The growing global incidence of malignant diseases underscores the importance of developing novel and effective cancer treatments. Cancer’s multifaceted nature is evident at both molecular and clinical levels, highlighting its diversity and resistance to treatment. Despite the challenges in developing cancer chemopreventive agents from natural sources, promising evidence supports evaluating potential active natural products to reduce or reverse premalignant tissues. The concept of cancer chemoprevention emerged from anecdotal experiences with nutritious meals and epidemiological studies, largely focused on cancer treatment. For example, individuals who consume plant-based foods are believed to have a lower risk of cancer, prompting increased interest in dietary phytochemical studies.
Coffee is one of the most widely consumed beverages globally and contains potent natural chemopreventive and antineoplastic agents. Derived from the berries of Coffea species, primarily Coffea arabica (Arabica) and Coffea canephora (Robusta), coffee is renowned for its stimulant effects due to high caffeine levels. However, the bioactive compounds in coffee have been increasingly explored for other biological activities, including antioxidant, anti-inflammatory, and anticancer properties. These discoveries have garnered the attention of health experts, especially as coffee consumption has rapidly expanded over the past few decades due to greater prosperity and economic interest.
The chemical constituents of coffee beverages are mostly determined by the processing procedures (pre-roasting and roasting) used to prepare green coffee beans. Additionally, harvesting methods and industrial processes for green coffee, as well as consumer ways of preparing coffee beverages, all contribute to variations in the concentration of particular substances in the final product. Various factors such as coffee species, growing circumstances, harvesting methods, and processing procedures (such as high-temperature roasting) affect the amount of bioactive chemicals in coffee, such as antioxidants and biogenic amines. Coffee beans comprise an abundance of xanthine-based caffeine, polyphenol chlorogenic acids, and tannins, followed by other polyphenols and flavonoids which possess antioxidant properties. Numerous epidemiological studies have demonstrated that coffee consumption has been associated with potential health advantages due to its anti-inflammatory and chemopreventive activities. The antioxidative properties of several coffee ingredients are proposed to reduce inflammation when coffee is consumed.
This article aims to review recent advances and knowledge in the association of major phytochemicals present in coffee, specifically caffeine and chlorogenic acid, with their preventive or therapeutic effects targeted at the cellular and molecular mechanisms that lead to cancer progression.
Dried green coffee contains approximately 1.67% caffeine (1,3,7-trimethylxanthine) regardless of geographical origins, which influence caffeine amounts. Upon oral consumption of caffeine in beverages, caffeine is primarily absorbed in the gastrointestinal tract and small intestine, with negligible first-pass effect. Following absorption, caffeine spreads swiftly throughout plasma-binding and has been found in bile, saliva, semen, breast milk, and umbilical cord blood. Caffeine-plasma concentration peaks between 15 and 120 minutes after oral consumption. Notably, caffeine rapidly passes through cell membranes, with detectable levels in the brain as early as five minutes post-ingestion.
A study by Lin et al. showed that daily caffeine intake affected higher concentrations of caffeine in gray matter and cerebral blood flow, indicating caffeine residual accumulation in the brain. The primary metabolism of caffeine occurs in the liver through phase-I oxidation by cytochrome P450 1A2, resulting in active paraxanthine as a major metabolite, followed by theobromine and theophylline. Previous reports have discovered the connection between daily coffee consumption and caffeine metabolism through the polymorphism of CYP1A2 and CYP2A6. The second phase conjugated-metabolism produces a mixture of di- and tri-methylated xanthine, uric acid, and acetylated uracil derivatives, all excreted through urine.
The biological effects of caffeine are closely associated with three primary modulatory points: an antagonistic action on adenosine receptors, calcium mobilization, and phosphodiesterase inhibition. Caffeine’s ability to inhibit adenosine receptors due to their similar purine structure significantly affects cellular energy and inflammatory response. Furthermore, caffeine induces intracellular activity on calcium and the cyclic adenosine monophosphate (cAMP) pathway by inhibiting phosphodiesterase in adipose tissue and skeletal muscle, resulting in cardiostimulatory and antiasthmatic actions. Adenosine receptor stimulation leads to an increase in cAMP production, potentially reducing the inflammatory response in various pathophysiological circumstances. Despite caffeine not being a selective adenosine receptor antagonist, its modulatory effects on adenosine receptors may exacerbate the acute inflammatory response, depending on its concentration.
Additionally, caffeine stimulates calcium release by activating ryanodine receptors in skeletal muscles, raising intracellular calcium and speeding up the excitation-contraction coupling process, playing a crucial role in neurotransmitter release by neurons. Recent studies of caffeine also documented several mechanisms involving systemic metabolism and oxidative-inflammatory signaling, indicating that caffeine affects peripheral signaling and may have beneficial effects on the human body regarding the aging process.
Green coffee beans contain more chlorogenic acid (CGA) than caffeine (5.43%), although much is lost during roasting. Most chlorogenic acid biotransformation in humans occurs in the colon, followed by the liver. Dietary chlorogenic acids are absorbed in the small intestine, hydrolyzed by esterases from the gut mucosa into quinic acid and caffeic acid, and then pass into the bloodstream. A substantial amount of unaltered chlorogenic acid enters the colon, where it is metabolized by esterases produced by colon microflora. The colon plays a crucial role in transforming both caffeic and ferulic acid into dihydroferulic acid and facilitating their absorption through the intestine. Caffeic acid is converted by the enzyme catechol-O-methyltransferase into another phenolic acid, ferulic acid. Both compounds can form an ester bond with quinic acid, resulting in various isomers within the chlorogenic acid family. Most metabolized products from chlorogenic acid result from reaction with transferase and are excreted as another form of benzoic acid called hippuric acid.
The targeted molecular pathways for developing and assessing future cancer-management techniques are carcinogenesis and chemoprevention. Chemoprevention refers to using pharmaceutical methods to stop or reverse cancer development before invasion and metastasis. Epidemiological research suggests that coffee consumption may be associated with a lower cancer risk. The potential role of coffee in cancer chemoprevention has been supported by several experimental models, including human studies. The scientific literature has hypothesized various coffee-dependent mechanisms, including the suppression of oxidative stress and damage, the activation of metabolizing liver enzymes involved in carcinogen detoxification processes, and modulation of the inflammatory response. Specific coffee ingredients have been shown to affect tumor cell apoptosis, proliferation, and metastasis and exhibit anti-angiogenic properties.
Table . The cytotoxic activities of chemical constituents of coffee bean against cancer cells.
| Compound | Concentration | In Vitro Model | Mechanism of Action |
|---|---|---|---|
| Chlorogenic acid | 10 µM | Human umbilical vein endothelial cells | Reduction in wound cell migration, cell invasion, hypoxia-induced tube formation |
| 25 and 50 µM | Glioma, lung cancer, colon cancer and solid tumor cell lines from hepatoma | Induction of cell differentiation, inhibition of cell proliferation, decreased expression of genes associated with poor differentiation, increased expression of key genes associated with differentiation | |
| 5 mM | Leukemia (K562 cells) | Induction of apoptotic topoisomerase−DNA complexes and generation of hydrogen peroxide | |
| 1–1000 µM | Liver cancer (HepG2 cells) | Inhibition of invasion and migration, inhibition of cell proliferation and colony formation, induction of cell death, decreased MMP2/TIMP-2, DNA methyltransferase1, ERK1/2 phosphorylation and MMP-9 expression, increased p53 and p21 | |
| 1–5000 µM | Lung cancer (A549 cells) | Inhibition of phorbol-12-myristate-13-acetate Stimulated invasion of A549 cells, induction of apoptosis, inhibition of cell proliferation, decreased stem cell marker related genes (CD44, NANOG, POU5F1, and SOX2), MAPK and PI3K/Akt signaling, inactivation of NF-κB, activator protein 1 and STAT3, hypoxia-induced HIF-1α protein level, transcriptional activity of HIF-1α, vascular endothelial growth factor and Bcl-2, increased Bax, Bax/Bcl-2, p38, JUN, and caspase 3 | |
| 20–200 µM | Irradiated plasmids | Decreased DNA single-strand breaks | |
| Caffeine | 0.5, 1, 2 mM | Prostate cancer (PC-3 and DU145 cells) | Inhibition of cell adhesion and motility and decreased cell proliferation |
| 0.1–5 mM | Breast cancer (MDA-MB-231, Tam-R, MCF-7 cells) | MDA-MB-231 cells: inhibition of cell proliferation by 40% MCF-7 cells: inhibition of cell proliferation by 80%, induction of cell death, decreased estrogen receptor, poly (ADP-ribose) polymerase cleavage, decreased cyclin D1, Akt and Bcl-xL, increased caspase 7, Tam-R cells: inhibition of cell proliferation | |
| 50–400 µM | Irradiated plasmids | Decreased DNA single-strand breaks | |
| 10–1000 mM | Liver inflammation (human hepatic stellate cells) | Decreased procollagen type Ic, alpha-smooth muscle actin expression and progression of intrahepatic induction of apoptosis, increased F-actin and cyclic adenosine monophosphate, fibrosis | |
| 0.1–4 mM | Leukemia (NB4 cells) | Bax, increase p21 and caspase 3, induction of apoptosis, inhibition of cell proliferation | |
| 2 mM | Lung cancer (HTB182 and CRL5985 cells) | Increase PUMA (CRL5985), inhibition of cell proliferation | |
| Cafestol | 1–40 µM | Renal cancer (Caki cells) | Induction of apoptosis, inhibition of proliferation, increased Bim, Bax and FADD-like IL-1β-converting enzyme)-inhibitory protein, increased caspases 2 and 3, cleavage of poly (ADP-ribose) polymerase, decreased Akt phosphorylation, Mcl-1, Bcl-xL, release of Cytochrome c and Bcl-2 |
| 40, 80, 150 µM | Leukemia (HL-60 and KG1 cells) | Decreased ROS generation and clonogenic potential, increased caspase 3, CD11b and CD15 differentiation markers, induction of apoptosis | |
| Kahweol | 1–25 µM | Human umbilical vein endothelial cells | Decreased MMP-2 expression, urokinase, cyclooxygenase-2 and monocyte chemoattractant protein-1, inhibition of tubule formation, inhibition of cell proliferation, inhibition of migration, inhibition of invasion |
| 40 µM | Liver inflammation (primary Kupffer cells and primary hepatocytes) | Decreased lipopolysaccharide-stimulated phospho-nuclear factor kappa B and signal transducer and activator of transcription 3 expression and lipopolysaccharide-induced production of interleukin 1 alpha, interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha | |
| 0.1–10 µM | Leukemia (U937 cells) | Decreased Bcl-2, Bcl-XL, Mcl-1, XIAP and Akt phosphorylation, increased JNK pathway, JNK, ROS generation and caspases 2, 3, 8, and 9, cytochrome c release, inhibition of cell proliferation, induction of apoptosis | |
| 1–200 µM | Colorectal cancer (HCT116, SW480, LoVo, HT-29 cells) | Decreased heat shock protein 70, Bcl2 and phosphorylated Akt, increased ATF3 transcription and caspase 3, poly (ADP-ribose) polymerase cleavage, induction of apoptosis | |
| 10–90 µM | Lung cancer (NCI-H358, NCI-H1299 cells) | Inhibition of cell proliferation, induction of apoptosis, increased p21 and Bax, decreased cyclin D1, basic transcription factor 3, ERK signaling pathway and Bcl-2, Bcl-xL |
Interestingly, higher intake of decaffeinated coffee significantly reduced the risk of colorectal cancer, but this effect was not observed with caffeinated coffee. However, caffeinated coffee is known to lower the risk of rectal tumors. Another cohort study found that both caffeinated and decaffeinated coffee consumption improved overall survival (OS) and progression-free survival (PFS) in patients with metastatic colorectal cancer. Furthermore, frequent consumption of all coffee types lowered the risk of liver disease and carcinoma, while daily coffee intake reduced tumor size in invasive breast tumors with positive estrogen receptors (ER) more effectively than in triple-negative tumors. These findings suggest that drinking coffee with or without caffeine provides equivalent health benefits, although caffeine may still play a role in some coffee-induced effects, likely depending on the tumor subsite.
In addition to the chemopreventive activities demonstrated by caffeine and chlorogenic acid, studies have indicated that coffee extracts and kahweol also possess anti-carcinogenesis properties in several cancer cell lines. Kahweol inhibits cancer growth in macrophage cells of mice by activating the NF-κB pathway. Moreover, co-treatment with kahweol and cafestol has demonstrated anti-carcinogenic effects in male F344 rats. Kahweol and cafestol together have been observed to provide chemoprevention against malignancies caused by heterocyclic amines. Given that coffee constituents have the potential to exhibit antioxidant, cytotoxic, anti-mutagenic, and carcinogenic properties, they are therefore being studied for the treatment of different types of cancer, with particular attention to cafestol and kahweol, as these compounds may serve as valuable supplements to cancer prevention or therapy.
Substantial research related to coffee extract and its metabolite constituents in cancer cells is summarized. Caffeine directly inhibits the cyclin D/CDK 4/6 complex, causing G1 arrest independently of p53. Several reports have also revealed that caffeine overrides the G2 phase arrest caused by DNA-damaging chemicals, propelling the cells into deadly mitosis. Caffeine’s capacity to restart Cdc25C and Cdc2 activity contributes to averting G2 arrest. Due to its planar xanthine structure, caffeine is hypothesized to form π-π complexes with nucleobases in DNA, similar to conventional anticancer drugs. Besides triggering DNA intercalation, a report found that caffeine had two possible roles: to protect DNA against DNA-damaging agents and to modulate intercalating drugs used in chemotherapy treatments.
Previous studies have documented that caffeine has a modulatory effect on the signaling cascades of AMP-activated protein kinase (AMPK), PI3K/Akt, and the mammalian target of rapamycin (mTOR) in melanoma cells. Moreover, caffeine downregulates the expression of several proteins, including retinoblastoma protein (Rb), extracellular signal-regulated kinases (ERK) 1/2, GSK3β, pyruvate dehydrogenase kinase 1 (PDK1), cyclin D1, cyclin E, c-Myc, Akt, and mTOR in various cancer cell lines. In another study, caffeine upregulates p300 expression in glioma cells. Caffeine has been observed to reduce the phosphorylation of ERK induced by NF-κB in osteoclasts. A similar phenomenon also occurred in macrophage RAW 264.7 to suppress pro-inflammatory genes following lipopolysaccharide (LPS)-induced inflammation. Additionally, coffee demonstrated antitumor activity in vivo, and several studies have been conducted in humans to assess the correlation of coffee consumption and cancer risk.
Chlorogenic acid in coffee has demonstrated antitumor action against cancer cell lines by reducing cell survival and suppressing reactive oxygen species (ROS). Additionally, it has been observed to suppress the production of cell adhesion molecules in human endothelial cells triggered by TNF-α16. Cafestol possesses anti-angiogenesis action in human umbilical vein endothelial cells, inhibiting the proliferation, migration, and tube-formation ability of the cells. Ferulic acid also inhibits angiogenesis via targeting FGFR1 and activating the PI3K/Akt signaling pathways, limiting cell proliferation via cell cycle arrest and death, in addition to reducing invasion, migration, and colony formation. Kahweol in green coffee beans has been shown to have an anti-angiogenic impact in zebrafish and chicken chorioallantoic membranes, in addition to exhibiting other significant activities, including cell cycle arrest, anti-angiogenesis/proliferative, and associated phenomena.
Currently, numerous cytotoxic medicines are utilized clinically for the treatment of various cancer types, despite their substantial side effects, low cure rate, and development of resistance. Coffee, owing to its widespread availability, low cost, and racial compatibility, may hold promise as a significant anti-cancer treatment option. Combining coffee constituents (caffeine or chlorogenic acid) with existing chemotherapeutic drugs in cancer therapy has been evaluated. The combination of caffeine with doxorubicin prevented the efflux effect of doxorubicin from cancer cells and enhanced cytotoxic activity. A similar result was demonstrated in the synergistic effect of caffeine in cisplatin-treated sarcoma tumors. Other antitumor drugs have also been summarized in a review by Ialongo et al. Clinical trials for caffeine have been reported in several publications, mainly combined with DNA-intercalating agents, including cisplatin, doxorubicin, and the tyrosine kinase inhibitor dovitinib.
Coffee induces apoptosis by altering various components of the apoptotic response. Different coffee compounds may target different apoptotic signaling mechanisms, such as increased cleavage of poly ADP ribose polymerase, downregulation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway, and upregulation of the cyclic AMP-dependent transcription factor ATF3. Caffeic acid has been shown to produce apoptotic cell death and dramatically decrease Akt signaling in PC-3 human prostate cancer cells, TW2.6, and HCT 15 colon cancer cell lines. Additionally, it has been proposed to decrease congenic survival and apoptotic cell death in SCC25, CAL27, and FaDu cell lines. Numerous studies suggest that chemical constituents in coffee may possess apoptotic potential. The antioxidant function of these substances is also influenced by their environment. Mechanisms of action include the inhibition of ROS generation and pro-survival gene expression, conformational changes in pro-apoptotic proteins, loss of the mitochondrial membrane that activates caspases, and transcription factor Sp1.
Despite its activity in triggering apoptosis, it was later found that caffeine intake should be avoided in colorectal tumors treated with cell cycle-modifying agents such as paclitaxel. This was confirmed by Xu et al., who described that caffeine interferes with the anticancer effect of the antimitotic drug paclitaxel by preventing α-tubulin acetylation, which could enhance the progression of lung and cervical tumors. It is important to note that caffeine’s effect in preventing the cytotoxicity of chemotherapy can be associated with cancer type, as caffeine enhanced apoptosis in paclitaxel-induced breast cancer cells. Nevertheless, these reports suggest that patients receiving antimitotic drugs as part of their cancer therapy regimen should avoid consuming foods or beverages containing caffeine.
Autophagy is an intracellular breakdown process involving the formation of a double-membrane autophagosome. This mechanism facilitates the removal of inclusion bodies and misfolded cytotoxic proteins more effectively than apoptosis. Apart from programmed cell death, autophagy-induced cancer may also involve phosphatidylinositol 3-kinase (PI3K) pathways and the endoplasmic reticulum (ER) stress response. Dysregulation in this pathway has been linked to cancer development and resistance to cancer treatment, potentially impacting the level of autophagy in tumor cells. Similarly, mTOR has also been identified as an autophagy mediator that contributes to cell growth, survival, and proliferation. The abnormal relationship between autophagy, inflammation, and oxidative stress may aid in developing innovative pharmacotherapeutic approaches for managing and treating cancer. Recent developments have proposed that induced autophagy is a novel target for cancer treatment.
Caffeine can suppress mTORC1 in both mice and in vitro models, promote autophagosome generation in HepG2 cells, reduce intracellular fats, enhance β-oxidation, and control hepatosteatosis. Caffeine in coffee has also exhibited cytoprotective effects in transformed skin cells, preventing cellular senescence and suppressing ROS generation by inducing SIRT3/AMPK-mediated autophagy. Despite its initial approach in normal tissues, many studies have proven that inducing autophagy in cancer cells can be beneficial for chemotherapy agents in eliminating cancer cells. A study by Erzurumlu et al. showed that adding caffeine in docetaxel-treated breast cancer cells activated the unfolded protein response (UPR)-associated pathway and accelerated autophagy signaling due to increased Beclin-1 protein; this led to apoptosis in cancer cells as detected by the cleaved effector caspase-3. Methylxanthines derivatives (theophylline and caffeine) activated autophagy signaling through PTEN activation, followed by mTOR suppression in gastric tumor cells. These findings open up new challenges in caffeine development of inducing autophagy to initiate apoptosis in tumor cells, necessitating further experimental and clinical studies.
This extensive review of coffee’s potential in cancer chemoprevention and treatment underscores its significant role due to its bioactive compounds like caffeine and chlorogenic acid. The detailed biochemistry and metabolism of these compounds reveal their complex interactions within the human body, contributing to their antitumor activities. With ongoing research and clinical trials, coffee and its constituents could become pivotal in developing new cancer therapies, offering a cost-effective and accessible option for many patients worldwide.
| Aspect | Details | Significance |
|---|---|---|
| Caffeine content in dried green coffee | 1.67% regardless of geographical origins | Essential for its stimulant effects |
| Caffeine absorption | Mostly in the gastrointestinal tract and small intestine | Rapid systemic distribution |
| Caffeine peak plasma concentration | Peaks between 15 and 120 minutes after oral consumption | Indicates rapid absorption and distribution in the body |
| Caffeine metabolism primary phase | Occurs in the liver through phase-I oxidation by cytochrome P450 1A2 resulting in active paraxanthine, theobromine, and theophylline | Highlights the liver’s role in caffeine metabolism |
| Caffeine metabolism secondary phase | Produces a mixture of di- and tri-methylated xanthine, uric acid, and acetylated uracil derivatives, excreted through urine | Illustrates caffeine’s extensive metabolic processing |
| Chlorogenic acid content in green coffee | 5.43%, most is lost during roasting | Chlorogenic acid’s presence and loss during coffee preparation |
| Chlorogenic acid absorption | Absorbed in the small intestine, hydrolyzed by esterases from gut mucosa into quinic acid and caffeic acid, then pass into the bloodstream | Details the initial metabolic steps of chlorogenic acid |
| Chlorogenic acid metabolism | Metabolized in the colon by esterases produced by colon microflora, converted into dihydroferulic acid | Describes the further metabolic steps in the colon |
| Chemopreventive properties of coffee | Suppression of oxidative stress and damage, activation of liver enzymes, modulation of inflammatory response, affect tumor cell apoptosis, proliferation, and metastasis | Emphasizes coffee’s role in cancer prevention |
| Antitumor activities of caffeine | Inhibits cyclin D/CDK 4/6 complex, overrides G2 phase arrest, forms π-π complexes with DNA nucleobases, modulates intercalating drugs in chemotherapy | Details caffeine’s mechanisms in cancer prevention and treatment |
| Antitumor activities of chlorogenic acid | Reduces cell survival, suppresses ROS, inhibits cell adhesion molecules production | Shows chlorogenic acid’s role in reducing cancer cell viability |
| Antitumor activities of cafestol | Inhibits cancer growth in macrophage cells via NF-κB pathway, provides chemoprevention against heterocyclic amines malignancies | Highlights cafestol’s contribution to cancer prevention |
| Autophagy induced by caffeine | Suppresses mTORC1, promotes autophagosome generation, prevents cellular senescence, induces SIRT3/AMPK-mediated autophagy | Shows caffeine’s role in autophagy and potential cancer treatment |
The in-depth study….
This article reviews the recent advances and knowledge in the association of major phytochemicals present in coffee, specifically caffeine and chlorogenic acid, with their preventive or therapeutic effects targeted at the cellular and molecular mechanisms that lead to cancer progression.
Biochemistry and Metabolism of Caffeine from Coffee Beans
Dried green coffee contains approximately 1.67% caffeine (1,3,7-trimethylxanthine) regardless of geographical origins, which influence caffeine amounts. Upon oral consumption of caffeine in beverages, caffeine is primarily absorbed in the gastrointestinal tract and small intestine, with negligible first-pass effect. Following absorption, caffeine spreads swiftly throughout plasma-binding and has been found in bile, saliva, semen, breast milk, and umbilical cord blood. Caffeine-plasma concentration peaks between 15 and 120 minutes after oral consumption. Notably, caffeine rapidly passes through cell membranes, with detectable levels in the brain as early as five minutes post-ingestion.
A study by Lin et al. showed that daily caffeine intake affected higher concentrations of caffeine in gray matter and cerebral blood flow, indicating caffeine residual accumulation in the brain. The primary metabolism of caffeine occurs in the liver through phase-I oxidation by cytochrome P450 1A2, resulting in active paraxanthine as a major metabolite, followed by theobromine and theophylline. Previous reports have discovered the connection between daily coffee consumption and caffeine metabolism through the polymorphism of CYP1A2 and CYP2A6. The second phase conjugated-metabolism produces a mixture of di- and tri-methylated xanthine, uric acid, and acetylated uracil derivatives, all excreted through urine.
The biological effects of caffeine are closely associated with three primary modulatory points: an antagonistic action on adenosine receptors, calcium mobilization, and phosphodiesterase inhibition. Caffeine’s ability to inhibit adenosine receptors due to their similar purine structure significantly affects cellular energy and inflammatory response. Furthermore, caffeine induces intracellular activity on calcium and the cyclic adenosine monophosphate (cAMP) pathway by inhibiting phosphodiesterase in adipose tissue and skeletal muscle, resulting in cardiostimulatory and antiasthmatic actions. Adenosine receptor stimulation leads to an increase in cAMP production, potentially reducing the inflammatory response in various pathophysiological circumstances. Despite caffeine not being a selective adenosine receptor antagonist, its modulatory effects on adenosine receptors may exacerbate the acute inflammatory response, depending on its concentration.
Additionally, caffeine stimulates calcium release by activating ryanodine receptors in skeletal muscles, raising intracellular calcium and speeding up the excitation-contraction coupling process, playing a crucial role in neurotransmitter release by neurons. Recent studies of caffeine also documented several mechanisms involving systemic metabolism and oxidative-inflammatory signaling, indicating that caffeine affects peripheral signaling and may have beneficial effects on the human body regarding the aging process.
Biochemistry and Metabolism of Chlorogenic Acid from Coffee Beans
Green coffee beans contain more chlorogenic acid (CGA) than caffeine (5.43%), although much is lost during roasting. Most chlorogenic acid biotransformation in humans occurs in the colon, followed by the liver. Dietary chlorogenic acids are absorbed in the small intestine, hydrolyzed by esterases from the gut mucosa into quinic acid and caffeic acid, and then pass into the bloodstream. A substantial amount of unaltered chlorogenic acid enters the colon, where it is metabolized by esterases produced by colon microflora. The colon plays a crucial role in transforming both caffeic and ferulic acid into dihydroferulic acid and facilitating their absorption through the intestine. Caffeic acid is converted by the enzyme catechol-O-methyltransferase into another phenolic acid, ferulic acid. Both compounds can form an ester bond with quinic acid, resulting in various isomers within the chlorogenic acid family. Most metabolized products from chlorogenic acid result from reaction with transferase and are excreted as another form of benzoic acid called hippuric acid.
The Role of Coffee in Chemoprevention Activities on Carcinogenesis
The targeted molecular pathways for developing and assessing future cancer-management techniques are carcinogenesis and chemoprevention. Chemoprevention refers to using pharmaceutical methods to stop or reverse cancer development before invasion and metastasis. Epidemiological research suggests that coffee consumption may be associated with a lower cancer risk. The potential role of coffee in cancer chemoprevention has been supported by several experimental models, including human studies. The scientific literature has hypothesized various coffee-dependent mechanisms, including the suppression of oxidative stress and damage, the activation of metabolizing liver enzymes involved in carcinogen detoxification processes, and modulation of the inflammatory response. Specific coffee ingredients have been shown to affect tumor cell apoptosis, proliferation, and metastasis and exhibit anti-angiogenic properties.
Interestingly, higher intake of decaffeinated coffee significantly reduced the risk of colorectal cancer, but this effect was not observed with caffeinated coffee. However, caffeinated coffee is known to lower the risk of rectal tumors. Another cohort study found that both caffeinated and decaffeinated coffee consumption improved overall survival (OS) and progression-free survival (PFS) in patients with metastatic colorectal cancer. Furthermore, frequent consumption of all coffee types lowered the risk of liver disease and carcinoma, while daily coffee intake reduced tumor size in invasive breast tumors with positive estrogen receptors (ER) more effectively than in triple-negative tumors. These findings suggest that drinking coffee with or without caffeine provides equivalent health benefits, although caffeine may still play a role in some coffee-induced effects, likely depending on the tumor subsite.
In addition to the chemopreventive activities demonstrated by caffeine and chlorogenic acid, studies have indicated that coffee extracts and kahweol also possess anti-carcinogenesis properties in several cancer cell lines. Kahweol inhibits cancer growth in macrophage cells of mice by activating the NF-κB pathway. Moreover, co-treatment with kahweol and cafestol has demonstrated anti-carcinogenic effects in male F344 rats. Kahweol and cafestol together have been observed to provide chemoprevention against malignancies caused by heterocyclic amines. Given that coffee constituents have the potential to exhibit antioxidant, cytotoxic, anti-mutagenic, and carcinogenic properties, they are therefore being studied for the treatment of different types of cancer, with particular attention to cafestol and kahweol, as these compounds may serve as valuable supplements to cancer prevention or therapy.
The Antitumor Activities of Coffee and Its Chemical Constituents
Substantial research related to coffee extract and its metabolite constituents in cancer cells is summarized. Caffeine directly inhibits the cyclin D/CDK 4/6 complex, causing G1 arrest independently of p53. Several reports have also revealed that caffeine overrides the G2 phase arrest caused by DNA-damaging chemicals, propelling the cells into deadly mitosis. Caffeine’s capacity to restart Cdc25C and Cdc2 activity contributes to averting G2 arrest. Due to its planar xanthine structure, caffeine is hypothesized to form π-π complexes with nucleobases in DNA, similar to conventional anticancer drugs. Besides triggering DNA intercalation, a report found that caffeine had two possible roles: to protect DNA against DNA-damaging agents and to modulate intercalating drugs used in chemotherapy treatments.
Previous studies have documented that caffeine has a modulatory effect on the signaling cascades of AMP-activated protein kinase (AMPK), PI3K/Akt, and the mammalian target of rapamycin (mTOR) in melanoma cells. Moreover, caffeine downregulates the expression of several proteins, including retinoblastoma protein (Rb), extracellular signal-regulated kin
ases (ERK) 1/2, GSK3β, pyruvate dehydrogenase kinase 1 (PDK1), cyclin D1, cyclin E, c-Myc, Akt, and mTOR in various cancer cell lines. In another study, caffeine upregulates p300 expression in glioma cells. Caffeine has been observed to reduce the phosphorylation of ERK induced by NF-κB in osteoclasts. A similar phenomenon also occurred in macrophage RAW 264.7 to suppress pro-inflammatory genes following lipopolysaccharide (LPS)-induced inflammation. Additionally, coffee demonstrated antitumor activity in vivo, and several studies have been conducted in humans to assess the correlation of coffee consumption and cancer risk.
Chlorogenic acid in coffee has demonstrated antitumor action against cancer cell lines by reducing cell survival and suppressing reactive oxygen species (ROS). Additionally, it has been observed to suppress the production of cell adhesion molecules in human endothelial cells triggered by TNF-α16. Cafestol possesses anti-angiogenesis action in human umbilical vein endothelial cells, inhibiting the proliferation, migration, and tube-formation ability of the cells. Ferulic acid also inhibits angiogenesis via targeting FGFR1 and activating the PI3K/Akt signaling pathways, limiting cell proliferation via cell cycle arrest and death, in addition to reducing invasion, migration, and colony formation. Kahweol in green coffee beans has been shown to have an anti-angiogenic impact in zebrafish and chicken chorioallantoic membranes, in addition to exhibiting other significant activities, including cell cycle arrest, anti-angiogenesis/proliferative, and associated phenomena.
Currently, numerous cytotoxic medicines are utilized clinically for the treatment of various cancer types, despite their substantial side effects, low cure rate, and development of resistance. Coffee, owing to its widespread availability, low cost, and racial compatibility, may hold promise as a significant anti-cancer treatment option. Combining coffee constituents (caffeine or chlorogenic acid) with existing chemotherapeutic drugs in cancer therapy has been evaluated. The combination of caffeine with doxorubicin prevented the efflux effect of doxorubicin from cancer cells and enhanced cytotoxic activity. A similar result was demonstrated in the synergistic effect of caffeine in cisplatin-treated sarcoma tumors. Other antitumor drugs have also been summarized in a review by Ialongo et al. Clinical trials for caffeine have been reported in several publications, mainly combined with DNA-intercalating agents, including cisplatin, doxorubicin, and the tyrosine kinase inhibitor dovitinib.
The Role of Coffee in Inducing Apoptosis Toward Cancer Cells
Coffee induces apoptosis by altering various components of the apoptotic response. Different coffee compounds may target different apoptotic signaling mechanisms, such as increased cleavage of poly ADP ribose polymerase, downregulation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway, and upregulation of the cyclic AMP-dependent transcription factor ATF3. Caffeic acid has been shown to produce apoptotic cell death and dramatically decrease Akt signaling in PC-3 human prostate cancer cells, TW2.6, and HCT 15 colon cancer cell lines. Additionally, it has been proposed to decrease congenic survival and apoptotic cell death in SCC25, CAL27, and FaDu cell lines. Numerous studies suggest that chemical constituents in coffee may possess apoptotic potential. The antioxidant function of these substances is also influenced by their environment. Mechanisms of action include the inhibition of ROS generation and pro-survival gene expression, conformational changes in pro-apoptotic proteins, loss of the mitochondrial membrane that activates caspases, and transcription factor Sp1.
Despite its activity in triggering apoptosis, it was later found that caffeine intake should be avoided in colorectal tumors treated with cell cycle-modifying agents such as paclitaxel. This was confirmed by Xu et al., who described that caffeine interferes with the anticancer effect of the antimitotic drug paclitaxel by preventing α-tubulin acetylation, which could enhance the progression of lung and cervical tumors. It is important to note that caffeine’s effect in preventing the cytotoxicity of chemotherapy can be associated with cancer type, as caffeine enhanced apoptosis in paclitaxel-induced breast cancer cells. Nevertheless, these reports suggest that patients receiving antimitotic drugs as part of their cancer therapy regimen should avoid consuming foods or beverages containing caffeine.
The Role of Coffee in Autophagy Process in Cancer Cells
Autophagy is an intracellular breakdown process involving the formation of a double-membrane autophagosome. This mechanism facilitates the removal of inclusion bodies and misfolded cytotoxic proteins more effectively than apoptosis. Apart from programmed cell death, autophagy-induced cancer may also involve phosphatidylinositol 3-kinase (PI3K) pathways and the endoplasmic reticulum (ER) stress response. Dysregulation in this pathway has been linked to cancer development and resistance to cancer treatment, potentially impacting the level of autophagy in tumor cells. Similarly, mTOR has also been identified as an autophagy mediator that contributes to cell growth, survival, and proliferation. The abnormal relationship between autophagy, inflammation, and oxidative stress may aid in developing innovative pharmacotherapeutic approaches for managing and treating cancer. Recent developments have proposed that induced autophagy is a novel target for cancer treatment.
Caffeine can suppress mTORC1 in both mice and in vitro models, promote autophagosome generation in HepG2 cells, reduce intracellular fats, enhance β-oxidation, and control hepatosteatosis. Caffeine in coffee has also exhibited cytoprotective effects in transformed skin cells, preventing cellular senescence and suppressing ROS generation by inducing SIRT3/AMPK-mediated autophagy. Despite its initial approach in normal tissues, many studies have proven that inducing autophagy in cancer cells can be beneficial for chemotherapy agents in eliminating cancer cells. A study by Erzurumlu et al. showed that adding caffeine in docetaxel-treated breast cancer cells activated the unfolded protein response (UPR)-associated pathway and accelerated autophagy signaling due to increased Beclin-1 protein; this led to apoptosis in cancer cells as detected by the cleaved effector caspase-3. Methylxanthines derivatives (theophylline and caffeine) activated autophagy signaling through PTEN activation, followed by mTOR suppression in gastric tumor cells. These findings open up new challenges in caffeine development of inducing autophagy to initiate apoptosis in tumor cells, necessitating further experimental and clinical studies.
REFERENCE : https://www.mdpi.com/1420-3049/29/14/3302
