Review Article | Volume: 11, Issue: 7, July, 2021

A review of the chemopreventive effects of the main bioactive compounds in coffee in colorectal cancer

Yurany Yepes Diego Uribe Sarah Röthlisberger   

Open Access   

Published:  May 27, 2021

DOI: 10.7324/JAPS.2021.110704
Abstract

Colorectal cancer (CRC) is a public health problem worldwide, and despite technological advances in diagnosis and treatment, its incidence and mortality continue to increase. In recent decades, considerable efforts have been made in evaluating natural dietary compounds as chemopreventive agents that help reduce the risk of cancer development, progression, or recurrence. Coffee is of particular interest as it has a high content of bioactive compounds, and there is strong epidemiological evidence that it has a protective effect against CRC. Here, we review the most abundant phytochemicals found in coffee [caffeine, chlorogenic acids (CGAs), cafestol, and kahweol] and their contribution to chemoprevention of CRC, as reported in in vitro studies and in animal studies. The literature shows that the chemopreventive effect of coffee is largely attributed to CGAs and cafestol/kahweol, rather than caffeine, although caffeine may have a small cumulative effect.


Keyword:     Cafestol caffeine chemoprevention chlorogenic acid colorectal cancer coffee.


Citation:

Yepes Y, Uribe D, Röthlisberger S. A review of the chemopreventive effects of the main bioactive compounds in coffee in colorectal cancer. J Appl Pharm Sci, 2021;11(07):046–054.

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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INTRODUCTION

According to the International Coffee Organization (www.ico.org), in 2019, 164.487.000 60 kg bags of coffee beans were sold worldwide, making it one of the most widely sought-after beverages. Interestingly, meta-analyses show that coffee consumption significantly reduces all-cause mortality, as well as reducing the risk of developing cardiovascular disease, several different types of cancer, and metabolic and liver conditions (Poole et al., 2017). Specifically, there is great interest in the effect of coffee on the incidence, severity, and response to treatment of colorectal cancer (CRC), as this is one of the most prevalent types of cancer worldwide, and the colon is directly exposed to the bioactive compounds in coffee when it is ingested. A literature review of epidemiological studies, as well as experimental in vitro and in vivo studies, has compiled evidence showing that coffee has a chemopreventive effect against CRC (Moreno-Ceballos et al., 2019).

Coffee beans contain multiple phytochemicals such as caffeine, chlorogenic acids (CGAs), cafestol, and kahweol, to which many of these health effects can be attributed. Caffeine is the most commonly recognized compound present in coffee. This alkaloid and the metabolites derived from it have been shown to exhibit antioxidant, antiproliferative, and anti-inflammatory effects (Cui et al., 2020). Kahweol and cafestol are two diterpenes in the lipid fraction of the coffee bean, which are particularly interesting as they have been shown to induce apoptosis of malignant cells in vitro (Lee et al., 2012), reduce cell proliferation and migration (Moeenfard et al., 2016), and counteract oxidative stress (Lee et al., 2007). One of the main components of coffee is CGAs. This abundant group of polyphenols are esters formed between caffeic and quinic acids, of which 5-caffeoylquinic acid (5-CQA) is the main CGA present in coffee (Perrone et al., 2010). Evidence shows that CGAs also have antioxidant and anti-inflammatory activities (Liang and Kitts, 2015).

In this paper, we will review the effects of the main bioactive compounds in coffee : caffeine, CGAs, cafestol, and kahweol, in cell and animal models of CRC, in order to provide a clearer picture of how these phytochemicals contribute to the chemopreventive properties of coffee in CRC.

Literature search

Results of the literature search are shown in Table 1. Studies were initially screened in order to eliminate review articles. After this screening, the remaining studies were assessed for eligibility independently by the authors in order to determine which ones were within the scope of this review. Bioinformatics and epidemiological studies were excluded, as well as studies with whole plant extracts, when it was not possible to determine if the effect was due to a specific component. For the case of cafestol and kahweol, all studies with cafestol included kahweol, so the studies were repeated when searching individually.

Bioactive compounds in coffee

The green coffee bean is composed of carbohydrates, lipids, proteins, alkaloids, minerals, and phenolic and aliphatic acids (see Fig. 1). The concentration of these components in the coffee bean varies according to variety and origin (altitude, climate, etc.). The toasting process, in particular, changes the chemical profile of the coffee bean, resulting in a decrease in total protein, reduction in CGAs, and a reduction in carbohydrates as these undergo a process of pyrolysis in which melanoidins are formed.

Table 1. Results of the literature search.

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Although all of these components are integral to the aroma and flavor of the coffee we consume, the health benefits of coffee have been mainly attributed to alkaloids (caffeine), diterpenes in the lipid fraction (cafestol and kahweol), and CGAs (Sarraguça et al., 2016). In the literature, we find ample evidence as to the chemopreventive and bioactive activities of these substances against the hallmarks of cancer (Gaascht et al., 2015); thereby we will only focus on these components in the next sections.

Caffeine

Caffeine (1,3,7-trimethylxanthine) is an alkaloid from the xanthine group (see Fig. 1), naturally present in tea leaves, coffee beans, cocoa beans, and cola seeds, among others. Coffee beans contain less than 3% caffeine depending on species, origin, and roasting times (Górecki and Hallmann, 2020). It is the most well-known bioactive compound present in coffee and is mainly recognized as a central nervous system stimulant. There are many studies that report a protective effect of coffee consumption on the colon (Moreno-Ceballos et al., 2019); however, it is not altogether clear to what extent caffeine contributes to this effect. In vitro and in vivo studies of caffeine in CRC models are summarized in Table 2.

In a study in which colorectal carcinoma (HCT116) and normal colon (CCD-18co) cells were treated with 2 mM of caffeine for 3 hours, a selective effect of caffeine was reported on apoptosis and cell cycle in HCT116 cells (Saito et al., 2003). In terms of apoptosis, this increased 2.77-fold in treated HCT116 cells, but only 0.23-fold in CCD-18co cells. Cell cycle analysis revealed a 14% reduction of HCT116 cells in the G2/M phase 72 hours after treatment and a 4.05% reduction of CCD-18co cells in the G2/M phase. In another study in which 35 synthetic caffeine-hydrazones were tested on several types of cell lines, including human colorectal carcinoma HCT116 cells and HCT116 p53−/− cell lines, it was reported that all the compounds induced apoptosis at concentrations ranging between 0.34 and 25 μM in both cell lines (Kaplánek et al., 2015).

Figure 1. Main components in coffee beans. Percentages correspond to the contribution of each component to the total dry weight. Melanoidins are only present in the roasted coffee bean. 3-Caffeoylquinic acid (3-CQA), 4-caffeoylquinic acid (4-CQA), 5-caffeoylquinic acid (5-CQA), 3,4-dicaffeoylquinic acid (3,4-diCQA), 3,5-dicaffeoylquinic acid (3,5-diCQA), and 4,5-dicaffeoylquinic acid (4,5-diCQA). Chemical structures were taken from PubChem. Cup of coffee: Deman/Shutterstock.com.

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Table 2. Summary of in vitro and in vivo studies in CRC models of the main bioactive compounds in coffee.

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These results are contradicted by a study in which HCT116 cells were pretreated for 2 hours with 2 mM caffeine and afterward treated with 100 nM doxorubicin for 5 days (Strzeszewska et al., 2018). This study showed that when cells were pretreated with caffeine, the activity of SA-β-Gal reduced between 2- and 3-fold and cell granularity was reduced between 1.8- and 4-fold. SA-β-Gal is a biomarker of cellular senescence, while cell granularity is a phenotypic marker of cellular growth arrest or death (Haynes et al., 2009), so this study showed that treatment with caffeine reduces cell cycle arrest and cell death caused by doxorubicin. These results were reflected in a 3-fold increase in cell proliferation when cells were pretreated with caffeine.

Another report, which is in accord with the results published by Strzeszewska, described that when human colon cancer cells Colo205 were treated with different doses of caffeine ranging from 0 to 20 μM, there was no effect on apoptosis (Mhaidat et al., 2014). Moreover, when cells were pretreated with 20 μM caffeine, followed by treatment with paclitaxel, cells were significantly protected from the paclitaxel-induced apoptosis that is normally observed. This antiapoptotic effect seems to be due to increased activation of the ERK1/2 survival pathway by caffeine. The effect of caffeine on several cell survival mediators was analyzed by Western Blot, showing that treatment of cells with caffeine induced a 2-fold increase in Mcl-1, an antiapoptotic member of the BCL-2 family, as well as a slight (approximately 1.3-fold) increase in GRP78, a chaperone protein which responds to endoplasmic reticulum stress.

In an in vivo model of male F344 rats treated with PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine) to induce the formation of intestinal tumors, followed by 0.065% caffeine as a sole source of fluid intake, only 18% of rats survived to 1 year, which was lower than the PhIP control group (32% survival) (Wang et al., 2008). There was also an increase in the incidence of colon tumors in rats treated with caffeine versus the controls (73.3% vs. 41.6%) and in tumor volume (1.8-fold). However, caffeine showed a protective effect on other organs, as the incidence of all noncolon tumors in the rats treated with caffeine was significantly lower than the controls (PhIP/HF + caffeine 13.3% vs. PhIP/HF controls 69.5%). There was a higher frequency of β-catenin mutations in caffeine-treated animals (79% vs. 36% in controls), as well as increased levels of expression of c-myc. This was reflected in an increase in cell proliferation and reduction of apoptosis in colonic crypts, as measured by cleaved-caspase three staining in the group treated with caffeine.

It has been shown that caffeine can have an effect on inflammation. In a study where PBMC cells were cocultured with HT-29 and RKO cells with 0, 25, 75, and 225 μg/ml caffeine for 24 hours, there was a dose-dependent effect of caffeine on the production of proinflammatory cytokines Tumor necrosis factor alpha (TNF-α) and IFNγ, as well as of anti-inflammatory cytokines IL-1ra and IL-10 by PBMC (Bessler et al., 2012). These results were confirmed by an animal study of colitis and colitis-associated carcinoma (CAC). In this in vivo study, WT Balb/c mice were treated with saline (control), dextran sodium sulfate (DSS) to induce colitis, or DSS followed by azoxymethane (AOM) in order to induce CAC (Ma et al., 2014). In the CAC group, when mice were also treated with caffeine, tumor incidence reduced 3-fold (25% in CAC + caffeine versus 75% in CAC). In the colitis group, inflammation was greatly reduced when mice were also treated with caffeine. This was confirmed by results that showed reduced expression of CHI3L1 in all groups treated with caffeine. This is significant as CHI3L1 has a role in inducing proinflammatory and protumorigenic and angiogenic factors that promote tumor growth and metastasis (Libreros et al., 2013). A widely used biomarker for oxidative stress, 8-OHdG, was also measured and showed reduced expression in the colon when mice were treated with caffeine.

In rats exposed to carcinogen N-methyl-N-nitro-N-nitrosoguanidine (MNNG) followed by daily oral gavage of caffeine, it was found that in the rats treated with caffeine there was a reduction in phosphorylation of histone γH2AX, which is an early cellular response to DNA damage, as well as a reduction in the expression of Cox-2, an enzyme involved in the production of prostaglandins during inflammation (Soares et al., 2019). This shows that caffeine reduces DNA damage and inflammation caused by MNNG. However, this same study showed conflicting results, as the treatment with caffeine post MNNG caused an increase in lipid peroxidation and a reduction in metallothionein expression, which is involved in protecting the cell against oxidative stress.

CGAs

CGAs are the most abundant phenolic acids found in green coffee extracts and tea, formed by the esterification of caffeic acid and quinic acid (see Fig. 1). They are divided into caffeoylquinic acids (CQAs: 3-CQA, 4-CQA, and 5-CQA), dicaffeoylquinic acids (diCQAs: 3,4-diCQA, 3,5-diCQA, and 4,5-diCQA), and feruloylquinic acids (FQAs: 3- FQA, 4- FQA, and 5-FQA). The content of these CGAs is approximately 10% of the dry weight of the coffee bean, although this varies according to species, origin, and roasting time (Ludwig et al., 2014). Many therapeutic properties have been ascribed to CGAs such as antioxidant, antibacterial, hepatoprotective, cardioprotective, and anti-inflammatory activities, among others (Naveed et al., 2018). In vitro and in vivo studies of CGAs in CRC models are summarized in Table 2.

A study in which Caco-2 cells were treated with 100–1,000 μM CGA for 24 hours showed an increase in cytotoxicity and apoptosis which brought about a decline in cell proliferation (Sadeghi Ekbatan et al., 2018). Cell membrane damage (cytotoxicity) was measured by the lactate dehydrogenase (LDH) assay, showing a dose-dependent effect of CGA on the release of intracellular LDH into the culture medium: 250 μM (12.2%), 500 μM (22.5%), and 1,000 μM (39.2%). There was also an increase in caspase-3 expression, which is one of the main proteins involved in the initiation of apoptosis, when cells were treated with concentrations of 500 and 1,000 μM CGA. As expected, this effect was also observed when measuring cell proliferation, with a significant reduction of 42.5% and 60.4% when cells were treated with 500 and 1,000 μM CGA. In terms of cell cycle, there was a significant reduction in the number of cells in the G0/G1 phase and an increase in cells in S phase, when treated with 250 μM of CGA or higher.

Similar doses of CGA (100–1,000 μM) were evaluated in HCT116 and HT29 cells, showing a dose-dependent effect on cell viability, with a 50.1% and 55.2% reduction at 1,000 μmol/l for HCT116 and HT29 (Hou et al., 2017). Induction of reactive oxygen species (ROS) production and S-phase arrest was also observed in both cell lines. The authors evaluated the activation of the mitogen-activated protein kinase (MAPK)/ERK pathway, which plays an important role in cell proliferation, and reported that treatment with CGA reduces ERK phosphorylation, suggesting an inactivation effect of CGA over the MAPK/ERK pathway. In another study with very similar results, the inhibition of HT-29 cell survival was evaluated when treated with doses of CGA from 0.01 to 5 mM, resulting in a significantly decreased growth rate of the cells (52% at 1 mM) (Nam et al., 2017).

The chemopreventive potential of CGA derivatives has also been of interest in the context of CRC. A study into the antiproliferative and proapoptotic effect of methyl 3,5-dicaffeoyl quinate (MDQ) in HT-29 cells found that MDQ reduces cell viability and induces apoptosis in a dose and time-dependent manner. When the molecular basis of this was effect was analyzed, it was found that MDQ modulates the mitochondria-dependent pathway of apoptosis by upregulating caspase-3 and cleaved PARP levels, altering the mitochondrial membrane potential and the Bcl-2/Bax ratio, which altogether results in cytochrome c release into the cytosol (Hu et al., 2011). This study also revealed that treatment with MDQ reduced ERK phosphorylation and NFκβ nuclear levels, thus confirming that the antiproliferative effects of these components are related to the MAPK/ERK and NFκβ pathways.

In another study with different CGA derivatives, known as diCQAs, the anticarcinogenic potential was explored in RKO and HT29 cells (Puangpraphant et al., 2011). The results demonstrate that these molecules inhibited cell proliferation and induced apoptosis in the colorectal carcinoma cell lines, with no effect over normal human colon fibroblasts. The anti-inflammatory potential of these diCQAs was evaluated by measuring nitric oxide (NO) and PGE2 production and the expression of iNOS and COX-2 on lipopolysaccharide-induced RAW 264.7 cells. All the compounds tested reduced NO production and iNOS expression, as well as proinflammatory markers and nuclear NFκβ levels.

In a DSS-induced ulcerative colitis mouse model, several dosages of CGA were used in order to evaluate if CGA could mitigate the damage caused by DSS in colon tissue (Gao et al., 2019). Low and medium doses of CGA had no significant effect; however, a high dose of 120 mg/kg/day CGA for 10 days inhibited the inflammatory reaction, reduced oxidative damage, and decreased apoptosis. The colon mucosal damage index was evaluated and treatment with CGA was shown to reduce the presence of ulcers, inflammation, and adhesions. This was further confirmed, as the levels of proinflammatory factors IL-1β, IL-6, and TNF-α were reduced, while anti-inflammatory cytokine IL-10 was increased by CGA. Oxidative damage caused by DSS was also improved by CGA, shown by a reduction in the expression of oxidative stress-related factors PAF, PGE2, and MPO, while levels of the antioxidant protein SOD increased. Apoptosis of intestinal tissue cells was also reduced by CGA, as seen by increased levels of Bcl-2, Bax, and reduced caspase 3. It appears that the protective effect of CGA is mediated by modulation of the MAPK/ERK/JNK pathway, as protein levels of ERK1/2, p-ERK, p38, p-p38, JNK, p-JNK, p-IκB, and p-p65 were reduced by CGA. These conclusions are supported by a previous study that used the same ulcerative colitis mouse model (Vukelić et al., 2018). This group of authors also reported that CGA decreased the expression of p-ERK1/2, as well as of other key players such as AKT, p-AKT, STAT3, and p-STAT3. Inflammatory proteins Cox-2, NF-κB p65, and TNF-α also reduced when mice were treated with CGA.

Cafestol and kahweol

Within the lipid fraction of the coffee bean, we find two important diterpenes, which are specific to coffee: cafestol and kahweol. Cafestol is found in both Coffea arabica and Coffea canephora, while kahweol is only found in C. arabica (de Toledo Benassi and Dias, 2015). In their structure and function, they are very similar, differing only by a double bond between the C1 and C2 carbon atoms (see Fig. 1). A range of biological effects with potential for cancer prevention and/or treatment have been reported for these two diterpenes (Cavin et al., 2002). In vitro and in vivo studies of cafestol and kahweol in CRC models are summarized in Table 2.

In one of the first studies with cafestol and kahweol, mice were pretreated with kahweol : cafestol (1:1) 0.2% for 10 days, followed by PhIP exposure, which is known to induce colon tumors in mouse models, and results showed a 54% reduction of PhIP-DNA adduct formation in the colon (Huber et al., 1997). Due to this promising result, the authors followed up with another study published in 2002 in which mice were treated with kahweol : cafestol (1:1) in concentrations of 0.2%, 0.1%, 0.04%, and 0.02% for 10 days or with cafestol alone at the same concentrations (Huber et al., 2002b). When treated with the combination of cafestol and kahweol, glutathione (GSH) levels and γ-glutamylcysteine synthetase (GCS) activity slightly increased in colon tissue at the higher doses (0.1% and 0.2%), effect which was much more prominent in the liver. GSH is a potent antioxidant, and GCS catalyzes the rate-limiting reaction in GSH biosynthesis, so this helps explain the protective role of cafestol and kahweol on the colon. The detoxification enzyme glutathione S-transferase (GST) is also increased with kahweol : cafestol (1:1) in the concentration of 0.2% (Huber et al., 2002a).

In human CRC cells HCT116 and SW480 and normal colon cells CCD-18co, treated with varying concentrations of kahweol, there was a dose-dependent decrease in cell proliferation in HCT116 and SW480 cells, but not in CCD-18co (Park et al., 2016). In order to explore the role of kahweol a bit further, levels of cyclin D1, an important regulator of cell cycle progression, were measured, and it was found that mRNA levels of cyclin D1 remained unchanged while protein cyclin D1 levels reduced noticeably. This indicated that kahweol could be promoting cyclin D1 proteasomal degradation, which was confirmed by pretreating cells with a proteasome inhibitor which blocked the kahweol-induced decrease of cyclin D1 protein levels. Threonine-286 (Thr286) phosphorylation of cyclin D1 has been reported to be associated with its proteasomal degradation, and increased levels of p-cyclin D1 (Thr286) by kahweol were confirmed. Similar to CGAs, kahweol also induced the phosphorylation of ERK1/2, JNK, and GSKb.

A study with HCT116, SW480, LoVo, and HT-29 cell lines showed an increase in cleaved PARP and ATF3 expression when treated with 25 and 50 μM of kahweol, although the effect was much more noticeable with 50 μM, so all subsequent experiments were carried out at this concentration (Park et al., 2017). In order to explore the role of kahweol-mediated ATF3 expression in apoptosis, ATF3 overexpression was induced in cells treated with kahweol and this increased cleaved PARP levels even more, while silencing of ATF3 drastically reduced cleaved PARP. Kahweol enhanced ATF3 promoter activity and thus ATF3 mRNA levels, and these levels were reduced when cells were treated with inhibitors of ERK1/2 and GSK3β, indicating that these are the upstream kinases involved in kahweol-mediated ATF3 expression.

In a study with several types of cell lines treated with kahweol, HT-29 cells exhibited reduced cell proliferation and a decreased number of colonies when treated with a concentration of 50 μM (Cárdenas et al., 2014). Apoptosis was increased at 25 μM; however, cell cycle analysis revealed no changes in the distribution of cells. A further study into the effect of kahweol on HT-29 cells showed that treatment with 200 μM kahweol significantly reduced cell proliferation and viability (50% at 200 μM) (Choi et al., 2015). LDH release increased 5-fold at 200 μM, confirming this cytotoxic effect. Levels of the proapoptotic protein caspase-3 noticeably increased in a dose-dependent manner, and cleaved PARP appeared with as low a concentration of kahweol as 10 μM. On the other hand, levels of antiapoptotic proteins, Bcl-2, and p-Akt decreased, thus confirming the proapoptotic effect of kahweol on these cells. Hsp70 was also diminished by treatment with kahweol which is significant as Hsp70 is often overexpressed in cancer cells, participating in the promotion of oncogenesis and resistance to chemotherapy (Boudesco et al., 2018). Overexpression of Hsp70 reduced kahweol-induced cytotoxicity, as well as levels of caspase-3 and cleaved PARP, and increased Bcl-2 and p-AKT, while an HSP70 inhibitor increased kahweol-induced cytotoxicity, indicating that this protein has a central role in the kahweol-mediated effect.


CONCLUSION

The effects of caffeine on many aspects of human physiology are well described; however, evidence regarding the potential chemopreventive effect of this compound on the colon is conflicting. Some in vitro studies report that caffeine induces cell cycle arrest and increases apoptosis in colorectal carcinoma cell lines, while other studies report no effect on cell cycle, increased cell proliferation, and protection from chemotherapy-induced apoptosis. Evidence from in vivo studies is also not clear, as one study described that treatment of mice with caffeine reduced animal survival in a CRC model, while another indicated a greatly reduced number of tumors and inflammation due to caffeine. These conflicting results could be due to the fact that there are not many studies available that look into the effect of caffeine on the colon, at a cellular and molecular level; however, it seems that the chemopreventive effect of coffee is likely to be attributed in a larger degree to other compounds, rather than caffeine, although caffeine may have a small cumulative effect.

On the other hand, results from different in vitro and in vivo studies with CGA or its derivatives were consistent, reporting cell cycle arrest, cytotoxicity, and reduced cell viability, as well as increased apoptosis. Additionally, anti-inflammatory properties were observed for these compounds, and the results suggest that this protective effect could be related to the modulation of the MAPK/ERK/JNK and NFκβ pathways.

In vitro results of kahweol consistently report a chemopreventive effect on the colon. All studies available in colorectal adenocarcinoma cell lines agree that kahweol increases cytotoxicity, reduces cell proliferation, and increases apoptosis. It appears that, similar to CGA, the protective effect of kahweol is mediated by the MAPK/ERK/JNK pathway. There are no in vitro studies of cafestol in colon-derived cell lines, most likely due to the fact that cafestol and kahweol are very similar in structure and function. Studies of cafestol and kahweol in a CRC animal model show that these compounds increase the expression of antioxidant and detoxification enzymes, contributing to colon health.

It is seen that often results from in vitro studies are not well supported in animal models. This is most likely due to the fact that all in vitro studies reported in this review use the traditional monolayer approach to cell culture, which does not reflect the three-dimensional structure of the colon or of a tumor. Cell–cell and cell–matrix interactions that occur in vivo, as well as limited diffusion of the compound through the tumor mass, are not taken into account in most in vitro studies. Therefore, it is important to migrate to three-dimensional culture models that mimic the microenvironment and cell heterogeneity of colon tumors more closely.


ACKNOWLEDGMENTS

This work was funded by the Instituto Tecnologico Metropolitano ITM, grant number P21105. Y.Y. was recipient of the Jovenes Investigadores e Innovadores ITM 2020 program of the Instituto Tecnologico Metropolitano ITM of Medellin-Colombia. All authors participated in the elaboration of this article, including selection, reading, and critical analysis of all articles used as a reference, as well as in writing and proofreading.


CONFLICT OF INTEREST

The authors declare that they have no conflicts of interest.


AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.


ETHICAL APPROVALS

Not applicable.


PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.


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Lee KJ, Choi JH, Jeong HG. Hepatoprotective and antioxidant effects of the coffee diterpenes kahweol and cafestol on carbon tetrachloride-induced liver damage in mice. Food Chem Toxicol, 2007; 45(11):2118–25; doi:10.1016/j.fct.2007.05.010 CrossRef

Liang N, Kitts DD. Role of chlorogenic acids in controlling oxidative and inflammatory stress conditions. Nutrients 2015; 8(1):16; doi:10.3390/nu8010016 CrossRef

Libreros S, Garcia-Areas R, Iragavarapu-Charyulu V. CHI3L1 plays a role in cancer through enhanced production of pro-inflammatory/pro-tumorigenic and angiogenic factors. Immunol Res, 2013; 57(1–3):99–105; doi:10.1007/s12026-013-8459-y CrossRef

Ludwig IA, Mena P, Calani L, Cid C, Del Rio D, Lean MEJ, Crozier A. Variations in caffeine and chlorogenic acid contents of coffees: what are we drinking? Food Funct, 2014; 5(8):1718–26; doi:10.1039/c4fo00290c CrossRef

Ma JY, Li RH, Huang K, Tan G, Li C, Zhi FC. Increased expression and possible role of chitinase 3-like-1 in a colitis-associated carcinoma model. World J Gastroenterol, 2014; 20(42):15736–44; doi:10.3748/wjg.v20.i42.15736 CrossRef

Mhaidat NM, Alzoubi KH, Al-Azzam SI, Alsaad AA. Caffeine inhibits paclitaxel-induced apoptosis in colorectal cancer cells through the upregulation of Mcl-1 levels. Mol Med Rep, 2014; 9(1):243–48; doi:10.3892/mmr.2013.1763 CrossRef

Moeenfard M, Cortez A, Machado V, Costa R, Luís C, Coelho P, Soares R, Alves A, Borges N, Santos A. Anti-angiogenic properties of cafestol and kahweol palmitate diterpene esters. J Cell Biochem, 2016; 117(12):2748–56; doi:10.1002/jcb.25573 CrossRef

Moreno-Ceballos M, Arroyave JC, Cortes-Mancera FM, Röthlisberger S. Chemopreventive effect of coffee against colorectal cancer and hepatocellular carcinoma. Int J Food Properties, 2019; 22(1):536–55; doi:10.1080/10942912.2019.1593193 CrossRef

Nam SH, Ko JA, Jun W, Wee YJ, Walsh MK, Yang KY, Choi JH, Eun JB, Choi J, Kim YM, Han S, Nguyen TTH, Kim D. Enzymatic synthesis of chlorogenic acid glucoside using dextransucrase and its physical and functional properties. Enzyme Microb Technol, 2017; 107:15–21; https://doi.org/10.1016/j.enzmictec.2017.07.011 CrossRef

Naveed M, Hejazi V, Abbas M, Kamboh AA, Khan GJ, Shumzaid M, Ahmad F, Babazadeh D, FangFang X, Modarresi-Ghazani F, WenHua L, XiaoHui Z. (2018). Chlorogenic acid (CGA): a pharmacological review and call for further research. In: Townsend DM (ed.). Biomedicine and pharmacotherapy. Elsevier Masson SAS, Moulineaux, France, vol 97, pp 67–74; doi:10.1016/j.biopha.2017.10.064 CrossRef

Park GH, Song HM, Jeong JB. Kahweol from coffee induces apoptosis by upregulating activating transcription factor 3 in human colorectal cancer cells. Biomolecules Ther, 2017; 25(3):337–43; doi:10.4062/biomolther.2016.114 CrossRef

Park GH, Song HM, Jeong JB. The coffee diterpene kahweol suppresses the cell proliferation by inducing cyclin D1 proteasomal degradation via ERK1/2, JNK and GKS3??-dependent threonine-286 phosphorylation in human colorectal cancer cells. Food Chem Toxicol, 2016; 95:142–8; doi:10.1016/j.fct.2016.07.008 CrossRef

Perrone D, Donangelo R, Donangelo CM, Farah A. Modeling weight loss and chlorogenic acids content in coffee during roasting. J Agric Food Chem, 2010; 58(23):12238–43; doi:10.1021/jf102110u CrossRef

Poole R, Kennedy OJ, Roderick P, Fallowfield JA, Hayes PC, Parkes J. Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes. BMJ Clin Res, 2017; 359:j5024; doi:10.1136/bmj.j5024 CrossRef

Puangpraphant S, Berhow MA, Vermillion K, Potts G, Gonzalez de Mejia E. Dicaffeoylquinic acids in Yerba mate (Ilex paraguariensis St. Hilaire) inhibit NF-κB nucleus translocation in macrophages and induce apoptosis by activating caspases-8 and -3 in human colon cancer cells. Mol Nutr Food Res, 2011; 55(10):1509–22; doi:10.1002/mnfr.201100128 CrossRef

Sadeghi Ekbatan S, Li XQ, Ghorbani M, Azadi B, Kubow S. Chlorogenic Acid and Its Microbial Metabolites Exert Anti-Proliferative Effects, S-Phase Cell-Cycle Arrest and Apoptosis in Human Colon Cancer Caco-2 Cells. Int J Mol Sci, 2018; 19(3):723; doi:10.3390/ijms19030723 CrossRef

Saito Y, Gopalan B, Mhashilkar AM, Roth JA, Chada S, Zumstein L, Ramesh R. Adenovirus-mediated PTEN treatment combined with caffeine produces a synergistic therapeutic effect in colorectal cancer cells. Cancer Gene Ther, 2003; 10(11):803–13; doi:10.1038/sj.cgt.7700644 CrossRef

Sarraguça M, Lopo M, Páscoa R, Sarraguca J, Lopes J. Bioactive compounds in coffee as health promotors. In Da Silva LR, Silva BM (eds.). Natural bioactive compounds from fruits and vegetables as health promoters part II (pp 180–220). Bentham Science Publishers, Sharjah, United Arab Emirates, p 255, 2016; doi:10.2174/9781681082431116010011 CrossRef

Soares PV, Kannen V, Jordão Junior AA, Garcia SB. Coffee, but neither decaffeinated coffee nor caffeine, elicits chemoprotection against a direct carcinogen in the colon of wistar rats. Nutr Cancer, 2019; 71(4):615–23; doi:10.1080/01635581.2018.1506489 CrossRef

Strzeszewska A, Alster O, Mosieniak G, Ciolko A, Sikora E. Insight into the role of PIKK family members and NF-kB in DNAdamage-induced senescence and senescence-associated secretory phenotype of colon cancer cells article. Cell Death Dis, 2018; 9(2):1–13; doi:10.1038/s41419-017-0069-5 CrossRef

Vukelić I, Detel D, Pučar LB, Potočnjak I, Buljević S, Domitrović R. Chlorogenic acid ameliorates experimental colitis in mice by suppressing signaling pathways involved in inflammatory response and apoptosis. Food Chem Toxicol, 2018; 121:140–50; doi:10.1016/j.fct.2018.08.061 CrossRef

Wang R, Dashwood WM, Löhr CV, Fischer KA, Pereira CB, Louderback M, Nakagama H, Bailey GS, Williams DE, Dashwood RH. Protective versus promotional effects of white tea and caffeine on PhIP-induced tumorigenesis and β-catenin expression in the rat. Carcinogenesis, 2008; 29(4):834–9; doi:10.1093/carcin/bgn051 CrossRef

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Gaascht F, Dicato M, Diederich M. Coffee provides a natural multitarget pharmacopeia against the hallmarks of cancer. Genes Nutr 2015; 10(6):1-17. https://doi.org/10.1007/s12263-015-0501-3

Gao W, Wang C, Yu L, Sheng T, Wu Z, Wang X, Zhang D, Lin Y, Gong Y. Chlorogenic acid attenuates dextran sodium sulfate-induced ulcerative colitis in mice through MAPK/ERK/JNK pathway. Biomed Res Int, 2019; 2019:6769789. https://doi.org/10.1155/2019/6769789

Górecki M, Hallmann E. The antioxidant content of coffee and its in vitro activity as an effect of its production method and roasting and brewing time. Antioxidants, 2020; 9(4):308. https://doi.org/10.3390/antiox9040308

Haynes MK, Strouse JJ, Waller A, Leitao A, Curpan RF, Bologa C, Oprea TI, Prossnitz ER, Edwards BS, Sklar LA, Thompson TA. Detection of intracellular granularity induction in prostate cancer cell lines by small molecules using the HyperCyt® high-throughput flow cytometry system. J Biomol Screen, 2009; 14(6):596-609. https://doi.org/10.1177/1087057109335671

Hou N, Liu N, Han J, Yan Y, Li J. Chlorogenic acid induces reactive oxygen species generation and inhibits the viability of human colon cancer cells. Anticancer Drugs, 2017; 28(1):59-65. https://doi.org/10.1097/CAD.0000000000000430

Hu W, Shen T, Wang MH. Cell cycle arrest and apoptosis induced by methyl 3,5-dicaffeoyl quinate in human colon cancer cells: involvement of the PI3K/Akt and MAP kinase pathways. Chem Biol Interact, 2011; 194(1):48-57. https://doi.org/10.1016/j.cbi.2011.08.006

Huber WW, McDaniel LP, Kaderlik KR, Teitel CH, Lang NP, Kadlubar FF. Chemoprotection against the formation of colon DNA adducts from the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) in the rat. Mutat Res, 1997; 376(1-2):115-22. https://doi.org/10.1016/S0027-5107(97)00033-X

Huber WW, Prustomersky S, Delbanco E, Uhl M, Scharf G, Turesky RJ, Thier R, Schulte-Hermann R. Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol. Arch Toxicol, 2002a; 76(4):209-17.

Huber WW, Scharf G, Rossmanith W, Prustomersky S, GraslKraupp B, Peter B, Turesky RJ, Schulte-Hermann R. The coffee components kahweol and cafestol induce γ-glutamylcysteine synthetase, the rate limiting enzyme of chemoprotective glutathione synthesis, in several organs of the rat. Arch Toxicol, 2002b; 75(11):685-94. https://doi.org/10.1007/s00204-001-0295-5

Kaplánek R, Jakubek M, Rak J, Kejík Z, Havlík M, Dolenský B, Frydrych I, Hajdúch M, KoláÅ™ M, Bogdanová K, Králová J, Džubák P, Král V. Caffeine-hydrazones as anticancer agents with pronounced selectivity toward T-lymphoblastic leukaemia cells. Bioorg Chem, 2015; 60:19-29. https://doi.org/10.1016/j.bioorg.2015.03.003

Lee KA, Chae JI, Shim JH. Natural diterpenes from coffee, cafestol and kahweol induce apoptosis through regulation of specificity protein 1 expression in human malignant pleural mesothelioma. J Biomed Sci, 2012; 19(1):60. https://doi.org/10.1186/1423-0127-19-60

Lee KJ, Choi JH, Jeong HG. Hepatoprotective and antioxidant effects of the coffee diterpenes kahweol and cafestol on carbon tetrachlorideinduced liver damage in mice. Food Chem Toxicol, 2007; 45(11):2118-25. https://doi.org/10.1016/j.fct.2007.05.010

Liang N, Kitts DD. Role of chlorogenic acids in controlling oxidative and inflammatory stress conditions. Nutrients 2015; 8(1):16. https://doi.org/10.3390/nu8010016

Libreros S, Garcia-Areas R, Iragavarapu-Charyulu V. CHI3L1 plays a role in cancer through enhanced production of pro-inflammatory/ pro-tumorigenic and angiogenic factors. Immunol Res, 2013; 57(1-3):99- 105. https://doi.org/10.1007/s12026-013-8459-y

Ludwig IA, Mena P, Calani L, Cid C, Del Rio D, Lean MEJ, Crozier A. Variations in caffeine and chlorogenic acid contents of coffees: what are we drinking? Food Funct, 2014; 5(8):1718-26. https://doi.org/10.1039/C4FO00290C

Ma JY, Li RH, Huang K, Tan G, Li C, Zhi FC. Increased expression and possible role of chitinase 3-like-1 in a colitis-associated carcinoma model. World J Gastroenterol, 2014; 20(42):15736-44. https://doi.org/10.3748/wjg.v20.i42.15736

Mhaidat NM, Alzoubi KH, Al-Azzam SI, Alsaad AA. Caffeine inhibits paclitaxel-induced apoptosis in colorectal cancer cells through the upregulation of Mcl-1 levels. Mol Med Rep, 2014; 9(1):243-48. https://doi.org/10.3892/mmr.2013.1763

Moeenfard M, Cortez A, Machado V, Costa R, Luís C, Coelho P, Soares R, Alves A, Borges N, Santos A. Anti-angiogenic properties of cafestol and kahweol palmitate diterpene esters. J Cell Biochem, 2016; 117(12):2748-56. https://doi.org/10.1002/jcb.25573

Moreno-Ceballos M, Arroyave JC, Cortes-Mancera FM, Röthlisberger S. Chemopreventive effect of coffee against colorectal cancer and hepatocellular carcinoma. Int J Food Properties, 2019; 22(1):536-55. https://doi.org/10.1080/10942912.2019.1593193

Nam SH, Ko JA, Jun W, Wee YJ, Walsh MK, Yang KY, Choi JH, Eun JB, Choi J, Kim YM, Han S, Nguyen TTH, Kim D. Enzymatic synthesis of chlorogenic acid glucoside using dextransucrase and its physical and functional properties. Enzyme Microb Technol, 2017; 107:15-21. https://doi.org/10.1016/j.enzmictec.2017.07.011

Naveed M, Hejazi V, Abbas M, Kamboh AA, Khan GJ, Shumzaid M, Ahmad F, Babazadeh D, FangFang X, Modarresi-Ghazani F, WenHua L, XiaoHui Z. (2018). Chlorogenic acid (CGA): a pharmacological review and call for further research. In: Townsend DM (ed.). Biomedicine and pharmacotherapy. Elsevier Masson SAS, Moulineaux, France, vol 97, pp 67-74. https://doi.org/10.1016/j.biopha.2017.10.064

Park GH, Song HM, Jeong JB. Kahweol from coffee induces apoptosis by upregulating activating transcription factor 3 in human colorectal cancer cells. Biomolecules Ther, 2017; 25(3):337-43. https://doi.org/10.4062/biomolther.2016.114

Park GH, Song HM, Jeong JB. The coffee diterpene kahweol suppresses the cell proliferation by inducing cyclin D1 proteasomal degradation via ERK1/2, JNK and GKS3?-dependent threonine-286 phosphorylation in human colorectal cancer cells. Food Chem Toxicol, 2016; 95:142-8. https://doi.org/10.1016/j.fct.2016.07.008

Perrone D, Donangelo R, Donangelo CM, Farah A. Modeling weight loss and chlorogenic acids content in coffee during roasting. J Agric Food Chem, 2010; 58(23):12238-43. https://doi.org/10.1021/jf102110u

Poole R, Kennedy OJ, Roderick P, Fallowfield JA, Hayes PC, Parkes J. Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes. BMJ Clin Res, 2017; 359:j5024. https://doi.org/10.1136/bmj.j5024

Puangpraphant S, Berhow MA, Vermillion K, Potts G, Gonzalez de Mejia E. Dicaffeoylquinic acids in Yerba mate (Ilex paraguariensis St. Hilaire) inhibit NF-κB nucleus translocation in macrophages and induce apoptosis by activating caspases-8 and -3 in human colon cancer cells. Mol Nutr Food Res, 2011; 55(10):1509-22. https://doi.org/10.1002/mnfr.201100128

Sadeghi Ekbatan S, Li XQ, Ghorbani M, Azadi B, Kubow S. Chlorogenic Acid and Its Microbial Metabolites Exert Anti-Proliferative Effects, S-Phase Cell-Cycle Arrest and Apoptosis in Human Colon Cancer Caco-2 Cells. Int J Mol Sci, 2018; 19(3):723. https://doi.org/10.3390/ijms19030723

Saito Y, Gopalan B, Mhashilkar AM, Roth JA, Chada S, Zumstein L, Ramesh R. Adenovirus-mediated PTEN treatment combined with caffeine produces a synergistic therapeutic effect in colorectal cancer cells. Cancer Gene Ther, 2003; 10(11):803-13. https://doi.org/10.1038/sj.cgt.7700644

Sarraguça M, Lopo M, Páscoa R, Sarraguca J, Lopes J. Bioactive compounds in coffee as health promotors. In Da Silva LR, Silva BM (eds.). Natural bioactive compounds from fruits and vegetables as health promoters part II (pp 180-220). Bentham Science Publishers, Sharjah, United Arab Emirates, p 255, 2016. https://doi.org/10.2174/9781681082431116010011

Soares PV, Kannen V, Jordão Junior AA, Garcia SB. Coffee, but neither decaffeinated coffee nor caffeine, elicits chemoprotection against a direct carcinogen in the colon of wistar rats. Nutr Cancer, 2019; 71(4):615- 23. https://doi.org/10.1080/01635581.2018.1506489

Strzeszewska A, Alster O, Mosieniak G, Ciolko A, Sikora E. Insight into the role of PIKK family members and NF-kB in DNAdamageinduced senescence and senescence-associated secretory phenotype of colon cancer cells article. Cell Death Dis, 2018; 9(2):1-13. https://doi.org/10.1038/s41419-017-0069-5

Vukelić I, Detel D, Pučar LB, Potočnjak I, Buljević S, Domitrović R. Chlorogenic acid ameliorates experimental colitis in mice by suppressing signaling pathways involved in inflammatory response and apoptosis. Food Chem Toxicol, 2018; 121:140-50. https://doi.org/10.1016/j.fct.2018.08.061

Wang R, Dashwood WM, Löhr CV, Fischer KA, Pereira CB, Louderback M, Nakagama H, Bailey GS, Williams DE, Dashwood RH. Protective versus promotional effects of white tea and caffeine on PhIPinduced tumorigenesis and β-catenin expression in the rat. Carcinogenesis, 2008; 29(4):834-9. https://doi.org/10.1093/carcin/bgn051

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