Aqueous Extract of Cinnamon (Cinnamomum spp.): Role in Cancer and Inflammation

Cinnamon (Cinnamomum spp.; family Lauraceae), a plant widely used as a spice and flavoring agent and in the perfume industry, has high therapeutic value. However, the components and chemical properties of cinnamon extracts vary depending on the part of the plant, the method, and the solvent used for extraction. Green extraction methods using safe and green solvents have gained increased interest in recent years. Water is an environmentally friendly and safe green solvent widely used for preparing cinnamon extracts. This review focuses on the various preparation techniques for the aqueous extract of cinnamon, its major bioactive components, and their beneficial roles in different pathological conditions, specifically cancer and inflammation. The aqueous extract of cinnamon contains several bioactive compounds, such as cinnamaldehyde, cinnamic acid, and polyphenols, and exerts anticancer and anti-inflammatory properties by altering key apoptotic and angiogenic factors. The whole extract is a better anticancer and anti-inflammatory agent than the purified fractions, indicating a synergistic effect between various components. Studies have indicated that aqueous cinnamon extract has immense therapeutic potential, and to better understand its synergistic effects, extensive characterization of the aqueous extract and its potential to be used with other therapies should be explored.


Introduction
According to 2020 statistics, cancer accounts for approximately 10 million cancer-related deaths with approximately 19.3 million cancer cases worldwide [1]. Carcinogenesis is the progressive transformation of normal cells into neoplastic cells, comprising four phases: tumor initiation, tumor promotion, malignant conversion, and tumor progression. Te frst phase of carcinogenesis, tumor initiation, is marked by changes in DNA (deoxyribonucleic acid) brought about by physical or chemical carcinogenic stimuli [2]. Changes in DNA lead to oncogene-mediated activation or tumor suppressor gene-mediated suppression of various genes [2,3]. During tumor promotion, genes involved in cell proliferation and vascularization are activated, resulting in the formation of neoplastic cells. In the malignant conversion step, the preneoplastic cells transform into cells expressing malignant phenotypes. In the tumor progression stage, the tumor aggressively proliferates and invades other tissues, accumulating several diferent mutations [3]. Hanahan [4] reviewed the hallmarks of cancer, providing a detailed description of changes occurring in a cell moving from a normal to a transformed state ( Figure 1).
Approximately 25% of cancer cases have a history of chronic infammation or infectious diseases [5,6]. Extrinsic factors, including smoking and infections, and intrinsic factors, such as tumor-associated infammation, contribute to an infammatory tumor microenvironment (TME) [7]. Additionally, changes in cell physiology and metabolism result in an increase in stress-related infammatory markers [8]. Cancer treatment using the conventional approach and biotherapeutics could also induce infammation and has been extensively studied in recent years [6].
Infammation is a protective response elicited by cells when tissue damage is caused by infection, trauma, exposure to a toxin, or physical or ischemic injury. A successful infammatory response leads to homeostasis and infammation resolution upon the removal of the stimulus [7,9]. However, a standof between the immune response and a stimulus that cannot be eradicated results in chronic infammatory conditions [6,10]. In chronic infammatory conditions, infammatory mediators such as reactive oxygen species cause DNA damage by oxidation and facilitate spontaneous mutagenesis mediated by 8-oxo-7-hydro-2′deoxyguanosine [11]. Te interplay between various proinfammatory factors in the TME plays a signifcant role in cancer development and progression [12,13]. Terefore, considerable research has been conducted in the last decade to understand the relationship between infammation and cancer [7,14,15].
One of the most well-studied genes involved in tumor initiation and progression is the mutated tumor suppressor gene Tp53, encoding the p53 protein that plays a pivotal role in cell homeostasis [16]. Wild-type p53 suppresses tumor growth by activating factors responsible for DNA repair and inducing apoptosis and senescence [16], prevents oncogenic transformation in cultured cells, and p53 null mice are highly likely to develop tumors [17]. Recent studies have reported the role of mutant p53 in the TME. Bhatta et al. [18] have reported that the presence of mutant p53 protein in the TME of nontransformed cells promotes tumor progression through cell reprogramming. Te cross-talk between the TME and the tumor is enhanced by mutant p53, resulting in the increased transcription of infammatory messengers such as nuclear factor kappa B (NFκB) [19]. A mutated p53 protein results in unchecked NF-kB activity, causing increased expression of proinfammatory signaling molecules; the resulting TME is characterized by hypoxia and increased ROS (reactive oxygen species) activity, further activating redox-sensitive factors such as hypoxia-inducible factor (HIF-1α) [6,20]. Hypoxia also increases the levels of proinfammatory cytokines, including interleukin 6 (IL-6), tumor necrosis factor (TNF-α), and proangiogenic factors, including the vascular endothelial growth factor (VEGF), resulting in chronic infammation [6,20]. An interplay of factors, p53, along with increased IL-6, results in increased activity of a signal transducer and activator of transcription (STAT-3), supporting tumor induction and providing a favorable environment for tumor growth [21]. Terefore, p53, IL6, VEGF, and STAT3 are attractive therapeutic targets for cancer treatment [22].
Complementary and alternative medicine (CAM) is gaining more attention among patients with cancer. Approximately 87% of the patients use at least one form of CAM, including herbal medicine, yoga, reiki, and naturopathy, to improve their overall quality of life [23]. Furthermore, ∼22% of patients are reported to opt for herbal medicines along with conventional therapies [24]. Plant polyphenols are potent anticancer and anti-infammatory agents and have been reported to reduce the side efects caused by chemotherapy and reverse prolonged treatmentinduced chemoresistance [25]. Even though several natural compounds such as curcumin, resveratrol, green tea extracts, quercetin, and lycopene have been used for clinical testing, the mechanism of action of these natural compounds and how they exert their efects remain largely unidentifed [26]. Several widely used spices, such as curcumin (from turmeric, Curcuma longa) [27,28], eugenol (clove, Syzygium aromaticum) [29], cinnamic acid, and transcinnamaldehyde (Cinnamomum spp.) [30], have been identifed to have anticancer, anti-infammatory, and antioxidative properties [31] and are the source of many active therapeutic compounds. Tis review focuses on cinnamon and details its extraction techniques, active compounds, and their therapeutic potentials.

Cinnamon and Extraction Methods
Cinnamon (Cinnamomum spp.) is a tropical plant belonging to the Lauraceae family and has been widely used as a spice, favoring agent, and in the perfume industry since ancient times. Cinnamomum comprises ∼250 species, of which true cinnamon or Ceylon cinnamon (Cinnamomum verum), Cassia cinnamon or Chinese cinnamon (Cinnamomum cassia), Indonesian cassia (Cinnamomum burmannii), and Vietnamese cinnamon (Cinnamomum loureiroi) are most commonly used [32]. Increasing research on this plant has unraveled several benefts of cinnamon consumption. Various parts of the cinnamon plant, such as the bark, leaves, fowers, and fruits, are used to extract the cinnamon essential oil with diferent active compounds such as cinnamaldehyde, eugenol, camphor, and trans-cinnamyl acetate, respectively [33], and therapeutic properties (such as antiinfammatory, antidiabetic, antioxidant and antimicrobial). Apart from essential oils, the anti-infammatory and anticancer therapeutic potentials of organic and aqueous extracts of cinnamon have also been reported [29,30], and several extraction methods using various solvents have been developed over the years [34][35][36]. Te aqueous polyphenol fraction has therapeutic potential as an anti-infammatory agent for the treatment of periodontal disease [37]. In addition, several reports have confrmed the therapeutic potential of the aqueous cinnamon extract against cancer [9,38,39]. Te extraction method and type of solvent afect the recovery of polyphenols and, thus, the therapeutic properties of the cinnamon extract [40]. Abd Wahab and Adzmi [41] compared two types of cinnamon extract, Soxhlet extract using methanol and water extract. Tey recorded the cytotoxic efects of these extracts and compared the results based on the observed half maximal inhibitory concentration (IC50) values. Tey observed that the Soxhlet extract works better at the 24-hour time point (in an MTT (tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay) and is more efective than water extract. However, their lab observed higher IC50 for the extract than the published literature. Tey speculated that this diference might result from the diference in extract yield (∼21% in reported literature vs. 7% in their lab) and cinnamaldehyde concentration per gram. Tey also opined that cinnamaldehyde which is responsible for apoptosis and cell death in cancer cells afects the IC50 values.
In another example, an aqueous solution of ethanol (30-60%) was efective for phenol recovery and increasing the aqueous fraction resulted in better recovery of polyphenols [42]. An in vivo study showed no signifcant antidiabetic activity of the aqueous cinnamon extract in patients with type 2 diabetes. Te overall polyphenol content of the extract was lower than what is reported in the literature, which could be attributed to the age of the tree, tree section, and extraction method used [43]. Te impact of environmental factors, propagation method, age, and the plant's physical state (fowering, etc.) on phytochemicals has been reported [44]. With the seeding type of propagation (Sri Gamunu), a plant grown in a wet climate that is 3 -5 years old and harvested during fowering time contains a high phytochemical content. While with the vegetative type of propagation (Sri Wijaya), > 5-year-old bark had a greater yield of phytochemicals [44]. A study conducted on two accessions of C. zeylanicum, namely, Sri Gamunu and Sri Vijaya, revealed a diference in the composition of the bark oil. 78% of Sri Gamunu bark oil was cinnamyl acetate and cinnamaldehyde, while only 63% of Sri Vijaya contained these active ingredients. Sri Vijaya had higher levels of benzyl benzoate and eugenol [45]. Processing of plants affects the total phenol content of the spice. Klejdus and Kováčik [46] reported that complete tissue disruption is necessary for maximum recovery of total phenols. In their study, when whole bark was used, the recovery of total phenols was much less when compared to processed samples such as crushed materials using pestle and mortar, powdered using a grinder, or a combination of the two. Drying the cinnamon parts (leaves, bark, roots, etc.) is one of the critical postharvest processes. Reports indicate that drying impacts the phytochemical properties of cinnamon. A study conducted by Bernard et al. [47] showed that sun-drying was very destructive and resulted in the degradation of phytochemicals and, thus, the radicals scavenging activity when compared with a fresh sample. Oven drying was reported to be one of the better methods for preserving active ingredients. Tese studies indicate that researchers should be mindful when acquiring the samples and collect as much data about them as possible. Reporting the details is equally important so that others can truly beneft from the information. Ribeiro-Santos et al. [32] have written an excellent review that contains a section on plant processing and the efects it can have on the fnal extract.
Conventional methods such as maceration, extraction chambers, and percolation use organic solvents such as methanol and acetone for preparing plant extracts. However, these methods have a few drawbacks, they are not environmentally friendly, and it is crucial to ensure the removal of residual solvent from the fnal preparation before testing its efects [39]. Terefore, many researchers now prefer the green extraction method, which aims to discover innovative extraction processes that are safe, yield high-quality extracts,    [48]. One of the principles of green extraction is using alternate solvents, principally water and agrosolvents also known as biosolvents as they are produced from biological materials (for example, methyl esters of fatty acids in vegetable oil, ethanol from fermentation of sugar beet, and glycerol from vegetable oil transesterifcation), to minimize the release of toxic waste into the environment. Some of the green extraction methods (Figure 2) and their advantages and limitations are captured in Table 1. Green extraction techniques use modern technologies and sometimes also referred to as technology-assisted extraction methods [52]. It should be noted that one technique may not sufce the extract requirements. A combination of various technology-assisted green extraction methods can be used to achieve maximum yield of desired compounds [49,52]. Subcritical water extraction, one of the green methods being performed at high temperatures (200°C) and pressure (1.5 MPa), has gained considerable attention [48,53]. During subcritical extraction, the physicochemical properties of water, such as its dielectric constant, are signifcantly reduced (similar to ethanol), making it a suitable solvent for extracting low-polarity compounds [48]. Hydrodistillation is conventionally used to extract essential oils from cinnamon, and recent advances in this process include microwaveassisted hydrodistillation, which is energy-saving and environmentally friendly [52,54]. Aqueous cinnamon extract preparation by boiling, preparing a decoction, and either lyophilizing or using it as such after sterile fltration have also been reported [55,56].
Aqueous cinnamon extract has been extensively used in studies related to type 2 diabetes mellitus to manage blood sugar levels and as an antioxidant [57][58][59]. Comprehensive information on the role of cinnamon in diabetes management has been described in a recent review article [60]. In addition, cinnamon also acts as an antioxidant, anti-infammatory, anticancer, and wound healing agent [30]. Cinnamon aqueous extract has been used as an anti-infammatory agent in hepatorenal toxicity [61] and as an antiproliferative agent in human prostate cancer cells [62]. It has also been shown to inhibit tumor angiogenesis and growth [63]. As water is considered the most suitable form of solvent in terms of safety [64], we searched for references that would provide information on preparing aqueous cinnamon extracts with or without sophisticated instruments.
We searched various databases such as PubMed/ MEDLINE, Scopus, Web of Science, Embase, and Google Scholar with keywords such as cinnamon aqueous extract, water extract of cinnamon, cinnamon and infammation, cinnamon and cancer, aqueous extract and infammation, and aqueous extract and cancer. Based on the literature search, we identifed the need for a comprehensive review of aqueous extract preparation methods and their potential therapeutic properties. Terefore, this review aimed to highlight the role of the aqueous extract of cinnamon as a potential anticancer and infammatory agent. To this end, we have summarized the published methods for aqueous extract preparations and their benefcial efects on cancer and infammatory conditions.

Extraction Methods.
Tis review identifed literature on relatively simple aqueous extraction methods that could be carried out in laboratories with limited resources ( Figure 3 and Table 2). However, the literature search revealed that even seemingly simple extraction methods involve several steps, including extracting at 40°C, stirring rapidly for 10 min, centrifugation, chilling the beaker with the extract in an ice bath, and stirring, followed by fltration and lyophilization [55], to a simple one-step extraction process, where the ground cinnamon powder was resuspended in sterile water (70°C for 1 h), centrifuged, and used after fltration [67]. A common feature of most extraction methods summarized in Table 2 is that the extract was lyophilized and stored at −70°C to −80°C [66,69,70]. In most of the studies, ground/pulverized cinnamon was used [55,65], while in some cases, the extract was prepared after soaking the bark in water [69].

Role of Aqueous Cinnamon Extract.
Aqueous cinnamon extract has been reported to have anticancer [65,66], antiinfammatory [37,69], and antioxidant [71] properties and exert these efects by various mechanisms, a few of which are described in this section and summarized in Table 2 and  [41,66,72]. Te cytotoxic efect of crude cinnamon aqueous extract was reported to be more potent than that of individual components such as cinnamaldehyde [66]. In an in vitro study, it was shown that aqueous cinnamon extract was toxic for oral squamous carcinoma cells (OSCC), reaching a 90% cytotoxicity with 10 mg/mL extract within 48 h. Moreover, treating OSCC with aqueous safron and cinnamon extracts had a synergistic efect, with more cytotoxicity at lower concentrations [9].

Anticancer Activity. Cinnamon extract is toxic to cancerous cells and inhibits tumor cell growth in vitro
Tumor cells require an abundant supply of nutrients and the removal of cellular metabolic waste for survival. Te genes involved in angiogenesis (formation of new blood vessels) or proangiogenesis are upregulated in the TME [80]. Aqueous cinnamon extract has been shown to downregulate the proangiogenic factors [65] and exhibit antiangiogenic properties [63,65,67]. It exerts its efects at various stages of angiogenesis [67] and modulates the expression of VEGF mediated by the inhibition of cyclooxygenase (Cox-2) in an in vitro as well as in vivo system [65] and that of HIF-1α, STAT3, and protein kinase B (AKT) in an in vitro system [63]. Cinnamaldehyde [63] and procyanidin [67] were identifed as active components in aqueous cinnamon extract, which inhibit VEGF expression and VEGFR2 signaling in vitro, respectively. An efective way to eliminate cancer cells is cytolysis which is mediated by CD8+ T cells. TME redesigns itself to evade the immune machinery and thus is refractory to the cytolytic CD8+ T cells [65]. Kwon et al. [65] have reported (ex vivo study) that cinnamon extracts enhance the cytolytic activities of CD8+ T cells which are Evidence-Based Complementary and Alternative Medicine associated with increased expression of perforin and granzymes.
NFκB regulates many factors that play a role in cell multiplication and cell survival. Increase in NFκB results in an increase in antiapoptotic molecules. One of the mechanisms by which tumor cells increase their chances of survival is by evading apoptosis; the mechanisms can vary from an increase in antiapoptotic molecules such as B-cell lymphoma 2 (BCL-2) and Bcl-2-like protein 4 (Bax), downregulation of death receptors, or inactivation of caspase-8 [81]. Many plant extracts, including aqueous cinnamon extract, act as proapoptotic agents [81]. One of the reported efects of the aqueous cinnamon extract both in in vitro and in vivo system was that it efectively inhibited the expression of proapoptotic genes, such as Bcl-2, BcL-xL, and survivin, which was mediated via a decrease in NFkB and activator protein AP-1 signaling [56]. Varalakshmi et al. [82] based on molecular docking studies have reported that procyanidin B2 has an inhibitory efect on NFkB and may act by inhibiting the translocation of this factor to the nucleus. Another mechanism by which aqueous cinnamon extract facilitates its proapoptotic activity is by increasing intracellular calcium, leading to loss of membrane potential and, eventually, apoptosis. In an independent study, authors observed an increase in intracellular calcium and depolarization of mitochondrial membrane potential, when SiHa cells were treated with 80 μg/mL of aqueous cinnamon extract [68].
Histone deacetylase family member 8 (HDAC8) is implicated in many cancers, and an HDAC8 knockdown system showed decreased cancer progression of human colon, lung, and cervical cells. In an in vitro and in silico study, aqueous extract of cinnamon, cinnamic acid, cinnamyl alcohol, and cinnamaldehyde, were all shown to bind  Figure 3: Summary of the methods used for preparation of aqueous cinnamon extract. Increased temperatures are used for extraction, but there is a lot of variation with respect to heating temperature and duration as seen in the fgure. Similarly, even when boiling is used to prepare the extract, lab-specifc methods have been used. 6 Evidence-Based Complementary and Alternative Medicine     Abdeen et al. [78] Results showed that when rats were pretreated with the aqueous cinnamon extract, it led to decreased acetaminophen-induced cellular alterations and apoptosis in healthy cells 10 Evidence-Based Complementary and Alternative Medicine to the HDAC8 enzyme. Te whole extract was much more efcient in inhibiting the enzyme compared to purifed components [76]. Transformed cancerous cells are associated with increased activity of 26S proteasome, the protein degrading machinery. Tis increased activity facilitates cancer cell proliferation and survival. Te aqueous cinnamon extract and one of its active components, procyanidin B2, were reported to have antiprotease activity (26S proteasome). Tese components inhibited the complete catalytic activity (all 3 activities of the 20S) and were selective for transformed cells only [62].

Anti-Infammatory
Activity. An infection-mediated immune response can be either innate when encountering the antigen for the frst time or acquired when the response is generated from immunological memory [83]. Te immune response is identifed as "good" infammation, which leads to an antigen-specifc T-cell response; however, prolonged and uncontrolled infammation can eventually lead to chronic infammatory diseases and cancer [5]. Te activated T-cell response is characterized by the production of cytokines such as interferon (IFN-c), interleukin 2 (IL2), and interleukin 4 (IL4) and changes in the expression of signaling molecules [69]. In an immune response generated by activated T-cells, the aqueous cinnamon extract reduced the IFN-c levels and inhibited p38, c-Jun amino-terminal kinases (JNK), extracellular signal-regulated kinases (ERK), signal transducer and activator of transcription 4 (STAT4), and signal transducer and activator of transcription 6 (STAT6), without afecting the inhibitor of kappa B (IkBα) [69]. Similarly, aqueous cinnamon extract downregulated lipopolysaccharide (LPS)-induced TNF-α levels in serum by inhibiting the activation of p38, JNK/ERK1 and 2, and IkBα [70]. LPS binds to receptors such as toll-like receptors which recognize a unique microbial pattern and elicit an immune response. Te response is mediated by NFkB and MAP kinase signal pathways. In this in vivo and in vitro study [70], cinnamon aqueous extract at low doses was able to decrease TNF-α and IL-6 levels in the serum. Chronic infammatory conditions are characterized by an IFN-c driven initial response followed by the release of other infammatory mediators. Aqueous extract of cinnamon as well as its polyphenol fraction exerts anti-infammatory activities which result in decrease of IFN-c, NFkB, and MAP kinase signal pathways and expression of IL6, IL8, and TNF-α [37,70]. Another study using a cellular intestinal infammation model revealed that aqueous cinnamon extract containing the active components, cinnamic acid and cinnamaldehyde, played a dual role in enhancing tight junction permeability and decreasing infammatory modulators interleukin 6 (IL6), interleukin 8 (IL8), TNF-α, and NFkB. Cinnamon aqueous treated mice had better gut microbiota diversity than untreated counterpart [79].   Ethanol extract has better radical scavenging activity then water extract Moselhy and Ali [86] Dried cinnamon powder was extracted in various solvents (water, ethanol, methanol, acetone and ethyl acetate).
Te extraction was optimized for solute to solvent ratio, extraction time and temperature and fnally the phenolic content and radical scavenging activity Evidence-Based Complementary and Alternative Medicine 3.5. Antioxidant Activity. One of the essential roles of aqueous cinnamon extract is its antioxidant activity. Te extraction method afects the total phenol content and antioxidant potential. Table 3 summarizes the efect of the extraction method and solvent on overall antioxidant capacity. To summarize, hydroethanolic solvent seems to perform better in terms of total phenol content and antioxidant activity than aqueous extract [42]. However, for the in vivo studies listed in the table, the preferred extraction solvent was water [49,52]. For cinnamon aqueous extract to be useful as CAM, we have discussed its anticancer and antiinfammatory role; in this section, we discuss the antioxidant role of aqueous extract which solidifes it as a CAM candidate. Efective chemotherapeutic agents, such as cisdiamminedichloroplatinum (CDDP), are associated with several side efects, one of which is increase in reactive oxygen species (ROS). Heme oxygenase-1 (HO-1) is upregulated in the kidneys to counteract the oxidative stress. In an in vitro study, Vero cells were treated with CDDP to induce toxicity and treatment with aqueous cinnamon extract which decreased CDDP-mediated ROS and helped in counteracting oxidative stress and decreased apoptotic cell death. One of the ways by which the extract brings about this efect is by upregulation of heme oxygenase-1 (HO-1) transcript levels without interfering with CDDP activity [74]. In another example, acetaminophen, an antipyretic and analgesic drug, if abused beyond therapeutic doses is associated with acute renal toxicity which results due to increased oxidative stress from increased ROS. In an in vivo study, the aqueous cinnamon extract has been shown to protect against acetaminophen-mediated cellular damage and apoptosis in renal cells by limiting/decreasing lipid peroxidation and apoptosis [87]. Small-molecule therapeutic agents are associated with acute toxicity when they exceed the recommended dose [74,87], and the chances of toxicity are further increased when multiple therapeutic agents are administered together [61]. Diclofenac sodium (DFS), a nonsteroidal anti-infammatory drug, is often consumed along with oxytetracycline (OTC) (an antibiotic), and the combination is associated with severe toxicities when abused. Te toxicities are associated with increased ROS, decreased activity of antioxidant superoxide dismutase (SOD), and reduced glutathione (GSH). Te antioxidant and anti-infammatory properties of the aqueous cinnamon extract protected against the toxicity induced by DFS and OTC, individually or in combination, by increasing the proapoptotic factors, hepatic and renal caspase-3, and cyclooxygenase-II [61].

Active Components of Aqueous Cinnamon Extracts
4.1. Cinnamaldehyde. Cinnamaldehyde (cinnamic aldehyde), a phenylpropanoid ( Figure 5), occurs naturally as a transcinnamaldehyde and imparts the odor and favor of cinnamon. It is one of the main components of cinnamon essential oils and is also present in the aqueous extract of cinnamon [61,63]. Several studies have reported the anticancer and antiinfammatory activities of cinnamaldehyde [65,89]. Te aqueous cinnamon extract containing cinnamaldehyde has been shown to exert higher cytotoxic activity than purifed cinnamaldehyde against cancerous cell lines, suggesting that cinnamaldehyde, in conjunction with other polyphenols present in the aqueous cinnamon extract, plays a role in cancer cell cytotoxicity [66]. Te aqueous cinnamon extract with cinnamaldehydes and polyphenols as the major bioactive compounds was cytotoxic to cancer cells. It downregulated human epidermal growth factor receptor-2 (EGFR-2) and matrix metalloproteinase (MMP-2) expression, afecting the invasion and metastasis of cervical cancer [68]. Liao et al. [90] showed that aqueous cinnamon extract and purifed cinnamaldehyde exert their efect on TNF-α-induced signaling in endothelial cells. Tis efect is seen when cells are pretreated with either aqueous cinnamon extract or purifed cinnamaldehyde. Te mechanism of action is through blocking the degradation of the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), when pretreatment is short term (up to 3 hrs). Tis results in a decrease in expression of intercellular adhesion molecule 1 (ICAM), vascular cell adhesion molecule 1 (VCAM), and NF-κB signaling. Over long-term (up to 12 hrs.) pretreatment cinnamaldehyde causes induction of nuclear factor erythroid 2related factor 2 (Nrf2)-related genes (including HO-1) which are cytoprotective. Cabello et al. [91], in their studies on A375 melanoma cells, demonstrated that cinnamaldehyde inhibited NFkB constitutive and TNF-α-induced transcriptional activity and suggested that Michael acceptor reactivity with this dietary electrophile is responsible for the observed efect. Angiogenesis is central to the development and growth of tumor cells. Several small-molecule inhibitors and targeted therapies are aimed at inhibiting angiogenesis. Te aqueous cinnamon extract decreased VEGF, a key molecule involved in angiogenesis, and was mediated by suppression of the HIF-1α gene via STAT3 and AKT. Te decrease in VEGF and the resulting antiangiogenic efects were attributed to cinnamaldehyde, a major component of the extract [63]. Liu et al. [89] identifed possible cinnamaldehyde targets in breast cancer using in silico and in an in vitro study demonstrated that cinnamaldehyde induced apoptosis, decreased proliferation, and reduced the ability of cells to migrate and invade.

Cinnamic Acid.
Cinnamic acid is a naturally occurring unsaturated carboxylic acid with a widely present trans isomer. Similar to other components of cinnamon, cinnamic acid ( Figure 6) is cytotoxic to cancerous cells. In an in vitro model, cinnamic acid inhibited cell growth and multiplication. It modulated the expression of MMP2 and reduced the invasive capacity of cancer cells, suggesting its potential to reverse malignant human tumor cells to benign cells [93]. Cancerous cells upregulate antiapoptotic signaling cascades, leading to increased survival [4], which can be reversed by cinnamic acid. Niero et al. [94] showed that cinnamic acid induced apoptosis in HT-144 human melanoma cells by upregulating the proapoptotic machinery, caspase-3 activity, and Bax and downregulating antiapoptotic Bcl-2 protein.
Over the years, it has become apparent that overexpression of MMP proteins and malignant cancers are correlated. Yen et al. [95] demonstrated that cis and trans stereoisomers of cinnamic acid could inhibit the MMP-2 and 9 activity, decreasing the invasive ability of A549 cells. Moreover, MMP downregulation can be linked to transcription factors, such as NFkB, AP-1, and the mitogenactivated protein kinases (MAPK) pathway [96]. Kwon et al. [56] elucidated the anticancer activity of the cinnamon extract containing cinnamic acid and cinnamaldehyde as the major bioactive compounds in several transformed cell lines. Furthermore, in an intestinal epithelial cell and monocyte- Evidence-Based Complementary and Alternative Medicine macrophage coculture model, a cinnamon water extract downregulated the infammatory markers, such as TNF-α, inducible nitric oxide synthase (iNOS), and COX-2, providing evidence for its anti-infammatory activity. Even though the specifc compound responsible for the antiinfammatory efect was not identifed in the study, cinnamic acid was one of the major bioactive compounds present in the extract.

Polyphenols.
Polyphenols are naturally occurring organic compounds abundant in fruits, vegetables, tea, and spices. Tese secondary metabolites play a role in defense against pathogens and are known to protect against ultraviolet radiation [97]. Procyanidins comprising (epi) catechin monomeric units (Figure 7) play a protective role against cancer and infammation [98,99]. It has been reported that procyanidin tetramers and pentamers in Cinnamomi cortex (dried bark of C. verum) extract suppressed Nrf2-regulated enzyme activity in human lung cancer cell line A549 [100]. Nrf2 is a crucial cytoprotective transcription factor, and its overexpression induces resistance to chemotherapy, the most pressing dilemma in cancer therapy [101].
Angiogenesis is critical for cancer cells to fourish and propagate [102]. Of several molecules known to regulate angiogenesis, VEGF is the most important; it binds to its cognate receptors, VEGFR1 and VEGFR2, and initiates a signaling cascade leading to angiogenesis [102]. Terefore, VEGF and its receptors are attractive targets for cancer therapy [103]. Te aqueous cinnamon extract could inhibit receptor kinase activity and downstream signaling of VEGFR2, suggesting the role of procyanidin trimers and tetramers in inhibiting VEGFR2 activity [67].
Proteosomes are another exciting target that has been identifed for cancer therapy. Proteosome levels are elevated in tumor cells, which play an antiapoptotic role [62]. Te procyanidin B2 component of the aqueous cinnamon extract was reported to selectively inhibit proteasome activity in cancer cells, decrease cell proliferation, and regulate genetic markers related to apoptosis and angiogenesis [2,62].
Cancer and infammation are intricately linked; therefore, targeting infammatory markers can help in chronic pathologic infammation and in cancers where infammatory molecules exacerbate cancer progression. NFkB modulates the expression of several proinfammatory molecules and triggers infammatory conditions. Targeting NFkB using Cinnulin PF ® , an aqueous cinnamon extract containing cinnamic acid, phenolic acids, favonoids, and procyanidins, primarily as trimers and tetramers, decreased the production of infammatory cytokines in an lipopolysaccharide (LPS)-stimulated macrophage cell system, concomitantly with a signifcant reduction in NFkB activity (60.1%) [37].

Conclusion
Te aqueous extract of cinnamon contains bioactive components that have signifcant protective efects against cancer and infammatory conditions. Te synergistic efects of these components have better therapeutic efciency than when a purifed component is used. Further studies are required to understand whether cinnamon extract should be used only as complementary and alternative medicine or if it could play a more signifcant role. A few studies have shown that cinnamon extract can work with chemotherapeutic agents; however, such studies are scarce. Further studies are essential to understand the potential of this multipurpose spice and identify its benefcial use as an adjunct therapy for various pathological conditions, especially cancer and chronic infammation. Better characterization of the aqueous extract would help formulate an efective dose and regime for treatment. Collaborations between academics and the pharmaceutical industry could expedite this process and greatly help patients.

Data Availability
No data were generated to support the fndings of this study.

Conflicts of Interest
Te authors declare that they have no conficts of interest.