3.1. Human Studies on Anti-Cancer Effects of Coffee
Coffee is the second most consumed beverage worldwide after tea. Some early epidemiological studies suggested that coffee consumption was associated with an increased cancer risk [87
]. For example, Yu et al. [88
] described that daily coffee consumption is a risk factor in females for renal cell carcinoma. Based on the results of 32 epidemiological studies, Wierzejska found that several studies showed that coffee consumption had no or even unfavorable association with colorectal, breast, bladder, prostate, lung and pancreatic cancers, but emphasized that other studies showed promising results for these cancers and liver cancer [87
Several early RCT suggested the coffee’s favorable effects on cancers as exemplified by following findings: When 64 participants were randomly assigned into two groups and consumed 1000 mL of cafetière coffee daily or no coffee for intervention and washout periods, the result indicated that unfiltered coffee significantly increased the glutathione content by 8% in the colorectal mucosa and by 15% in plasma [89
]. The increase in the detoxification capacity and anti-mutagenic properties in the colorectal mucosa through an increase in glutathione concentration suggests the possible lowering effect on the colon cancer risk [89
A clinical trial with 10 participants found that consumption of 1L unfiltered coffee/day over 5 days resulted in a weak induction of glutathione-S
-transferases (GSTs) and 3-fold increase in induction of placental type GST in blood, although other clinical markers for organ damage such as creatinine, aminotransferases, and alkaline phosphatase were not altered [90
]. The finding suggests that coffee’s induction of placental type GST may lead to protection from chemical carcinogenesis.
In a controlled intervention trial with a cross-over design with 38 participants, consumption of 800 mL coffee daily over 5 days demonstrated the decrease by 12.3% in the extent of DNA-migration attributable to formation of oxidized purines, although other biochemical parameters such as the total anti-oxidant levels in plasma, glutathione concentrations in blood, and the activities of superoxide dismutase and glutathione peroxidase in lymphocytes were not markedly altered. The result indicates that coffee consumption prevents endogenous formation of oxidative DNA-damage in human [91
Recent evidence has also suggested that coffee drinking may have health benefits on some types of cancer. A review by an International Agency for Research on Cancer working group conducted in 2016 on a large number of epidemiological and experimental studies on anti-cancer effects of coffee found an inverse association for liver and endometrial cancers [92
Similarly, a comprehensive review of the beneficial effects of coffee and its components on gastrointestinal and liver carcinogenesis summarized observational epidemiological studies: four studies on oropharyngeal cancer, four on esophagus cancer, four on stomach cancer, four on CRC, and seven HCC [11
]. Comparing the highest and lowest consumptions, all study results showed 31–37% risk reduction in oropharyngeal cancer, no risk reduction in esophagus cancer, no risk reduction in CRC and 34–43% risk reduction in HCC, although some subgroup analyses gave different results. In the case of stomach cancer, one study found reduced risk, two no effect and one increased risk. These results indicate that the coffee’s benefit might be limited to liver cancer.
In addition, a recent meta-analysis of observational studies on associations between coffee intake and 26 different cancers including 364,749 cancer cases provided evidence to show that coffee intake is inversely associated with endometrial cancer, liver cancer, melanoma, oral cancer, and oral/pharyngeal cancer [93
]. Additional evidence was also obtained to suggest the reduced risk of cancers of the mouth, pharynx and larynx, and skin cancer. Coffee consumption may also be inversely associated with breast, colon, colorectal, esophageal and nonmelanoma skin cancers.
Conversely, the same analysis showed the conflicting result whereby a higher coffee intake was associated with an increased risk of childhood acute lymphocytic leukemia, bladder cancer, and possibly lung cancer [93
]. Similarly, a more recent pooled analysis of 12 cohort studies, comprising of 2601 cases out of 501,604 participants found a significantly increased risk for bladder cancer in male smokers: when compared the consumers of >4 cups/day with the non-consumers, hazard ratios were 1.75 (CI = 1.27–2.42) for current smokers and 1.44 (CI = 1.12–1.85) for former smokers [94
In a review on the association of CRC risk with coffee, caffeinated coffee and decaffeinated consumptions, Buldak et al. [10
] discussed eight, seven and three observational epidemiological studies showing no association, inverse association, and association with increased risk, respectively. These authors pointed out that caffeine is not an important component for coffee to exhibit the anti-cancer activity, since several studies found significant inverse correlation for both caffeinated and decaffeinated coffee consumptions.
A recent RCT on 160 healthy human subjects who consumed 3 or 5 cups of coffee per day for 8 weeks found that blood pressure, oxidation of DNA and lipids, blood levels of glucose, insulin, cholesterol, triglycerides, and inflammatory markers were unchanged, although a slight elevation of serum creatinine level and a significant elevation of serum γ-glutamyltransaminase levels in the 5 cups/day group [95
]. The results indicated no detectable effects, either beneficial or harmful, on human health.
Thus, these findings from clinical studies are conflicting. The recall bias and confounding effects including tobacco smoking, a method for brewing coffee, differences in ingredients, and genetic background may contribute to these differences.
3.2. Comparison of Anti-Cancer Effects of Tea and Coffee in Simultaneous Human Studies
Several epidemiological studies have examined the anti-cancer effects of tea and coffee at the same time. For example, the European Prospective Investigation into Cancer and Nutrition on 486,799 subjects with a median follow-up of 11 years found that both coffee and tea intakes were inversely associated with HCC risk. Coffee and tea consumers in the highest compared to the lowest quintile had lower HCC risk by 72% and 59%, respectively [96
]. In a study in which 10,399 of total 97,334 subjects developed cancers of 145 head and neck, 99 oesophageal, 136 stomach, 1137 lung, 1703 breast, 257 endometrial, 162 ovarian, 3037 prostate, 318 kidney, 398 bladder, 103 gliomas, and 106 thyroid, tea consumption of ≥1 cups/day was inversely associated with cancer overall combined (RR = 0.95, CI = 0.94–0.96) as compared to <1 cup consumption, but no association of coffee consumption with the risk of all cancers combined was found. However, coffee intake decreased a risk for endometrial cancer (RR = 0.69, 95% CI = 0.52–0.91 for ≥2 cups per day), while tea did not [97
A meta-analysis of 12 case-control studies, comprising a total of 3649 cases and 5705 controls found that a high maternal coffee consumption increased a risk of acute lymphoblastic leukemia in childhood (OR = 1.43), whereas low to moderate tea consumption was inversely associated (odds ratio (OR) = 0.85, CI = 0.75–0.97), although the trend was not significant [98
shows a brief comparison of anti-cancer effects of tea and coffee in simultaneous studies reported since 2018 based on the Medline data base. Several investigations revealed that tea and coffee may have different effects in some cancer types. It is noticeable that coffee may increase a risk in certain types of cancer (bladder cancer, lung cancer, and childhood leukemia) in line with the finding from aforementioned studies which examined effects of either tea or coffee, individually [93
The reason for the difference is not known at present. As pointed out by Milne et al. [99
], the fact that both tea and coffee contain numerous different compounds, are prepared by various methods, and have differences in bioavailability makes it difficult to determine the factor(s) involved in the difference.
3.3. Basic Research on Anti-Cancer Action of Coffee and CGA
A number of cell-based and animal studies have provided evidence to support anti-cancer effects of coffee and CGA [117
]. Salomone et al. [118
] have elegantly discussed molecular basis of anti-cancer effects of coffee and some of its components including CGA. They summarized the results of 10 animal studies showing anti-cancer effects of coffee and CGA as examined in experimental models of liver cancer. For example, in an experiment of Miura et al. [119
] coffee inhibited the proliferation and invasion of rat ascites hepatoma AH109A cells and the serum from rats given coffee orally also exhibited anti-proliferative and anti-invasive activities against these cells.
Similarly, Buldak et al. [10
] reviewed the human and basic studies on anti-cancer effects of coffee and its components on CRC. These authors discussed the results of three cell-based studies on CGA. In an experiment by Hou et al. [120
], CGA was shown to inhibit the proliferation of human colon cancer HCT116 and HT29 cells. CGA induced ROS generation and cell cycle arrest at the S phase, and suppressed the activation of ERK in both cell types, leading to the anti-cancer effect against CRC.
More recently, Romualdo et al. [11
] discussed these issues on the basis of animal studies of the effects of coffee and CGA on oral and esophagus cancers (four studies), colon cancer (nine studies) and HCC (four studies). For example, the included data showed that two of four studies of coffee and four of five studies of CGA demonstrated beneficial effects on colon cancer. These authors summarized the mechanistic aspects of CGA’s action which are associated with molecular pathways involving ROS and others such as Bax, interleukin (IL)-8, caspase-3, MMPs and miR-21. Although these articles also reviewed comprehensively other coffee components such as caffeine, caffeic acid, and kahweol, this review focuses CGA which is considered to be the major player in the coffee’s anti-cancer mechanism as discuss below.