An overview on the role of dietary phenolics for the treatment of cancers

Phenylalanine and/or tyrosine are the precursors for the synthesis of phenolic acids through shikimate pathway [6] (Fig. 1). Addition of hydroxyl groups into the phenyl ring is the key step involved in the biosynthesis of phenolic acids [6]. Due to the heterogeneous structures of these phenolic acids, which range from low molecular weight single aromatic ring structure to high molecular weight polymeric compounds, they can be broadly classified into simple and complex phenolics (Fig. 2), which are discussed in detail in the following sections.

Phenolic acids are widely distributed among various parts of the plants including roots, leaves, fruits and vegetables [16]. The caffeic acid is the most common type of phenolic acid found widely in the fruits, while the ferulic acid is found in the cell walls of seed coat, bran and fruits in esterified form [17]. The leaves and stems of plants contain higher levels of phenolic acids with significant variations found among different species [16]. For instance, complex polyphenols are found in the cell vacuoles, tissues present in the leaf, epidermis, flowers and fruits [12]. Likewise, barks, wood and fruit pods are rich in tannins, while flowers contain more flavonoids [18].

Plant phenolic acids form an integral part of our diet and thus making them a prime focus of interest. For example, cereals, legumes, soybeans, coffee, tea, rosemary and thyme, which are widely utilized in diet, are the rich sources of phenolic acids [19]. A study has shown that gallic acid is the most common phenolic acid found among fruits, vegetables, chestnuts and green chicory [20]. While a separate study by Kivilompolo M 2007 et al., reported that herbs like thyme, oregano and sage are rich in caffeic acids [21], another study by J Perez-Jimenez 2010 et al., identified polyphenolic compounds in the seasonings such as star anise, cloves, peppermint and celery seeds [22]. Fruits from berry and citrus family members, apples and pears have also known to contain considerable amounts of phenolic acids [12]. Among vegetables the yellow onions followed by artichokes, potatoes, rhubarb, red cabbage and cherry tomatoes harbor high phenolic content [23, 24]. Among the different vegetables consumed, the potatoes account for up to 25% of total phenolics such as chlorogenic acid and caffeic acid [25].

Phenolic acids are the major essential non-nutrients present in the diet. However, most often, they are considered as antinutrients due to the adverse effects of tannins on protein digestibility [26]. But, in recent years, an increased interest in developing diets rich in plant derived polyphenols is observed due to the realization that the phenolic compounds exhibit anti-oxidant, anti-inflammatory and anti-proliferative effects [4]. Since these activities are essential for preventing or treating cancers, cardiovascular diseases, atherosclerosis and neurodegenerative disorders, supplementing diets with extracts rich phenolic compounds help to effectively manage these disorders [27]. For instance, polyphenols from green tea were shown to inhibit the progression of tumors in different animal models [28]. Similarly, a much lowered risk of colon, prostate and breast cancers observed among the Asian population was attributed to the intake of polyphenol and flavonoid rich diets [29]. In addition, a study carried out in Finland reported healthier carotid arteries with less obstruction from atherosclerosis when individuals consumed higher amounts of flavonoids and polyphenols [30]. Likewise, a separate study in France revealed that individuals consuming diets supplemented with flavonoid-based plant products had lesser incidence of cognitive disorders over the age of 65 years [31]. In summary, these studies highlight the importance of consuming diets with phenolic compounds in mitigating the disease severity.

The polyphenolic compounds present in nature are usually glycosylated and exist as complex molecules with poor solubility and less bioavailability [32]. Once ingested in diet, these complex insoluble phenolics undergo transformation in the human gastro-intestinal tract by the enzymes and microbiota to produce phenolic compounds with more bioavailability and better pharmacological properties [32]. For example, a recent study has demonstrated that ellagic acid, a phenolic acid derived from berries, is transformed by the gut microbiota in to urolithin. The bio-transformed urolithin effectively inhibits heme peroxidases such as myeloperoxidase and lactoperoxidase thereby reduce the inflammation mediated cellular damage [33]. In addition, urolithin reduces superoxide radicals’ generation while ellagic acid failed to do so [33]. In animal models oral administration of urolithin, at 40 mg/kg body weight, inhibited PMA-induced edema and MPO activity compared to ellagic acid [33]. A separate study by Marin et al., demonstrated the production of soluble phenolic compounds such as ferulic acid and coumaric acid by the hydrolytic activity of gut microbiota on ester linked arabinoxylans [32]. Additional studies have further shown that the dimers of ferulic acid are degraded by micro-organisms present in the gut in to vanillin and 3-(4-hydroxyphenyl)-propionic acid with enhanced anti-cancer activity [32]. Therefore, transformation of phenolic compounds by gut microbiota has several important roles and influences their biochemical properties as well as contribute for the variations in the response to treatment with phenolic compounds among individual [34] (Fig. 3).

Purification of phenolic compounds from natural sources to homogeneity is a challenging task. Therefore, several studies have tested the ability of either crude extracts rich in phenolic compounds or the fractions containing a mixture of phenolic compounds for inhibiting cancers in vitro and in vivo. For example the extracts of Pandanus amaryllifolius (herbal plant from Malaysian region) containing gallic acid, cinnamic acid and ferulic acid are reported to inhibit breast cancer cell lines in vitro [35]. Similarly, the extracts of Baccharis trimera, containing gallic acid, pyrogallol, syringic acid and caffeic acid were shown to suppress the formation of tumor cell colonies and proliferation of SiHa cells in a dose dependent manner [36]. Likewise, Thanaset et al., 2014 have demonstrated the time- and dose dependent growth inhibitory effect of water soluble constituents of commercially available Houttuynia cordata fermentation products on HeLa, HCT116, and HT29 cells. Seven phenolic acids including protocatechuic, p-hydroxybenzoic, vanillic, syringic, p-coumaric, ferulic, and sinapic acids were identified in the water soluble fraction of H.cordata [37]. Another study isolated and characterized gallic acid from Toona sinensis leaf extracts which inhibited the growth of prostate cancer cell lines [38]. In a separate study Kurata et al 2007, could identify caffeic acid, chlorogenic acid, 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, 4,5-di-O-caffeoylquinic acid, and 3,4,5-tri-O-caffeoylquinic acid in the leaves of the sweet potatoes inhibited the growth of stomach cancer (Kato III), a colon cancer (DLD-1), and a promyelocytic leukemia cell (HL-60) [39]. Thus it can be concluded that the antitumor activity exerted by these plant extracts could be due to the presence of phenolic acids. However, utility of crude extracts containing a mixture of phenolic compounds as drugs require more careful investigations as the proportion of each phenolic compound in the extract might vary from source to source as well as from the method of isolation and fractionation.

Uncontrolled cellular proliferation is a hall mark feature of cancer cells [54]. Therefore, the efficiency of anticancer drugs can be measured by their ability to: (a) decrease cell proliferation measured using the incorporation of tritiated Thymidine or Bromodeoxy Uridine; (b) attenuate the viability of cells as measured using MTT or SRB; (c) arrest the cells in interphase (G0/G1, S or G2/M) [55]. Phenolic compounds isolated from plant sources have been demonstrated to inhibit the proliferation of cancer cells [12]. For example, cinnamic acid reduced the viability of HT-44 melanoma cell line in a dose dependent manner with the IC₅₀ of 2.4 mM [56]. Mechanistically, cinnamic acid decreased the number of S phase cells thereby inhibited the proliferation of HT-44 cells [56]. Likewise, a separate study showed the induction of cell cycle arrest at G2/M phase when breast cancer cells MDA-MB-231 and MCF-7 were exposed to 4-(3,4,5-Trimethoxyphenoxy) benzoic acid [57]. Similarly, many other studies have also demonstrated the efficacy of phenolic compounds to retard cancer cell proliferation [52]. For instance, p-coumaric acid decreased the viability of HCT-15 and HT-29 cells at a concentration of 1400 and 1600 μmol/L, respectively [52]. Reduction in the number of colonies formed in the coumaric acid treated HCT-15 (32) and HT-29 (51) against the untreated (105 and 154) at 72 h confirmed the anti-proliferative effects of these compounds [52]. Other phenolic acids that have shown to exhibit antiproliferative activity include: (a) Caffeic- and 5-caffeoylquinic acid that reduced the cell viability of HT-29 colorectal carcinoma cell line and HT-1080 fibrosarcoma cells at 96 h by modulating cell cycle stages [58, 59]; (b) Di-caffeoylquinic acid, isolated from sweet potato, which inhibited the proliferation of DLD-1 human colon cancer cells [39]; (c) Ferulic acid and p-Coumaric acid that were shown to inhibit the pancreatic cancer cell line MIA-Pa-Ca-2 [60]; (d) Gallic acid, which inhibited cervical carcinomas cells HeLa and HTB-35 and Jukart [61, 62]. Similarly, even the phenyl substituted cinnamic acids also exhibited significant cytotoxicity in HT-29, A-549, OAW-42, MDA-MB-231 and HeLa cell lines with IC₅₀ values of <60 μM [63]. Efficacy evaluation studies comparing the potency of phenyl substituted acids reported that at 0.1 mM concentration ~84–92% cells were killed compared to the non-substituted derivatives, which had an effect of ~20–63% [63]. The IC₅₀ values of phenolic compounds are tabulated in Table 2. In conclusion both cinnamic and benzoic acid derivatives possess potent anti-proliferative activity as evident by the low IC₅₀ values exhibited by them on several cancer cell lines.

Apoptosis, a suicidal cell death mechanism, is a well-controlled process that gets activated either by the intrinsic or the extrinsic pathways [64]. The cells undergoing apoptosis exhibit caspase mediated cell death through transforming pro-caspases into active caspases [64]. Whereas the extrinsic pathway gets activated when the binding of Fas ligands to Fas proteins, the intrinsic pathway is triggered by oxidative stress inside the cells releasing the cytochrome-C from the disrupted mitochondria [65]. A prior study reported the induction of caspase-9 when HT-44 cells were treated with cinnamic acid [56]. Activated caspase-9 in turn activated other caspases such as Caspase-3 and -7 [56]. A separate study demonstrated that Ferulic acid could upregulate Bax and downregulate Bcl-2 to induce apoptosis in osteosarcoma cells [64]. Similarly, FA has induced the expression of Bax, caspase-3 and -9 in fibrosarcoma cells [60]. Elevated caspase-3 was also observed when breast cancer cells were treated with 4-(3,4,5-Trimethoxyphenoxy) benzoic acid [57]. Propidium iodide staining of cells followed by analyzing the stained cells with flow cytometer is another way of measuring the apoptotic cell death [66]. Elevated subG0/G1 population is a clear indicator of apoptosis induced by pharmacological agents promoting DNA damage [67]. A recent study showed that colon cancer cells treated with p-coumaric acid have undergone apoptosis as evidenced by a significant increase in the subG1 phase cell population [52]. Further confirming this data, analysis of cellular images captured by scanning electron microscope (SEM) exhibited typical signs of apoptosis such as membrane blebbing and shrinkage, which were absent among the normal cells [52]. Likewise, Protocatechuic acid also elevated the caspase-3 levels and reduced the membrane potential in breast, prostate, lung, cervical and hepatic cell lines in a dose dependent manner [47]. Similarly, a dose dependent increase in the caffeic acid concentration resulted in an increase in the apoptosis in human HT-1080 fibrosarcoma cell line [59]. Induction of apoptosis by caffeic acid was confirmed by the morphological changes and the acridine orange and ethidium bromide staining methods [59]. In summary, the induction of apoptosis is a major phenomenon exhibited by phenolic compounds.

Tumor cell migration and invasions are the strategies developed and adopted by cancer cells to localize into distant organs and to escape drug treatment [68]. Since metastatic tumor cells are hard to treat due to their ability to circulate in the blood as well as unusual expression of oncogenic proteins compared to primary tumors, better strategies are required to prevent the metastatic spread [54]. One such strategy is to use naturally occurring plant derived phenolic compounds, which are known to halt the migration of cells by interfering with epithelial-to-mesenchymal transition (EMT), cell invasion and extravasation [69]. For instance, ferulic acid suppressed metastasis in breast cancer cell lines by reversing the epithelial-mesenchymal transition (EMT) [69]. Similarly, 4-methyl-3-nitrobenzoic acid derivative inhibited the epidermal growth factor (EGF)-induced migration and chemotaxis of breast cancer cell lines [57]. Caffeic acid phenyl esters inhibited the metastasis of breast (MDA-MB-231 and MDA-MB-468), colon (SW620) and non-small cell lung cancer (H460) cell lines by blocking the voltage-gated sodium channels [70]. Recent studies have shown that voltage-gated sodium channels could modulate vascular endothelial growth factor (VEGF)-induced proliferation, tubular differentiation and adhesion by elevating the intracellular Ca²⁺, which activates PKC and ERK-1/2 [71]. However, in a separate study the caffeic acid phenyl esters was shown to retard migration of cells by 38, 56, and 82% at 24, 48, and 72 h, respectively [72]. Gallic acid, another simple phenolic compound, also increased the expression of RhoB thereby inhibiting the metastasis of gastric cancer cells [43]. In summary these phenolic acids inhibit tumor cell migration and invasions and thus localize the cancer cells thereby sensitizing them to drugs.

Compared to many synthetic and semi-synthetic compounds, naturally occurring phenolic compounds are less toxic and safe even at higher doses [73]. However, before evaluating in the clinical trials, one has to determine the safety and toxicity profiles of phenolic compounds using animal models. Since some of the phenolic compounds are also known to induce the formation of tumors by transforming the normal cells, it is mandatory to study the safety and toxicity of these plant derived products [74]. Protocatechuic acid is another phenolic compound tested in mice for safety and toxicity. The LD₅₀ of protocatechuic acid in mice was reported to be 800 mg/kg by i.p., and 3.5 g/kg by i.v. route [75]. However, when administered orally, the LD₅₀ of protocatechuic aldehyde was about 1.7 g/kg [75]. Sub-chronic toxicity assessment of gallic acid, a well-known antioxidant benzoic acid derivative, in rats showed a relatively safe profile [76]. Experimentally, rats fed with gallic acid (0, 0.2, 0.6, 1.7 and 5%) containing diet for 13 weeks exhibited no toxic symptoms even at 119 and 128 mg/kg/day for male and female rats, respectively [76]. In mice, oral administration of a dose up to 5000 mg/kg was also found to be safe [77]. Compared to gallic acid, p-coumaric acid exhibited low toxicity with LD₅₀ ~ 2850 mg/kg body weight [78]. In conclusion, the safety and toxicity profiles of phenolic compounds vary depending upon their structure, route of administration and the animals that are being studied. Therefore, it is recommended to determine the safety and toxicity profiles of phenolic compounds before moving them in to preclinical and clinical studies.

Efficacy of a compound depends on its absorption, distribution, metabolism, excretion, availability, stability, route of administration, target specificity and ability to control key pathways regulating cancer cell proliferation [79]. A number of studies have reported variability in these properties for various plant phenolic compounds. Most of the soluble phenolic acids are rapidly absorbed in the small intestine while the insoluble esterified forms are absorbed in the colon [80, 81]. The phenolic acids are rapidly absorbed by the Monocarboxylic acid transporters (MCT) or through para-cellular diffusion [82], while, excretion is majorly through urine with only a low percent of it is through bile [83].

Phenolic compounds with good ADME properties are likely to exhibit potent anti-tumor activities [84]. For example, caffeic acid phenyl propyl ester (CAPPE) and caffeic acid phenyl ethyl ester (CAPE), which are the better bioavailable versions of caffeic acid, significantly inhibited the growth of colorectal tumors in xenografted mouse models by decreasing the number of proliferating cells as evident by reduced expression of proliferating cell nuclear antigen (PCNA), and by inhibiting fatty acid synthetase (FASN) as well as matrix metalloproteinase 9 (MMP-9) [85]. Likewise, a separate study showed that athymic mice harboring HepG2 xenografted tumors were susceptible to growth inhibition when treated subcutaneously (5 mg/kg, thrice a week up-to 10 days) or orally (20 mg/kg, daily up-to 6 weeks) with CAA and CAPE [86]. The data revealed that tumor size decreased significantly as evident by 61 and 56.7% inhibition among the CAA and CAPE subcutaneously treated groups respectively [86]. However, when these compounds were administered orally, the reduction was around 53.6 and 47.1%, respectively with caffeic acid and caffeic acid phenyl ester groups [86]. Similarly, 10 mg/kg of CAPE administered intraperitoneally inhibited the development of cholangiocarcinoma [87]. Anti-cancer activity of other phenolic compounds is also well explored [33, 80, 81]. For instance, a recent study has shown that oral administration of protocatechuic acid at a dose of 20 and 40 mg/100 g reduced the metastatic nodule formation in C57/BL6 mice [44]. In a similar fashion, ferulic acid at a dose of 10, 30 and 50 mg/kg body weight inhibited the melanoma tumor development in nude mice [88]. The trihydroxy benzoic acid (gallic acid at 0.3 and 1.0%) also inhibited the growth of osteocarcinomas in xenograft mice models [89]. The data showed a significant reduction in the tumor volume from 2392.99 mm³ in control group to 1896.34 mm³ and 1476.55 mm³ in the treated groups [89]. Another study also demonstrated the anti-tumor potential of gallic acid. Mice fed with 0.3 and 1% gallic acid for 20 weeks inhibited the prostate cancer growth and progression to advanced stages [90]. Even the derivatives of phenolic compounds also exhibited anti-cancer activity, which is either similar to- or much better than parent underivatized compound. A study reported that 4-methyl-3 nitro benzoic acid derivative along with paclitaxel synergistically inhibited the metastasis of breast cancer in SCID xenograft mice models [57]. Zhu, B. et al showed that intragastric administration of cinnamic acid suppressed the colon cancer in athymic mouse at a well-tolerated dose 1.0 and 1.5 mmol/kg [91]. Irrespective of the mode of administration, these phenolic acids are capable of inhibiting the tumor growth in-vivo.

Reactive oxygen species such as hydroxyl radicals, hydrogen peroxide and superoxide radicals are generated on a regular basis during the mitochondrial respiration [92]. Lower levels of ROS is involved in regulating several signaling pathways that include cell survival, cell proliferation, metabolism, anti-oxidant and anti-inflammatory responses, iron homeostasis etc. [93]. Moderate increase in the ROS levels is suppressed by the anti-oxidant chemicals or proteins present in the cells [94]. Therefore, in general, normal cells maintain a fine balance in terms of ROS level. However, under certain conditions the levels of ROS exceeds the anti-oxidant defense capacity leading to oxidative stress [95]. The free radicals produced in cells during oxidative stress are highly reactive and capable of inducing tissue damage by reacting with membrane lipids, nucleotides, sulphydryl groups of proteins and by cross-linking/fragmentation of ribonucleoproteins [96]. As a result of these ROS induced insults, the cells undergo transformation and form a variety of tumors [97]. ROS generated in the cancer cells are involved in activation of several transcription factors including the NF-kβ, STAT3, activator protein-1 etc. which is essential in controlling cellular proliferation, tumor survival, angiogenesis etc. [98]. In addition to DNA damage, ROS can induce alkali labile sites, single strand breaks and damages to purines and pyrimidines [98]. Although, tumor cells have higher levels of ROS than the normal cells; elevated levels beyond the threshold for prolonged duration can induce damage in cancer cells [52]. Therefore, promoting ROS generation in cancer cells is a viable strategy to inhibit tumor growth. For example, cinnamic acid derivative p-coumaric acid triggered cancer cell death via increasing the levels of ROS [52]. Likewise, a reduction in the mitochondrial membrane potential in the colon cancer cell HCT-15 was reported when cells were exposed to caffeic acid [99]. Thus elevating the ROS levels by treating with phenolic compounds is a viable strategy to control cancer cells proliferation.

Mutations in the proto-oncogenes leads to formation of oncogenes, which code for proteins that help cancer cells proliferate and survive even in the conditions that are not hostile [100]. For instance, oncogenic mutations in B-Raf kinase have been reported in melanomas, colorectal, and ovarian cancers [101]. Mutant ^V600EB-Raf is constitutively active and doesn’t require the translocation and association with Ras proteins for enzyme activity [102]. As a result, cells harboring this protein proliferate in an uncontrolled fashion, which ultimately leads to the formation of malignant metastatic tumors [103]. Prior reports evaluating the efficacy of targeting mutant oncogenic proteins such as ^V600EB-Raf have shown decreased tumor growth in preclinical animal models as well as in Phase-III clinical trials [104]. Therefore identifying natural products such as phenolic compounds that could effectively inhibit B-Raf kinase signaling are the potential candidates for developing clinically viable drugs [105, 106].

Recently, caffeic acid has shown to inhibit the metastasis of colon cancer by inhibiting the phosphorylation of Extracellular signal Regulated Kinases (ERK) which is a downstream target of Raf [107].

In addition, caffeic acid has been demonstrated to inhibit LPS-induced oxidative stress by retarding the ERK signaling in endothelial cells [108]. Likewise, protocatechuic acid inhibited NF-kβ and MAPK signaling cascades to down-regulate the proliferation of lung and gastric carcinoma cells [44, 109]. Similarly, even the ferulic acid and caffeic acid phenyl ester also down regulated phosphorylated PI3K and AKT signaling cascades to inhibit melanoma cells proliferation as well as to induce apoptosis [88, 110]. Furthermore, in addition to downregulating the phosphorylation of Akt kinase, Caffeic acid phenyl ester has suppressed the expression of AKT isoforms in prostate cancer cells [111]. Few other studies have also reported the therapeutic efficacy of cinnamic acid derivatives such as ferulic acid, caffeic acid and chlorogenic acids for treating cancers [112]. The data revealed that these cinnamic acid derivatives down modulate MAPK and AKT signaling pathways to inactivate the NF-kβ, AP-1 and STAT3 in lung adenocarcinomas [112]. Thus phenolic acids are known to play a crucial role in blocking the oncogenic pathways to inhibit cancer progression as shown in Fig. 5.

Tumor suppressor genes protect normal cells by preventing the oncogenic transformation into cancer cells [113]. In general, tumor suppressors such as p53, PTEN, Rb proteins help prevent the damage to DNA caused by the high intensity radiation, toxic chemicals such as dyes and infections especially by viruses [100]. In addition, tumor suppressor proteins also help in the scavenging of damaged cells through apoptosis [113]. Proof-of-principle studies expressing the tumor suppressors, in the cells where the expression of these genes is lost, due to the chromosomal deletions or mutational inactivation; have confirmed the anti-oncogenic role of these proteins [76]. Therefore, compounds that can trigger the expression of tumor suppressor proteins are likely to inhibit the development and transformation of cells into cancerous ones [114]. In a recent study, caffeic acid phenyl esters has been shown to arrest castration resistant prostate cancer (CRPC) cells in the G0/G1 phase of the cell cycle by upregulating p53, p21 and p27 proteins [115]. Confirming this data, knocking down these tumor suppressors using siRNA attenuated the efficacy of caffeic acid phenyl esters [115]. Similarly, an increase in the expression of p53 was observed when cervical cancer cells were exposed to caffeic acid [116]. Likewise, caffeic acid phenyl ester and caffeic acid octyl ester could also inhibit the growth of ME180 cervical cancer cells [117]. Another phenolic compound that has been demonstrated to upregulate tumor suppressors is ferulic acid. Ferulic acid enhanced the levels of p53 and p21 mRNA when transformed keratinocyte cell line HaCaT is exposed to UVB radiation [118]. Even the benzoic acid derivatives such as protocatechuic acid also induced the levels of p21 and p27 in leiomyoma cells. However, no major changes were reported, by this study, in the expression of p53 [119]. In summary, both cinnamic acid and benzoic acid derivatives can induce cell cycle arrest by inducing the expressions of the tumor suppressor genes and thereby inhibit the tumor cell proliferation.

Cytokines such as interferons, interleukins, tumor necrosis factor, lymphokines are low molecular weight proteins involved in cell signaling, development and immune responses [120]. Uncontrolled release of cytokines during oxidative stress or chronic inflammation induces malignancy in normal cells [121]. Cancer cells responds to the cytokines released by the host cells to induce cell growth, inhibit apoptosis and induce metastasis [122]. For example, cytokine IL-21 activates the STAT3 pathways by upregulating the Myc-c expression [123]. Myc-c is a key regulatory gene and is mutated in 70% cancers [114]. Mutated Myc-c fails to control the differentiation of cells [124]. Moreover, Myc-c gene is involved in cell cycle regulation, differentiation, metabolism and cell growth. Hence, molecules that promote anti-proliferative cytokines expression are important anticancer agents. Protocatechuic acid is one such molecule known to lower the levels of oncogenic IL-6 and IL-8 in a dose dependent fashion in cancer cell lines representing the breast, prostate, cervix, lung and liver [47]. Similar way, ferulic acid blocks the secretion of IL-6 and TNF-α in HaCaT cells [118]. Other phenolic compounds such as p-coumaric acid and caffeic acid have downregulated the expression of Myc-c, CCNB1, CCNA2 in CaCo2, HCT-116/SW480 cells leading to inhibition of cellular differentiation and proliferation [125].

Matrix metalloproteinases are endopeptidases capable of degrading the extracellular matrix [126]. Tumor cells express high levels of MMP, which degrade the extracellular matrix to promote tumor invasion and metastasis [127]. Thus molecules that inhibit MMPs can successfully inhibit the tumor growth and proliferation. A recent study demonstrated that protocatechuic acid suppressed the matrix metalloproteinase (MMP-2 and MMP-9) [109]. Similarly, ferulic acid inhibited the MMP2 and MMP9 in HUVEC and melanoma cells thereby inhibited the metastasis and angiogenesis of these cells [88]. CAA and CAPE, two other cinnamic acid derivatives, could selectively suppress the MMP-9 and MMP-2 activities to prevent hepatoma cells’ growth and metastasis [86]. Hence, phenolic compounds with MMP inhibitory properties could be considered for inhibiting the metastatic spread of tumor cells. However, further studies are warranted to conclusively and experimentally prove this data in preclinical animal models and clinical testing in humans.

Although phenolic acids are well known for their antioxidant activity, they also act as pro-oxidants in presence of redox active metals. This pro-oxidant effect leads to deleterious effects on DNA, proteins and lipids [128]. Further, at higher concentrations phenolic acids can induce blisters and harm healthy cells. Thus the dose and exposure time are critical while administering phenolic acids [129]. Development of nanoformulations is likely to help reduce these off target effects caused by the phenolic acids.

Despite the antitumor effects of phenolic acids, few reports have shown tumor inducing properties [130]. For instance, a study conducted by Miller et al in 2001 showed estrogenic activity of phenolic acids, which lead to the development of breast cancer [130]. In addition a study in animal models has shown that 2% Caffeic acid administered through diet could induce 57% forestomach squamous cell carcinomas in female F344 rats and B6C3F1 mice [74]. Further, since some phenolic acids at lower doses are known to activate oncogenes, their administration is likely to induce tumors growth [131]. For example, Nrf-2, a key redox regulator, is activated by gallic acid and causes the induction of chemoresistance [131]. Similarly, a study conducted by Ashok et al 2015, also showed the ability of gallic acid to upregulate Nrf-2 activity in mice models [132]. Few recent studies have also demonstrated the ability of cinnamic acids to upregulate Nrf2. For instance, a study has shown that caffeic acid phenyl ester and ferulic acid activated the Nrf-2 expression in cancer cell lines [133, 134]. Despite these adverse effects, the research and use of phenolic compounds for treating cancers continues due to the predominance of health beneficial effects compared to adverse events. In addition, due to recent advancements in drug delivery and treatment options, even the adverse effects of phenolic compounds could also be easily managed, making the phenolic compounds as the choice of treatment for cancers.