Chemopreventive effect of coffee against colorectal cancer and hepatocellular carcinoma

Figures & data

Figure 1. Main components in coffee beans. Percentages correspond to the contribution of each component to the total dry weight. 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), 4,5-dicaffeoylquinic acid (4,5-diCQA)

Table 1. Epidemiological association between coffee and CRC

Type of study	Country/ Period	n	Coffee consumption	Relative risk	Main Results	Ref
Case control	Japan	816 cases of CRC and 815 controls	Total coffee polyphenol intake in quintiles: Q1 (low intake) Q2 Q3 Q4 Q5 (high intake)	1.00 0.81 0.65 0.65 0.82	Risk of CRC ↓35% in moderately high (Q3/4) intake groups, especially for distal colon cancer. Non-coffee derived polyphenols showed no association with CRC risk.	^[Citation26]
Case control	Japan 1988–2005	2696 cases of CRC and 13480 controls	< 1 cup/day 1–2 cups/day ≥ 3 cups/day	0.88 0.90 0.78	Risk of CRC ↓22% with ≥3 cups/day, especially for distal colon cancer.	^[Citation27]
Prospective cohort study	USA 1995–2006	489706 (9646 developed CRC)	4–5 cups/day	0.85 0.86 (Decaf)	Coffee intake had a strong inverse association for proximal colon cancer. Similar results for decaffeinated coffee.	^[Citation28]
Prospective cohort study	USA 1982–2012	922896	1 cup/day 2–3 cups/day 4–5 cups/day ≥ 6 cups/day	0.96 0.95 0.90 0.86	Coffee consumption inversely associated with CRC mortality (dose-dependent).	^[Citation29]
Meta-analysis (19 prospective cohort studies)	Europe, USA, Asia 1986–2014	204657 (22629 developed CRC)	Non drinkers 1 cup/day 2 cups/day 3 cups/day 4 cups/day 5 cups/day 6 cups/day 7 cups/day 8 cups/day	0.98 1.0 1.0 1.0 0.98 0.96 0.93 0.90 0.87	Risk of CRC ↓7% for every 4 cups per day.	^[Citation30]
Case control	Northern Israel 1998–2015	5145 cases and 4097 controls	1–2 cups/day 2–2.5 cups/day > 2.5 cups/day Decaffeinated coffee	0.78 0.78 0.46 0.82	Risk of CRC ↓54% with >2.5 cups/day.	^[Citation31]
Meta-analysis (14 cohort and 12 case-control)	Japan 1988–2009	7734 cases and 26782 non-cancer	1–3 cups/day ≥ 4 cups/day	< 1.0 >1.0	Coffee consumption may not be associated or only weakly associated with the CRC risk in Japanese population.	^[Citation32]
Meta-analysis (21 cohort studies)	Europe, Japan, USA	2141 (185 developed CRC)	Highest vs lowest intake	0.96	No significant association between coffee intake and CRC.	^[Citation33]
Prospective cohort	Japan	96162 (1163 developed CRC)	Almost never 1–2 days/week 3–4 days/week 1–2 cups/day 3–4 cups/day ≥ 5 cups/day	Reported by subsite and by sex.	Risk of colon cancer ↓ in women with ≥3 cups/day. No significant association for rectal cancer in women. No significant association for CRC in men.	^[Citation34]
Prospective cohort	USA 1993–2010	Postmenopausal women 83778 (1282 developed CRC)	None 1–4 cups/day ≥ 4 cups/day	1.20 1.43 (Compared to non-drinkers)	Risk of CRC ↑ with higher coffee consumption.	^[Citation35]
Prospective cohort	USA 6 months	953 stage III colon cancer patients after adjuvant chemotherapy	≥4 cups/d vs never drinkers	HR: 0.58	Coffee consumption is associated with significantly reduced cancer recurrence and death in patients.	^[Citation36]

CRC: Colorectal cancer

Table 2. Experimental evidence of the chemopreventive effect of coffee against CRC

Experimental model	Intervention/Dose	Duration	Evaluated parameters	Main results	Ref
In vitro: Caco-2 cells	Coffee extracts: 0, 0.31, 0.63, 1.25, 2.5, 3.75 and 5.0% (v/v) Caffeine, CA, CGA, and trigonelline at 100 µM	Treated for 3 days	KRAS expression measured by qPCR and western blot.	No effect on cell viability ↓ proliferation ↓ KRAS	^[Citation42]
In vivo: Male Wistar rats	p-CA: 100mg/kg/day	15 weeks	Gene expression in colon tissue measured by IHC, immunoblotting and qPCR.	↓ cyclin B1, cdc2, mdm2 (cell cycle regulation) ↓c-fos, c-jun, c-myc (proto-oncogenes) ↑ apoptotosis ↑ detoxification	^[Citation43]
In vitro: HCT-15 HT 29 cells	p-CA: 1400 and 1600 μmol/L	12, 24 and 48 h	Effects associated with apoptosis were measured by MTT assay, cell cycle analysis, ROS levels and mitochondrial membrane potential.	↑ sub G1 cell cycle arrest ↓ proliferation ↓ mitochondrial membrane potential ↑ intracellular ROS ↑ apoptosis	^[Citation44]
In vitro: HCT116, SW480, LoVo and HT-29 cells	Kahweol: 0, 12.5, 25 and 50 mM.	Treated for 24 h	Apoptosis and ATF3 expression (with/without siRNA) measured by RT-PCR, and western blot.	↑ ATF3 expression ↑ apoptosis	^[Citation45]
In vitro: HT-29 cells	Kahweol: 10, 50, 100 and 200 μM	Treated for 16–20 h	Apoptosis and HSP70 expression measured by MTT, LDH activity assay, and western blot.	↑ caspase-3 ↓ Bcl-2 and p-Akt ↓ HSP70 ↑ apoptosis	^[Citation46]
In vitro: HCT-116 and SW-480 cells In vivo: BALB/C AnN-Foxn1 nude mice	CA derivatives: 5, 10, 20, 50 and 100 µM	2–24 h Orally for 6 weeks	Colon cancer growth was measured by proliferation assays, cell cycle analysis, western blot, reporter gene assay, and in a mouse xenograft model.	In cell lines: ↑ G0/G1 cell cycle arrest ↓ proliferation ↓ phosphorylation of PDK1, Akt and mTOR ↑ phosphorylation of FOXO3 proteins ↑ 14–3-3 protein ↑ N-cadherin In animal model: ↓ tumor growth	^[Citation47]
In vitro: Caco-2 cells	3-CQA, 4-CQA, 5-CQA, 3,4-diCQA, 3,5-diCQA, 4,5-diCQA: 0.2, 1, and 2 mM	Pretreated for 24 h	Oxidative-stress response pathway and Nrf2 signaling pathway were evaluated.	↓ Oxidative stress ↓ intracellular ROS ↑ GSH ↓ IL-8 ↑ Nrf2 signaling	^[Citation48]
In vitro: Caco-2 cells	Colombian coffee (2 ground and 4 soluble): 1, 10, 100, 500 and 1000 µg/mL	Pretreated for 24 h	Antioxidant capacity was evaluated by MTT, cell cycle assay, and measurement of ROS levels.	↓ intracellular ROS ↑ cell viability	^[Citation49]
In vitro: Caco-2 cells	CGA and CA: 0.25–2 mM	Pretreated for 24 h	ROS scavenging and PKD-NFkappaB-IL-8 signaling pathway evaluated by western blot, ROS measurement, and qPCR.	↓ ROS ↓ IL-8 and NF-κB transcriptional activity ↓ nuclear translocation of the p65 subunit ↓ phosphorylation of IKK ↓ PKD	^[Citation50]
In vitro: Caco-2 cells In vivo: Female C57BL/6 mice	CGA and CA: 0.5, 1, 2 mmol/l CGA and CA: 1 mM	Pretreated for 24 h Orally for 15 days	Quantification of IL-8, TNFα and pro- inflammatory cytokines by ELISA, qPCR, and luciferase activity.	In Caco-2 cells: ↓ NFα ↓ IL-8 In animal model: ↓MIP-2 ↓IL-1βmRNA	^[Citation51]

3-CQA: 3-caffeoylquinic acid; 4-CQA: 4-caffeoylquinic acid; 5-CQA: 5-caffeoylquinic acid; 3,4-diCQA: 3,4-dicaffeoylquinic acid; 3,5-diCQA: 3,5-dicaffeoylquinic acid; 4,5-diCQA: 4,5-dicaffeoylquinic acid; ATF3 activating transcription factor 3; CA: Caffeic Acid; CGA: Chlorogenic Acid; CRC: Colorectal Cancer; ELISA: enzyme-linked immunosorbent assay; FOXO3: Forkhead box protein O3; IHC: Immunohistochemistry; Hsp 70: 70-kDa heat shock proteins; IL: interleukin; IKK: IkappaB kinase; LDH: Lactate Dehydrogenase; MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide; MIP-2: Macrophage Inflammatory Protein 2; NF-κB: Nuclear factor kappa B; Nrf2: nuclear factor-like 2; p-CA: p-Coumaric Acid; PDK-1: Phosphoinositide-dependent kinase-1; PKD: protein kinase D; qPCR: real-time polymerase chain reaction; ROS: Reactive Oxygen Species; TNFα: tumor necrosis factor α.

Table 3. Epidemiological evidence of the chemopreventive effect of coffee against HCC

Type of study	Country/period	n	Coffee consumption	Relative risk	Main Results	Ref
Meta-analysis: 2 cohorts and 3 case-control	Japan 2002–2010	500 studies included	1–2 cups/day	0.70)	Risk of HCC ↓ 50% Dose-dependent	^[Citation60]
			≥3 cups/day	0.45
Prospective study	Japan 1994–2005	334 cases and 90,452 cohort	Never drank	0.49	In the Japanese population, habitual coffee drinking may be associated with reduced risk of HCC.	^[Citation61]
			1–2 cups/day	0.52
			3–4 cups/day	0.48
			≥ 5 cups/day	0.24
Meta-analysis: 4 cohorts and 5 case-control	Japan, Italy and Grece 1996–2006	2,260 cases and 239,146 controls	2 cups/day	0.57	Risk of HCC ↓ 43%	^[Citation62]
Meta-analysis: 8 cohorts and 8 case-control	Italy, Greece, Serbia, Finland, Japan and China 1966–2012	3,153 cases of HCC	Low vs. high consumption (≥3 cups/day) Increment of 1 cup/day	0.72 0.44 0.80	The risk of HCC ↓ 40% for any coffee consumption vs. no consumption.	^[Citation63]
Meta-analysis: 9 cohort studies	Europe, Japan, USA	968,517 samples	Highest vs. lowest intake	0.46	Inverse associations observed between coffee consumption and risk of HCC.	^[Citation33]
Meta-analysis: 15 prospective studies (11 HCC and 69 CLD)	Europe, USA, Japan and China 1966–2017	3,414 cases of HCC and 1,463 cases of CLD	Regular consumption	0.66	There is a 34% ↓ in the risk of primary HCC among regular coffee drinkers compared with no/occasional drinkers.	^[Citation64]
			Low consumption	0.78
			High consumption	0.50
			1 cup/day	0.85
Meta-analysis: 18 cohorts and 8 case-control	Japan, Hong Kong, Singapore, Finland, USA, Greece, Italy and other regions of Europe. 1992–2016	Cohorts: 2,272,642 participants (2905 cases) Case-control: 1825 cases and 4,652 controls	Caffeinated	0.73	Two cups of caffeinated and decaffeinated coffee associated with reductions of 27% and 14% in the risk of HCC. Pre-existing liver disease did not affect the association.	^[Citation65]
			Decaffeinated	0.86
Nested case-control study	Europe 1992–2006	520,000 participants	1 cup/day	0.87	There is an inverse association between coffee intake and liver cancer.	^[Citation66]
			≥4 cups (600 mL) vs 2 cups (300 mL)/day	0.25

CLD: Chronic liver disease; HCC: Hepatocellular carcinoma.

Table 4. Experimental evidence of the chemopreventive effect of coffee against hepatocellular carcinoma

Experimental model	Intervention/Dose	Duration	Evaluated parameters	Main Effects	Ref
In vitro: LX-2 cells In vivo: Sprague-Dawley rats	Caffeine: 0, 1, 5, and 10 mmol 50 mg/kg	24, 48 h Intraperitoneal injection for 8 weeks	Effect of caffeine on liver fibrosis measured by cell migration and proliferation, and western blot of important markers.	In cells: ↑ apoptosis ↓ TGF- β ↑ F-actin ↑ cAMP ↓ procollagen type Ic and α-SMA In animal model: ↓ periportal inflammation ↓ inflammatory cells ↓ fibrosis	^[Citation68]
In vitro: HepG2 cells In vivo: Male Wistar rats treated with CCl4	Pickering emulsion with caffeine at 1.5% 37.5 mg/kg/day	14 days	Hepatoprotective effect of caffeine on liver damage measured by cell viability assays, measurement of AST, ALT, NO and catalase.	↓ cell viability ↓ AST, ALT ↓ NO ↑ catalase ↓ PKC	^[Citation69]
In vitro: HepG2 cells	Green coffee bean extract: 1, 10 and 50 μg/mL 5-CQA and 3,5-DCQA: 1, 10, 20 and 40 μM Caffeine: 1, 10, 20 and 40 μM	Pretreated for 20 h	Effect of coffee on oxidative stress measured by cell viability, LDH assay, ROS production, and enzyme activity assays.	↓ cellular and macromolecular damage ↓ cytotoxicity ↓ROS ↑ GSH ↓ GPx and GR No effect with caffeine.	^[Citation70]
In vitro: AML-12, LX2 cells and primary pepatocytes In vivo: C57BL/6 mice were	Kahweol 20 and 40 µM 75 mg/kg	Orally for 8 weeks	Histological and immunohistohistochemical analysis	↓ALT and AST ↓hepatic fibrosis ↓ type I collagen, α-SMA ↓TGF-β ↓CTGF ↓phospho-Smad3, STAT3, ERK and JNK	^[Citation71]
In vitro: Primary Kupffer Cells and primary hepatocytes	Kahweol 40 µM	Pretreated	Effect on LPS-induced inflammatory response by determination of inflammatory cytokine Levels.	↓ pro-inflammatory cytokines IL-1, IL-6 and TNF-α. ↓phosphorylation of NFκB. ↓phosphorylation of STAT3	^[Citation72]
In vitro: HepG2 cells In vivo: BALB/c, nu/nu mice with HepG2 xenograft	CGA: 0, 250, 500 or 1000 μM CGA: 30, 60 and 120 mg/kg/day	24 h Orally for 6 weeks	Effect of CGA on HCC progression by cell viability, cell cycle assays, western blot and IHC.	In cells: ↓ cell viability ↑ Arrest in S-phase In animal model: ↓ tumor size In both: ↓ pERK1/2 ↓ MMP-2 and MMP-9	^[Citation73]
In vitro: HepG2 and Hep3B cells	5-FU: 20 μmol/l CGA: 250 μmol/l	48 h	Effect of CGA on HCC measured by cell viability assay, ROS measurement and western blot	5-FU + CGA ↓ proliferation ↑ ROS ↓phosphorylation of ERK1/2	^[Citation74]
In vivo: Male Wistar rats treated with capecitabine	CA: 100 mg/kg	Orally for 14 days	Effect of CA on induced oxidative stress by measuring biomarkers of hepatic toxicity and antioxidant levels.	↓ TBILI, ALT, AST, and ALP (biomarkers of hepatotoxicity) ↑ SOD, CAT, GST and GPx (enzymatic antioxidants) ↑ ascorbic acid and GSH (non-enzymatic antioxidants) ↓ lipid peroxidation	^[Citation75]
In vitro: N1-S1 hepatoma cells In vivo: Sprague-Dawley rats	In cells: CA or FA: 1 mM In animal model: TAE + CA or FA 30 mg	14 days	Metabolism and tumor growth measured by lactate excretion and ultrasound of animal model.	↓ extracellular acidification rate ↓ lactate efflux ↓ tumor size	^[Citation76]
In vitro: WCH-17 cells	CA: 1 mM	12, 24, 36, and 48 h	Toxicity of CA in HCC model measured by cell proliferation, caspase assay, mitochondrial membrane potential and ROS measurement.	↓ proliferation ↑ Caspases 3/7. ↑ROS ↓ mitocondrial membrane potential	^[Citation77]
In vitro: Huh-7 and HepG2 cells In vivo: Male Wistar rats with DEN-induced HCC	In cells: ZnONPs, FA and ZnONPs-FAC: 0.05. 0.1, 0.5, 1, 5, 10, 15, 25 μg/ml In animal model: ZnONPs, FA and ZnONPs-FAC: 5mg/kg	24 h Orally for 4 weeks	Toxicity of FA in HCC model measured by cell viability, ROS generation, mitochondrial membrane permeability, comet assay, cell cycle analysis, IHC and western blot.	In cells: ↑ ROS ↓ mitocondrial membrane potential ↑ DNA damage ↑ Arrest in S-phase ↑ Bax, Bad, Cas-3, PARP (pro-apoptosis) ↓ Bcl-2, Bcl-xL (anti-apoptosis) ↑ apoptosis In animal model: ↓ liver nodules ↓ cirrhosis ↓ inflammatory markers	^[Citation78]

3,5-DCQA: 3,5-dicaffeoylquinic acid; 5-CQA: 5-caffeoylquinic acid; 5-FU: 5-fluorouracil; α-SMA: α-smooth muscle actin; ALT: alanine transaminase; AST: aspartate transaminase; CA: caffeic acid; cAMP: cyclic adenosine monophosphate; CAT: catalase; CTGF: connective tissue growth factor; ERK: extracellular signal-regulated kinases;FA: Ferulic Acid; GPx: Glutathione peroxidase; GR: glutathione reductase; GSH: Reduced glutathione; GST: Glutathione S-transferase; IHC: Immunohistochemistry; IL: interleukin; JNK: c-Jun N-terminal protein kinase; LDH: lactate dehydrogenase; MgO NPs: Synthesized magnesium oxide nanoparticles; MMPs: matrix metalloproteinases; NO: nitrous oxide; PKC: Protein kinase C; ROS: Reactive oxygen species; Smad 3: Mothers Against Decantaplegic homolog 3; SOD: superoxide dismutase; STAT 3: Signal transducer and activator of transcription 3; TAE: Transarterial embolization; TBili: total bilirubin; TGF- β: Transforming growth factor‐β; TNF-α: tumor necrosis factor-α; ZnONPs: ZnO nanoparticles.

Experimental evidence of the chemopreventive effect of coffee against hepatocellular carcinoma.

3,5-DCQA: 3,5-dicaffeoylquinic acid; 5-CQA: 5-caffeoylquinic acid; 5-FU: 5-fluorouracil; α-SMA: α-smooth muscle actin; ALT: alanine transaminase; AST: aspartate transaminase; CA: caffeic acid; cAMP: cyclic adenosine monophosphate; CAT: catalase; CTGF: connective tissue growth factor; ERK: extracellular signal-regulated kinases;FA: Ferulic Acid; GPx: Glutathione peroxidase; GR: glutathione reductase; GSH: Reduced glutathione; GST: Glutathione S-transferase; IHC: Immunohistochemistry; IL: interleukin; JNK: c-Jun N-terminal protein kinase; LDH: lactate dehydrogenase; MgO NPs: Synthesized magnesium oxide nanoparticles; MMPs: matrix metalloproteinases; NO: nitrous oxide; PKC: Protein kinase C; ROS: Reactive oxygen species; Smad 3: Mothers Against Decantaplegic homolog 3; SOD: superoxide dismutase; STAT 3: Signal transducer and activator of transcription 3; TAE: Transarterial embolization; TBili: total bilirubin; TGF- β: Transforming growth factor‐β; TNF-α: tumor necrosis factor-α; ZnONPs: ZnO nanoparticles.

Figure 2. Overview of the molecular mechanisms involved in the chemoprotective effect of coffee in CRC and HCC. The main experimental findings related to caffeine, chlorogenic acids and/or coffee diterpenes are summarized. Liver-specific effects are shown on the right and CRC specific effects are shown on the left. Oxidative stress mechanisms play a central role in the chemopreventive effect of coffee, in the negative regulation of cell proliferation and tumor growth, as well as increasing apoptosis and autophagy

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