistic effects of cisplatin-caffeic acid induces apoptosis in human cervical cancer cells via the mitochondrial pathways. Oncol. Lett. 2018, 15, 7397–7402. [Google Scholar] [CrossRef]
  68. Sarwar, T.; Zafaryab, M.; Husain, M.A.; Ishqi, H.M.; Rehman, S.U.; Rizvi, M.M.; Tabish, M. Redox cycling of endogenous copper by ferulic acid leads to cellular DNA breakage and consequent cell death: A putative cancer chemotherapy mechanism. Toxicol. Appl. Pharmacol. 2015, 289, 251–261. [Google Scholar] [CrossRef]
  69. Eroglu, C.; Secme, M.; Bagci, G.; Dodurga, Y. Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines. Tumour Biol. 2015, 36, 9437–9446. [Google Scholar] [CrossRef]
  70. Sevgi, K.; Tepe, B.; Sarikurkcu, C. Antioxidant and DNA damage protection potentials of selected phenolic acids. Food Chem. Toxicol. 2015, 77, 12–21. [Google Scholar] [CrossRef]
  71. Yang, G.W.; Jiang, J.S.; Lu, W.Q. Ferulic Acid Exerts Anti-Angiogenic and Anti-Tumor Activity by Targeting Fibroblast Growth Factor Receptor 1-Mediated Angiogenesis. Int. J. Mol. Sci. 2015, 16, 24011–24031. [Google Scholar] [CrossRef] [PubMed]
  72. Fahrioglu, U.; Dodurga, Y.; Elmas, L.; Secme, M. Ferulic acid decreases cell viability and colony formation while inhibiting migration of MIA PaCa-2 human pancreatic cancer cells in vitro. Gene 2016, 576, 476–482. [Google Scholar] [CrossRef] [PubMed]
  73. Zhang, X.D.; Wu, Q.; Yang, S.H. Ferulic acid promoting apoptosis in human osteosarcoma cell lines. Pak. J. Med. Sci. 2017, 33, 127–131. [Google Scholar] [CrossRef] [PubMed]
  74. Wang, T.; Gong, X.; Jiang, R.; Li, H.; Du, W.; Kuang, G. Ferulic acid inhibits proliferation and promotes apoptosis via blockage of PI3K/Akt pathway in osteosarcoma cell. American J. Trans. Res. 2016, 8, 968. [Google Scholar]
  75. Zhang, X.; Lin, D.; Jiang, R.; Li, H.; Wan, J.; Li, H. Ferulic acid exerts antitumor activity and inhibits metastasis in breast cancer cells by regulating epithelial to mesenchymal transition. Oncol. Rep. 2016, 36, 271–278. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Dodurga, Y.; Eroglu, C.; Secme, M.; Elmas, L.; Avci, C.B.; Satiroglu-Tufan, N.L. Anti-proliferative and anti-invasive effects of ferulic acid in TT medullary thyroid cancer cells interacting with URG4/URGCP. Tumour Biol. 2016, 37, 1933–1940. [Google Scholar] [CrossRef]
  77. Yue, S.J.; Zhang, P.X.; Zhu, Y.; Li, N.G.; Chen, Y.Y.; Li, J.J.; Zhang, S.; Jin, R.Y.; Yan, H.; Shi, X.Q.; et al. A Ferulic Acid Derivative FXS-3 Inhibits Proliferation and Metastasis of Human Lung Cancer A549 Cells via Positive JNK Signaling Pathway and Negative ERK/p38, AKT/mTOR and MEK/ERK Signaling Pathways. Molecules 2019, 24, 2165. [Google Scholar] [CrossRef] [Green Version]
  78. Sudhagar, S.; Sathya, S.; Anuradha, R.; Gokulapriya, G.; Geetharani, Y.; Lakshmi, B.S. Inhibition of epidermal growth factor receptor by ferulic acid and 4-vinylguaiacol in human breast cancer cells. Biotechnol. Lett. 2018, 40, 257–262. [Google Scholar] [CrossRef]
  79. Muthusamy, G.; Gunaseelan, S.; Prasad, N.R. Ferulic acid reverses P-glycoprotein-mediated multidrug resistance via inhibition of PI3K/Akt/NF-kappaB signaling pathway. J. Nutr. Biochem. 2019, 63, 62–71. [Google Scholar] [CrossRef]
  80. Ezhuthupurakkal, P.B.; Ariraman, S.; Arumugam, S.; Subramaniyan, N.; Muthuvel, S.K.; Kumpati, P.; Rajamani, B.; Chinnasamy, T. Anticancer potential of ZnO nanoparticle-ferulic acid conjugate on Huh-7 and HepG2 cells and diethyl nitrosamine induced hepatocellular cancer on Wistar albino rat. Nanomedicine 2018, 14, 415–428. [Google Scholar] [CrossRef]
  81. Zheng, Y.; You, X.; Chen, L.; Huang, J.; Wang, L.; Wu, J.; Guan, S. Biotherapeutic Nanoparticles of Poly(Ferulic Acid) Delivering Doxorubicin for Cancer Therapy. J. Biomed. Nanotechnol. 2019, 15, 1734–1743. [Google Scholar] [CrossRef] [PubMed]
  82. Kilinc, K.; Demir, S.; Turan, I.; Mentese, A.; Orem, A.; Sonmez, M.; Aliyazicioglu, Y. Rosa canina Extract has Antiproliferative and Proapoptotic Effects on Human Lung and Prostate Cancer Cells. Nutr. Cancer 2019, 1–10. [Google Scholar] [CrossRef] [PubMed]
  83. Boz, H.J.I. p-Coumaric acid in cereals: Presence, antioxidant and antimicrobial effects. IJFST 2015, 50, 2323–2328. [Google Scholar] [CrossRef]
  84. Sharma, S.H.; Rajamanickam, V.; Nagarajan, S. Antiproliferative effect of p-Coumaric acid targets UPR activation by downregulating Grp78 in colon cancer. Chem. Biol. Interact. 2018, 291, 16–28. [Google Scholar] [CrossRef]
  85. Sharma, S.H.; Chellappan, D.R.; Chinnaswamy, P.; Nagarajan, S. Protective effect of p-coumaric acid against 1,2 dimethylhydrazine induced colonic preneoplastic lesions in experimental rats. Biomed. Pharmacother. 2017, 94, 577–588. [Google Scholar] [CrossRef] [PubMed]
  86. Sharma, S.H.; Rajamanickam, V.; Nagarajan, S. Supplementation of p-coumaric acid exhibits chemopreventive effect via induction of Nrf2 in a short-term preclinical model of colon cancer. Eur. J. Cancer Prev. 2019, 28, 472–482. [Google Scholar] [CrossRef] [PubMed]
  87. Lu, Y.; Shan, S.; Li, H.; Shi, J.; Zhang, X.; Li, Z. Reversal Effects of Bound Polyphenol from Foxtail Millet Bran on Multidrug Resistance in Human HCT-8/Fu Colorectal Cancer Cell. J. Agric. Food Chem. 2018, 66, 5190–5199. [Google Scholar] [CrossRef]
  88. Turan, I.; Demir, S.; Aliyazicioglu, R.; Kilinc, K.; Ozer Yaman, S.; Akbulut Cakiroglu, K.; Kanbolat, S.; Ayazoglu Demir, E.; Mentese, A.; Aliyazicioglu, Y.; et al. Dimethyl Sulfoxide Extract of Dianthus carmelitarum Induces S Phase Arrest and Apoptosis in Human Colon Cancer Cells. Nutr. Cancer 2019, 71, 1181–1188. [Google Scholar] [CrossRef]
  89. El-Hawary, S.S.; Sayed, A.M.; Mohammed, R.; Hassan, H.M.; Zaki, M.A.; Rateb, M.E.; Mohammed, T.A.; Amin, E.; Abdelmohsen, U.R. Epigenetic Modifiers Induce Bioactive Phenolic Metabolites in the Marine-Derived Fungus Penicillium brevicompactum. Mar. Drugs 2018, 16, 253. [Google Scholar] [CrossRef] [Green Version]
  90. Eroglu, C.; Avci, E.; Vural, H.; Kurar, E. Anticancer mechanism of Sinapic acid in PC-3 and LNCaP human prostate cancer cell lines. Gene 2018, 671, 127–134. [Google Scholar] [CrossRef]
  91. Saenglee, S.; Jogloy, S.; Patanothai, A.; Leid, M.; Senawong, T. Cytotoxic effects of peanut phenolics possessing histone deacetylase inhibitory activity in breast and cervical cancer cell lines. Pharmacol. Rep. 2016, 68, 1102–1110. [Google Scholar] [CrossRef] [PubMed]
  92. Gierach, G.L.; Freedman, N.D.; Andaya, A.; Hollenbeck, A.R.; Park, Y.; Schatzkin, A.; Brinton, L.A. Coffee intake and breast cancer risk in the NIH-AARP diet and health study cohort. Int. J. Cancer 2012, 131, 452–460. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Oresajo, C.; Stephens, T.; Hino, P.D.; Law, R.M.; Yatskayer, M.; Foltis, P.; Pillai, S.; Pinnell, S.R. Protective effects of a topical antioxidant mixture containing vitamin C, ferulic acid, and phloretin against ultraviolet-induced photodamage in human skin. J. Cosmet. Dermatol. 2008, 7, 290–297. [Google Scholar] [CrossRef] [PubMed]
  94. Henning, S.M.; Wang, P.; Abgaryan, N.; Vicinanza, R.; de Oliveira, D.M.; Zhang, Y.; Lee, R.P.; Carpenter, C.L.; Aronson, W.J.; Heber, D. Phenolic acid concentrations in plasma and urine from men consuming green or black tea and potential chemopreventive properties for colon cancer. Mol. Nutr. Food Res. 2013, 57, 483–493. [Google Scholar] [CrossRef] [Green Version]
  95. Hodgson, J.M.; Morton, L.W.; Puddey, I.B.; Beilin, L.J.; Croft, K.D. Gallic Acid Metabolites Are Markers of Black Tea Intake in Humans. J. Agric. Food Chem. 2000, 48, 2276–2280. [Google Scholar] [CrossRef]
  96. Liskova, A.; Kubatka, P.; Samec, M.; Zubor, P.; Mlyncek, M.; Bielik, T.; Samuel, S.M.; Zulli, A.; Kwon, T.K.; Busselberg, D. Dietary Phytochemicals Targeting Cancer Stem Cells. Molecules 2019, 24, 899. [Google Scholar] [CrossRef] [Green Version]
  97. Samec, M.; Liskova, A.; Kubatka, P.; Uramova, S.; Zubor, P.; Samuel, S.M.; Zulli, A.; Pec, M.; Bielik, T.; Biringer, K.; et al. The role of dietary phytochemicals in the carcinogenesis via the modulation of miRNA expression. J. Cancer Res. Clin. Oncol. 2019, 145, 1665–1679. [Google Scholar] [CrossRef]
  98. Jasek, K.; Kubatka, P.; Samec, M.; Liskova, A.; Smejkal, K.; Vybohova, D.; Bugos, O.; Biskupska-Bodova, K.; Bielik, T.; Zubor, P.; et al. DNA Methylation Status in Cancer Disease: Modulations by Plant-Derived Natural Compounds and Dietary Interventions. Biomolecules 2019, 9, 289. [Google Scholar] [CrossRef] [Green Version]
  99. Moreno-Jimenez, M.R.; Lopez-Barraza, R.; Cervantes-Cardoza, V.; Perez-Ramirez, I.F.; Reyna-Rojas, J.A.; Gallegos-Infante, J.A.; Estrella, I.; Rojas-Contreras, J.A.; Gonzalez-Laredo, R.F.; Rocha-Guzman, N.E. Mechanisms associated to apoptosis of cancer cells by phenolic extracts from two canned common beans varieties (Phaseolus vulgaris L.). J. Food Biochem. 2019, 43, e12680. [Google Scholar] [CrossRef]
  100. Eskra, J.N.; Dodge, A.; Schlicht, M.J.; Bosland, M.C. Effects of Black Raspberries and Their Constituents on Rat Prostate Carcinogenesis and Human Prostate Cancer Cell Growth In Vitro. Nutr. Cancer 2019, 1–14. [Google Scholar] [CrossRef]
Biomolecules 10 00221 g001 550
Figure 1. Molecular pathways targeted in cancer treatment.
Figure 1. Molecular pathways targeted in cancer treatment.
Biomolecules 10 00221 g001
Biomolecules 10 00221 g002 550
Figure 2. Biosynthesis of phenolic acids in plants via the shikimic acid pathway. Adapted from [3].
Figure 2. Biosynthesis of phenolic acids in plants via the shikimic acid pathway. Adapted from [3].
Biomolecules 10 00221 g002
Biomolecules 10 00221 g003a 550Biomolecules 10 00221 g003b 550
Figure 3. (a) Benzoic acids: vanillic, gentisic, protocatechuic, gallic, and syringic acid; (b) Cinnamic acids: caffeic, ferulic, p-coumaric, and sinapic acid.
Figure 3. (a) Benzoic acids: vanillic, gentisic, protocatechuic, gallic, and syringic acid; (b) Cinnamic acids: caffeic, ferulic, p-coumaric, and sinapic acid.
Biomolecules 10 00221 g003aBiomolecules 10 00221 g003b
Biomolecules 10 00221 g004 550
Figure 4. (a) Molecular targets of benzoic acids; vanillic, gallic, gentisic, protocatechuic and syringic in cancer treatment (b) Molecular targets of cinnamic acids; caffeic, ferulic, p-coumaric, and sinapic in cancer treatment.
Figure 4. (a) Molecular targets of benzoic acids; vanillic, gallic, gentisic, protocatechuic and syringic in cancer treatment (b) Molecular targets of cinnamic acids; caffeic, ferulic, p-coumaric, and sinapic in cancer treatment.
Biomolecules 10 00221 g004
Table
Table 1. Main anticancer pathways of phenolic acids.
Table 1. Main anticancer pathways of phenolic acids.
CompoundSourceAnticancer EffectCancer TypeType of StudyMechanismReferences
Vanillic AcidAngelica sinensis and green tea(-) growth and proliferationColonin vitro(-) mTOR/p70S6K/4E-BP1[8]
Vanillic Acid(+) apoptosis and antioxidantEndometrial rat modelin vivo(+) SOD, CAT, GPx, GSH, and vitamins C and E, (-) TBARS, LOOH[13]
Vanillic Acid(-) metastasisEndometrial rat modelin vivo(-) Cyclin D1, MMP -2, -9[13]
Gentisic acidcitric fruits, grapes, artichoke, sesame, and olives(+) apoptosis and antioxidantGlioblastomain vitrodirect free radical scavenging activity
indirect agonist of NRF2		[14]
Protocatechuic acidplum, star anise, melissa, rosemary, cinnamon, sudan mallow, St. John’s wort, berries, cauliflower, and lentils(+) apoptosis and antioxidantLeukemia
Gastric		in vitro(+) ROS, DNA fragmentation, Bax, RB phosphorylation, Fas/FasL pathway, (-) Bcl-2, loss of mitochondrial membrane potential[19]
Protocatechuic acid(-) metastasisGastricin vitro(-) MMP-2[21]
Gallic acidchestnut green chicory, blackberry, raspberry, walnuts, chocolate, wine, green tea, and vinegar(-) proliferationMesotheliomain vitro(-) VEGF and EGFR[32]
Gallic acid(+) apoptosis and antioxidantCervical
Prostate
Colon
GBM		in vitro(+) ROS & GSH
(-) p38 MAPK
Changes in calcium ion homeostasis		[27,30,34]
Gallic acid(-) metastasisProstate
Nasopharyngeal		in vitro(-) MMP-1, -2, -9[27,31,40]
Syringic aciddates, olives, pumpkin, grapes, spices, acai, red wine, palm and honey(+) apoptosis and antioxidantColon in vitroextrinsic, intrinsic, and mitochondrial pathways; (+) p53, Bax, Bak, Bad, Bid, Bim, Apaf1, AIF Smac, caspases-2, 3, 6, 7, 8 and 9, endoplasmic stress markers. cytochrome c, ROS
(-) in the mitochondrial membrane potential, Bcl-2		[50,54]
Syringic acid(+) apoptosis and antioxidantHamster buccal pouchin vivo(-) TBARS, LOOH, (+) enzymatic (SOD, CAT and Gpx) and non-enzymatic (vitamin E and GSH) antioxidants[53]
Syringic acidcell cycleColon in vitroarrest at S-phase, (-) cell cycle proteins CDK4, 6 and cyclins B, C, E1, H and (+) p19, p21Cip1/Waf1 and p27kip1[54]
Caffeic acidwheat, quinoa, triticale, barley, corn, oat, rye, rice, thyme, oregano millet, sage, and sorghumantioxidantColonin vitroiron- chelating property (-) Fenton-induced oxidative damage and preventing the formation of free hydroxyl radicals[55]
Caffeic acid(-) metastasisLung
Colon		in vitro(-) cell adhesion[3,57]
Ferulic acidwheat, buckwheat, rice, corn, oats, rye, orange, corn, herbs, spices, sorghum, millet, quinoa, and barley(-) metastasisEndothelial
Breast		in vitro(-) FGF, cell adhesion, MMP -2, -9[71,75]
Ferulic acidCell cycle arrestLung
Colon
Osteosarcoma		in vitroG0/G1 arrest (-) CDK 2, 4 and 6, PI3K/Akt, Cyclins D1 and E[3,57,73,74,77]
Ferulic acid(-) proliferationBreastin vitro(-) EGF[78]
Ferulic acid(+) apoptosis and antioxidantThyroid
Lung
Osteosarcoma		in vitro(+) Bax, PARP, PUMA, NOXA, Bid, p53, PTEN, caspases-3 and -9,
(-) CDK 4/6, CD 1, Bcl-2		[73,74,76,77]
p-Coumaricwheat, barley oat, corn, rye, quinoa, rice, millet, honey sorghum barley grains and buckwheat(+) apoptosis and antioxidantLung
Prostate
Colon		in vitro(+) the ROS levels, Bax/Bcl-2 ratio, loss of mitochondrial membrane potential, Rh-123(-) MRP1, P-gp, and BCRP[82,85,86,87]
p-Coumaricanti-inflammatoryColonin vitro(-) IL-6, COX-2, TNF-α, PGE2, p-p65 and p-IκBα[84]
Sinapic acidcereal grains, rye, wheat triticale, barley, oat, rye, rice, rapeseed, kale, white cabbage, turnip, broccoli, citrus fruits, sage and thyme(+) apoptosis and antioxidantProstatein vitro(+) activities of enzymatic and non- enzymatic antioxidants; SOD, CAT, and GSH
(+) Bax, caspases -3, -7, -8, FAS, TIMP-1, cytochrome c		[21,90]
Sinapic acid(-) metastasisProstatein vitro(-) MMP-2, -9, CDH 1, 2[90]

Share and Cite

MDPI and ACS Style

Abotaleb, M.; Liskova, A.; Kubatka, P.; Büsselberg, D. Therapeutic Potential of Plant Phenolic Acids in the Treatment of Cancer. Biomolecules 2020, 10, 221. https://doi.org/10.3390/biom10020221

AMA Style

Abotaleb M, Liskova A, Kubatka P, Büsselberg D. Therapeutic Potential of Plant Phenolic Acids in the Treatment of Cancer. Biomolecules. 2020; 10(2):221. https://doi.org/10.3390/biom10020221

Chicago/Turabian Style

Abotaleb, Mariam, Alena Liskova, Peter Kubatka, and Dietrich Büsselberg. 2020. "Therapeutic Potential of Plant Phenolic Acids in the Treatment of Cancer" Biomolecules 10, no. 2: 221. https://doi.org/10.3390/biom10020221

APA Style

Abotaleb, M., Liskova, A., Kubatka, P., & Büsselberg, D. (2020). Therapeutic Potential of Plant Phenolic Acids in the Treatment of Cancer. Biomolecules, 10(2), 221. https://doi.org/10.3390/biom10020221

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop