Anticancer, Cardio-Protective and Anti-Inflammatory Potential of Natural-Sources-Derived Phenolic Acids

Phenolic acids (PAs) are one of the utmost prevalent classes of plant-derived bioactive chemicals. They have a specific taste and odor, and are found in numerous medicinal and food plants, such as Cynomorium coccineum L., Prunus domestica (L.), and Vitis vinifera L. Their biosynthesis, physical and chemical characteristics and structure–activity relationship are well understood. These phytochemicals and their derivatives exert several bioactivities including but not limited to anticancer, cardioprotective, anti-inflammatory, immune-regulatory and anti-obesity properties. They are strong antioxidants because of hydroxyl groups which play pivotal role in their anticancer, anti-inflammatory and cardioprotective potential. They may play significant role in improving human health owing to anticarcinogenic, anti-arthritis, antihypertensive, anti-stroke, and anti-atherosclerosis activities, as several PAs have demonstrated biological activities against these disease during in vitro and in vivo studies. These PAs exhibited anticancer action by promoting apoptosis, targeting angiogenesis, and reducing abnormal cell growth, while anti-inflammatory activity was attributed to reducing proinflammatory cytokines. Pas exhibited anti-atherosclerotic activity via inhibition of platelets. Moreover, they also reduced cardiovascular complications such as myocardial infarction and stroke by activating Paraoxonase 1. The present review focuses on the plant sources, structure activity relationship, anticancer, anti-inflammatory and cardioprotective actions of PAs that is attributed to modulation of oxidative stress and signal transduction pathways, along with highlighting their mechanism of actions in disease conditions. Further, preclinical and clinical studies must be carried out to evaluate the mechanism of action and drug targets of PAs to understand their therapeutic actions and disease therapy in humans, respectively.


Introduction
Phytochemicals are not only a pivotal source of numerous active pharmaceuticals but also help in the adaptation of plants to their natural environment [1]. Plants are considered to be the primary source of naturally occurring bioactive compounds such as secondary metabolites and antioxidants. Approximately one to two hundred thousand plant secondary metabolites have been discovered in the world, of which almost 8000 naturally existing compounds belong to the class of phenolics [2,3]. Vegetables, fruits, cereals, and nuts are ample sources of polyphenols.
Polyphenols are a diverse and structurally complex group, with molecular weights between 50 to 3000 Daltons. Polyphenols are further distributed into numerous major classes, including flavonoids, phenolic acids (PA), stilbenes, and lignans. Coumarins (simple and polycyclic) exist as a separate subclass. Flavonoids, as a major class, can be characterized as flavanones, isoflavones, flavanols, anthocyanins, and flavonolignans [4]. PAs are welldistributed in plants such as Coffea arabica L., Camellia sinensis (L.), Cynomorium coccineum L., and Phyllanthus embelica L. The second most common subclasses of polyphenols are chiefly categorized into benzoic and cinnamic acid derivatives [3,5]. Another class, "stilbenes", is only produced during pathogenesis. Lastly, lignans are known as phytoestrogens with a high abundance in flaxseed oil. Generally, the structural features of the polyphenol family contribute substantially to its bioavailability, pharmacokinetics, biomolecular interactions and effectiveness [4].
In contrast to flavonoids, free PAs, for instance, hydroxybenzoic acid (HBA) and hydroxycinnamic acid (HCA), have profound water solubility and bioavailability. Similar to flavonoids, they have profound antioxidant action. PAs and flavonoids have gained more interest because of their potential biological actions, such as antioxidant, cardioprotective, anti-inflammatory, anti-atherosclerotic, immunoregulatory, anti-allergenic, antithrombolytic, antimicrobial, antitumor, anti-obesity, anticancer and anti-diabetic properties [6][7][8]. This study aims to provide information on the distribution of phenolic acids in natural plants in the rich quantities required for their potential pharmacological activities, and their mechanisms of action in disease prevention. From the literature review, the use of PAs as drugs is promising. However, more clinical research is required before this class of phytochemicals can be used for treatment.

Sources and Classification of PAs
PAs are obtained from all plant-derived food sources and different plant parts; for instance, seeds, stem, leaves and roots [9]. There is an unequal PA distribution throughout plants that depends on various factors such as stress, temperature and abiotic conditions [10]. Figure 1 summarizes some important plants from which various PAs in higher content have been isolated. The two main sub-classes of PAs are comprised of two distinguishing constitutive carbon substructures: hydroxybenzoic acid (HBA) and hydroxycinnamic acid (HCA), as described in Figure 2.
A variation in structures arises due to hydroxylation and methylation of the aromatic ring [3,12]. Derivatives of HBAs are mostly obtained from vegetables. Other derivatives such as SA, GA and VA are obtained in small quantities from Valerianella locusta L., Foeniculum vulgare Mill., Petroselinum crispum (Mill.), and Spinacia oleracea L. Rheum rhabarbarum L. contains a minor concentration of GA, followed by protocatechuic acid (PRCA) and VA. Allium cepa L. has the highest concentrations of PRCA in outer dry skin and a minor proportion is accumulated in pulp tissues [13].
Daucus carota L., Apium graveolens L. and Armoracia rusticana G., B.Mey and Scherb contain small quantities of p-HBA, GA, SyA and VA. Gentisic acid is found in small amounts in vegetables and crops such as Solanum lycopersicum L., Solanum melongena L., Capsicum species, Cucumis melo L. and Cucumis sativus L. Brassica oleracea L. contains minor quantities of p-HBA, GA, gentisic acid, and ferulic acid (FA) [8].  A variation in structures arises due to hydroxylation and methylation of the aromatic ring [3,12]. Derivatives of HBAs are mostly obtained from vegetables. Other derivatives such as SA, GA and VA are obtained in small quantities from Valerianella locusta L., Foeniculum vulgare Mill., Petroselinum crispum (Mill.), and Spinacia oleracea L. Rheum rhabarbarum L. contains a minor concentration of GA, followed by protocatechuic acid (PRCA) and VA. Allium cepa L. has the highest concentrations of PRCA in outer dry skin and a minor proportion is accumulated in pulp tissues [13].
Daucus carota L., Apium graveolens L. and Armoracia rusticana G., B.Mey and Scherb contain small quantities of p-HBA, GA, SyA and VA. Gentisic acid is found in small amounts in vegetables and crops such as Solanum lycopersicum L., Solanum melongena L., Capsicum species, Cucumis melo L. and Cucumis sativus L. Brassica oleracea L. contains minor quantities of p-HBA, GA, gentisic acid, and ferulic acid (FA) [8].

Derivatives of Hydroxycinnamic Acids and Their Sources
Quinic acid (QA) is the basic derivative of HCA, having four hydroxyls plus one carboxylic acid moiety. Sinapic acid (SA), p-coumaric acid (PCA), FA, and caffeic acids (CA) are amongst the major derivatives of HCA that originate in the free form, while glycosylated derivatives of QA, tartaric acid (TA), and shikimic acid (ShA) are the bound forms, as presented in Figure 4.

Derivatives of Hydroxycinnamic Acids and Their Sources
Quinic acid (QA) is the basic derivative of HCA, having four hydroxyls plus one carboxylic acid moiety. Sinapic acid (SA), p-coumaric acid (PCA), FA, and caffeic acids (CA) are amongst the major derivatives of HCA that originate in the free form, while glycosylated derivatives of QA, tartaric acid (TA), and shikimic acid (ShA) are the bound forms, as presented in Figure 4.    Chlorogenic acid, formed by a combination of QA and CA, is present in several fruits such as Vaccinium myrtillus L., Prunus domestica L., Prunus avium L., and Malus domestica (Suckow) Borkh. These have 0.5-2 g HCA/kg. In Solanum tuberosum L., chlorogenic acid is the chief PA, ranging from 0.20-2193.0 mg/100 g of dry weight, as mentioned in Figure 5 [14]. Chlorogenic acid, formed by a combination of QA and CA, is present in several fruits such as Vaccinium myrtillus L., Prunus domestica L., Prunus avium L., and Malus domestica (Suckow) Borkh. These have 0.5-2 g HCA/kg. In Solanum tuberosum L., chlorogenic acid is the chief PA, ranging from 0.20-2193.0 mg/100 g of dry weight, as mentioned in Figure 5 [14]. HCA is mainly found in leafy vegetables such as Brassica species, Lactuca sativa L., and Amaranthus cruentus L., etc. HCA is found in high levels in ripened fruits in contrast to other parts of the plant. However, their concentrations usually reduce during ripening. High amounts of synaptic acids are found in Nasturtium officinale W.T., Lepidium sativum L., Brassica rapa L., and Brassica juncea (L.) [15]. The FA (0.8-2 g/kg of dry weight) is among HCA is mainly found in leafy vegetables such as Brassica species, Lactuca sativa L., and Amaranthus cruentus L., etc. HCA is found in high levels in ripened fruits in contrast to other parts of the plant. However, their concentrations usually reduce during ripening. High amounts of synaptic acids are found in Nasturtium officinale W.T., Lepidium sativum L., Brassica rapa L., and Brassica juncea (L.) [15]. The FA (0.8-2 g/kg of dry weight) is among the most abundant HCA that is present in cereals and wheat grains as esterified to arabinoxylans [16]. The FA is also found in Brassica species, Abelmoschus esculentus (L.), Vigna unguiculate (L.), and Portulaca oleracea (L.) [17]. Generally, CA, GA, FA and PCA contents in Solanum tuberosum L. are about 5 mg/100 g dry weight [8].

Biosynthesis of PAs
L-phenylalanine, or L-tyrosine, is the primary precursor in the ShA pathway for the synthesis of Pas in bacteria, fungi and plants. The mevalonic acid pathway is also involved in the synthesis of PAs in higher plants but is of less importance. A total of seven enzymatic phases lead to a last-known precursor called chorismite, as mentioned in Figure 5 [18].

Structure Activity Relationship of PAs
The pharmacological activities, such as antioxidant, anti-inflammatory, anticancer, etc., of Pas depend upon its structural components, such as number and position of hydroxyl groups (-OH), unsaturated fatty acid chain, methoxy (-OCH 3 ), and carboxylic acid (-COOH), as described in Figure 6A. The number of hydroxyl groups is proportional to antioxidant activity [21].

Structure Activity Relationship of PAs
The pharmacological activities, such as antioxidant, anti-inflammatory, anticancer, etc., of Pas depend upon its structural components, such as number and position of hydroxyl groups (-OH), unsaturated fatty acid chain, methoxy (-OCH3), and carboxylic acid (-COOH), as described in Figure 6A. The number of hydroxyl groups is proportional to antioxidant activity [21]. The anti-cancer properties of PAs vary from one compound to another based upon their structural variability and molecular targets. The number and position of phenolic hydroxyl groups also impart crucial roles in the anticancer action of PAs ( Figure 6B). The anti-cancer properties of PAs vary from one compound to another based upon their structural variability and molecular targets. The number and position of phenolic hydroxyl groups also impart crucial roles in the anticancer action of PAs ( Figure 6B). There is a direct relationship between the -OH group and anticancer potential. For instance, PAs are devoid of anticancer action with the absence of an -OH group and the presence of methoxy (OCH3) group. Additionally, the existence of unsaturated short-side chains of fatty acids also contributes to the activity [12].

Pharmacological Activities of PAs
The literature survey validates the vital role of PAs in the treatment of various diseases, prophylaxis and other health benefits. Recent updates have linked antioxidant properties of PAs with the prevention of diseases such as cardiopulmonary and cardiometabolic diseases, stroke, myocardial infarction (MI), and cancers [22]. Various PAs, such as CA, ellagic acid (EA), ShA, PCA, gentisic acid, VA, SA, PCA, FA, and 3,4-DHBA have exhibited anticancer, antiapoptotic, hepatoprotective, antidiabetic, nephroprotective, antiinflammatory, analgesic, antioxidant, gastroprotective and cardioprotective potential in numerous in vitro and in vivo studies ( Table 1). The p-hydroxybenzoic acid (p-HBA) is known for anti-inflammatory and antimicrobial potential. The PCA is known for antibacterial, antiviral and anticancer activities. VA is effective for its anti-inflammatory, antiaging and antioxidant action. Various PAs and their bioactivities are shown in Figure 7.  There is a direct relationship between the -OH group and anticancer potential. For instance, PAs are devoid of anticancer action with the absence of an -OH group and the presence of methoxy (OCH3) group. Additionally, the existence of unsaturated short-side chains of fatty acids also contributes to the activity [12].

Pharmacological Activities of PAs
The literature survey validates the vital role of PAs in the treatment of various diseases, prophylaxis and other health benefits. Recent updates have linked antioxidant properties of PAs with the prevention of diseases such as cardiopulmonary and cardiometabolic diseases, stroke, myocardial infarction (MI), and cancers [22]. Various PAs, such as CA, ellagic acid (EA), ShA, PCA, gentisic acid, VA, SA, PCA, FA, and 3,4-DHBA have exhibited anticancer, antiapoptotic, hepatoprotective, antidiabetic, nephroprotective, antiinflammatory, analgesic, antioxidant, gastroprotective and cardioprotective potential in numerous in vitro and in vivo studies ( Table 1). The p-hydroxybenzoic acid (p-HBA) is known for anti-inflammatory and antimicrobial potential. The PCA is known for antibacterial, antiviral and anticancer activities. VA is effective for its anti-inflammatory, antiaging and antioxidant action. Various PAs and their bioactivities are shown in Figure 7.

Anti-Cancer Actions of PAs
The "two-steps carcinogenesis" hypothesis elaborates how a single cell is generated from a normal cell, which leads to the progression of cancer [42]. PAs exhibit anti-cancer action by promoting apoptosis, targeting angiogenesis, and reducing abnormal cell growth that might be due to an aromatic ring, location of hydroxyl groups and highly unsaturated chains in their structure [43].
Mutations in phosphatidyl inositide 3-kinase (PI3Ks or Akt) molecules and mitogenactivated protein kinases (MAPKs), or the Ras/Raf/Erk pathway, are the crucial steps for most cancer types blocked by PAs as described in Figure 8 [44,45]. Epidemiological studies have shown the role of PA-rich fruits and vegetables in reducing several cancers, suggesting their efficacy against cancer incidence, prevention and mortality [7]. Most PAs inhibit different cancers depending on their antioxidant capacity, and regulation of transcriptional factors, such as nuclear factor-erythroid-related factor (Nrf-2) [46][47][48]. The studies on the anticancer action of various PAs are described in Table  2. 7.1.1. Anticancer Activity of EA It was revealed that the EA had induced apoptosis and inhibited cell cycle and cell growth in cervical squamous carcinoma cells (CaSki) time-and concentration-dependently. Within two days of the cycle, EA arrested G1 phase dose dependently, representing the sensitivity of these cells towards EA [49].
NF-κB has potential activity against inflammation and cancers. However, its role in Epidemiological studies have shown the role of PA-rich fruits and vegetables in reducing several cancers, suggesting their efficacy against cancer incidence, prevention and mortality [7]. Most PAs inhibit different cancers depending on their antioxidant capacity, and regulation of transcriptional factors, such as nuclear factor-erythroid-related factor (Nrf-2) [46][47][48]. The studies on the anticancer action of various PAs are described in Table 2. 7.1.1. Anticancer Activity of EA It was revealed that the EA had induced apoptosis and inhibited cell cycle and cell growth in cervical squamous carcinoma cells (CaSki) time-and concentration-dependently.
Within two days of the cycle, EA arrested G1 phase dose dependently, representing the sensitivity of these cells towards EA [49].
NF-κB has potential activity against inflammation and cancers. However, its role in cancer progression is multifarious. Two transcription factors, p50 and p65, in the absence of any stimulus, are sequestered in a regulated signal transduction regulator (I-κBα) activated by the I-κBα kinase enzyme. This causes proteasome deprivation of I-κBα [48]. NF-κB controls the expression of the proteins controlling the cell production, existence, angiogenesis, and metastasis. Signal transducer and activator of transcription (STAT-1) causes up-regulation of cells that ends in cancer cell survival [50]. On the contrary, down-regulation of NF-κB causes cell sensitization and eventually apoptotic action. Genes such as Bcl-2 or XL, survivin, Cyclin D1, TRAF1 and 2 block apoptosis by up-regulation of NF-κB. The apoptosis is activated by the activation of caspase-9, -3, -8, and -7, which is hindered by the loss of p53 protein (tumor suppressant). The EA can delay cell development and cell cycle movement by initiating apoptosis of prostate, colorectal, oral, pancreatic, and bladder cells [51]. CA has also demonstrated significant anticancer potential. A study on CA revealed its anti-proliferative, free radical scavenging activity, mitochondrial colony development and apoptotic effects in HCT15 cells with an IC 50 of 800 µM [54]. In another study, it was reported that the different derivatives of CA inhibited cell proliferation in vitro in a dosedependent manner. The IC 50 for CA phenethyl ester (CAPE) and CA phenyl propyl ester (CAPPE) in the CRC HCT-116 cell line were 44.2 and 32.7 mM, respectively, while in human CRC SW-480 cells, IC 50 were 132.3 mM and 130.7 mM, respectively. These derivatives significantly augmented the signaling pathways and also induced G0/G1 cell cycle arrest. In an animal model, CAPE-or CAPPE-mediated suppression of tumor growth was related to the modulation of the PI3-K/Akt, AMPK and mammalian target of rapamycin (mTOR) signaling pathways in experimental animals as described in Table 2 [55].
FA has shown anti-inflammatory activity in several models of disease. FA at 100 mg/kg reduced cerebral infarction in middle cerebral artery occlusion (MCAO) and exhibited anti-inflammatory effect in rats [56]. Meanwhile, the anti-inflammatory activity of PRCA was observed at 1-25 µM in LPS-induced inflammation in RAW 264.7 cells via reducing TNF-α, IL-1β, and prostaglandin (PGE2) [57]. The mechanisms of action and effect of different PAs on various inflammatory diseases are explained in Figure 9. PCA and SA have demonstrated anti-inflammatory activity through modulation inflammatory cytokines. PCA at 100 mg/kg exhibited anti-arthritic and immunosuppressant action in Complete Freund's Adjuvant (CFA)-induced arthritic rats via reducing NF-κβ, and macrophage phagocytic index [72,73]. SA at 819-2500 mg/kg dose exhibited anti-inflammatory activity in male mice via downregulation of TNF-α and IL-6 [58]. Various research has reported the anti-inflammatory and analgesic activities of PAs, as described in Table 3. PCA and SA have demonstrated anti-inflammatory activity through modulation inflammatory cytokines. PCA at 100 mg/kg exhibited anti-arthritic and immunosuppressant action in Complete Freund's Adjuvant (CFA)-induced arthritic rats via reducing NF-κβ, and macrophage phagocytic index [72,73]. SA at 819-2500 mg/kg dose exhibited antiinflammatory activity in male mice via downregulation of TNF-α and IL-6 [58]. Various research has reported the anti-inflammatory and analgesic activities of PAs, as described in Table 3.

Cardio-Protective Actions of PAs
PAs have been widely studied for their protective effects against cardiovascular disorders such as atherosclerosis, ischemia, stroke and hypertension. Cardiopulmonary disorders are among the foremost causes of deaths in both economically developed and developing states [75][76][77][78][79][80][81][82][83][84][85][86][87]. It was found that CAPE derivatives of caffeic acid at 3 and 15 mg/kg had shown cardio-protective activity against I/R injury in rabbits. The results suggested an increased inhibition of MPAK phosphorylation along with a decline in IL-1B and TNF-a expression [88][89][90][91][92]. In another study, it was revealed that syringic acid and revasterol at 50 mg/kg had shown efficient cardio-protective action in cardiotoxicity induced by isoproterenol for 30 days in rats [92].

Atherosclerosis
Atherosclerosis, a chronic inflammatory disease, is characterized by the deposition of white blood cells in the vessels. Risk factors contributing to the development of the disease include high blood cholesterol levels, specifically low-density lipoproteins (LDL). Platelets bind with leukocytes via P-Selectin or P-Selectin glycoprotein ligand-1 (PSGL-1) to form thrombus and atherosclerotic depositions in the walls [76]. The anti-atherosclerotic mechanism of PA has been presented in Figure 10.
In atherogenesis, the key factors are endothelial dysfunction and oxidative modification of LDL. Normally, endothelial cells maintain the integral structure of vessels and act as a permeable wall. Moreover, it is also responsible for regulating vascular tone by producing excess nitric oxide (NO), growth hormones, and prostaglandins [77].
PAs such as GA exhibits anti-atherosclerotic activity because of its association with white blood cells and inhibition of platelets. P-selectin endothelial expression is activated by a decrease in intracellular calcium. This stimulation occurs by adenosine diphosphate (ADP) via controlled signal transduction of PKCα/p38 MAPK and Akt/GSK3β [78]. The studies on cardioprotective action of various PAs are described in Table 4.
A previous study showed that protocatechuic aldehyde, a derivative of protocatechuic acid derived from Salvia miltiorrhiza, had shown reduced platelet-derived growth factor (PDGF)-induced growth and movement of smooth muscle cells through regulation of the (PI3K)/Akt and M Kinase pathways ( [79]).
It is previously found that EA proficiently diminished oxidative stress and plasma lipids, and prevented lipid peroxidation. It also blocked the oxidized LDL uptake in murine macrophages by down-regulating SR-B1 (a membrane receptor that controls the internalization of oxidized LDL, which eventually stimulates the deposition of cholesterol in cells). Likewise, the results also revealed EA induced ATP-binding cassette transporter (ABCA1) membrane receptor expression and cholesterol efflux in lipid-loaded macrophages. This ABCA1 regulates cholesterol homeostasis to protect an atherosclerotic event [80].
Atherosclerosis, a chronic inflammatory disease, is characterized by the deposition of white blood cells in the vessels. Risk factors contributing to the development of the disease include high blood cholesterol levels, specifically low-density lipoproteins (LDL). Platelets bind with leukocytes via P-Selectin or P-Selectin glycoprotein ligand-1 (PSGL-1) to form thrombus and atherosclerotic depositions in the walls [76]. The anti-atherosclerotic mechanism of PA has been presented in Figure 10. In atherogenesis, the key factors are endothelial dysfunction and oxidative modification of LDL. Normally, endothelial cells maintain the integral structure of vessels and act as a permeable wall. Moreover, it is also responsible for regulating vascular tone by producing excess nitric oxide (NO), growth hormones, and prostaglandins [77].
PAs such as GA exhibits anti-atherosclerotic activity because of its association with white blood cells and inhibition of platelets. P-selectin endothelial expression is activated by a decrease in intracellular calcium. This stimulation occurs by adenosine diphosphate (ADP) via controlled signal transduction of PKC /p38 MAPK and Akt/GSK3 [78]. The studies on cardioprotective action of various PAs are described in Table 4.
A previous study showed that protocatechuic aldehyde, a derivative of protocatechuic acid derived from Salvia miltiorrhiza, had shown reduced platelet-derived growth factor (PDGF)-induced growth and movement of smooth muscle cells through regulation of the (PI3K)/Akt and M Kinase pathways ( [79]).

Myocardial Infarction and Stroke
It was found that SA tended to prevent complications related to cardiovascular diseases such as myocardial infarction and stroke [81]. The mechanism is to obstruct the plateletinhibitory role and activate an enzyme called Paraoxonase 1 that in return defends the oxidation of serum lipids and reduces macrophage formation and treats atherosclerosis [82]. Gentisic acid showed anti-hypertrophic and anti-fibrotic effects during an in vivo study on mice at a subsequent dosage of 100 mg/kg/day for three weeks through substantial down-regulation of the sp1 and ERK1 and 2 pathways [83]. In an in vivo study on cardiac damage induced with doxorubicin (5 mg/kg), gentisic acid prevented cardiotoxicity by preventing cardiac myofibrillar and hyalinization necrosis in male BALB mice [84].
Earlier research stated that FA at 20 mg/kg and ascorbic acid at 80 mg/kg had synergistically reduced MI by neutralizing oxidative stress and restored CAT and SOD biomarkers, and reduced CPK and LDH levels in isoproterenol-induced myocardial infarction in rats [85]. PRCA provided cardio-protection against streptozotocin-induced Type 1 diabetic rats at 50 and 100 mg/kg. During 12 weeks of treatment with PCA, cardiac function and autonomic nervous system balance were significantly restored due to improved cardiac mitochondrial damage (Semaming, Kumfu, Pannangpetch, Chattipakorn, and Chattipakorn, 2014).
PAs have tremendous cardio-protective action through retarding atherosclerosis via acting on thrombin-induced matrix invasion of vascular smooth muscle cells. They protect against angiotensin II-induced hypertension in rats by blunting endothelial dysfunction and promoting formation of nitric oxide [86]. Furthermore, PAs prevent the damage caused by ischemic reperfusion by activating pro-survival pathways [87].

Toxicity of Phenolic Acids
PA are known for antioxidant action because of the hydroxyl group, but they also act as pro-oxidants that lead to toxicity after reacting with redox-active metals. As a pro-oxidant, PAs deteriorate nucleic acid components, lipids and protein. The repeated intake of a high level of PAs is associated with allergic reactions and toxic effects. PAs are also known for tumorgenicity. At low doses, PAs such as GA, CIA, CA, and FA initiated cancer via stimulating Nrf-2 (redox regulator). There is an immense need to use PAs in the recommended dosage for the required duration in order to avail the therapeutic response, otherwise their use would be counterproductive [12].

Conclusions and Future Aspects
The association between phytochemicals and disease therapy is a major focus of health research. As reviewed, phenolic acids, either hydroxyl benzoic acids or hydroxycinnamic acids and their derivatives, have demonstrated significant potential for treatment and prevention of anticancer, anti-inflammatory and cardiovascular diseases. These activities of PAs have mostly been attributed to modulation of oxidative stress and signal transduction pathways.
However, further in vitro and in vivo studies regarding the efficacy, possible side effects, molecular mechanisms, and targets involved in specified physiological functions and pathologies, as well as clinical trials as adjuvants to already-used therapies, will explore further attributes of these phytochemicals, which will help to produce innovative pharmacological and nutraceutical products. These studies will guide in the drug development of safe and effective treatments of anticancer, inflammatory and cardiovascular diseases. As the clinical data lack a direction, we emphasize the evaluation of PAs in isolated or mixed forms for medicinal purposes. Moreover, targeted drug delivery approaches such as nano-formulation should be incorporated to achieve maximum beneficial effects and prevent toxicity.

Conflicts of Interest:
The authors declare no conflict of interest.