Cancer Letters

Cancer Letters

Volume 247, Issue 1, 8 March 2007, Pages 26-39
Cancer Letters

Mini-review
The enigmatic effects of caffeine in cell cycle and cancer

https://doi.org/10.1016/j.canlet.2006.03.032Get rights and content

Abstract

Caffeine may very well be the most frequently ingested neuroactive drug in the world. Mechanistically, caffeine has been reported to affect cell cycle function, induce programmed cell death or apoptosis and perturb key cell cycle regulatory proteins. Although the effects of caffeine have been heavily investigated, much of the research data regarding caffeine's effects on cell cycle and proliferation seem ambiguous. One important factor may be that caffeine has been used experimentally in numerous cell types under a variety of conditions at concentrations ranging from micromolar to high millimolar. Physiologically, achieving experimental blood levels of caffeine would be extremely difficult without adverse side effects. Therefore, the relevance of experimental data obtained by using high concentrations of caffeine is not clear and may account for some of the discrepancies in the literature. This review attempts to reconcile data regarding the cellular effects of caffeine by examining reported effects on cell cycle, proliferation and apoptosis with careful attention to differences in experimental conditions and caffeine concentration utilized.

Introduction

Caffeine (1,3,7-trimethylxanthine; Fig. 1) is a natural stimulatory compound that is ubiquitously present in many plants including cocoa beans, coffee beans, cola nuts, and tea leaves. Caffeine is also commonly used as a stimulant to prevent sleepiness and is found in several over-the-counter medications including some pain remedies. Because of its frequent and common consumption in tea, coffee and soft drinks, caffeine may very likely be the most frequently ingested neuroactive drug in the world [1]. For many years, caffeine has been generally believed to suppress cell proliferation [2], abolish chemical- or radiation-induced delays in cell cycle progression [3], [4] and enhance the toxicity of radiation and anti-cancer agents [3], [5], [6]. Caffeine has also been shown to inhibit ultraviolet B (UVB)-induced skin cancer in mice [7] and recent work by Nomura et al. [8] showed that caffeine (0.5 mM) suppressed epidermal growth factor (EGF)-induced malignant cell transformation.

Mechanistically, caffeine has been reported to affect cell cycle function, induce programmed cell death or apoptosis and perturb key regulatory proteins, including the tumor suppressor protein, p53 [9], [10]. Following DNA damage, p53 has a major influence on whether a cell will live or die. Cells exposed to DNA damaging agents such as γ-radiation or many chemotherapeutic agents pause in their cell cycle progression to allow time for DNA repair. If the damage is too extensive, the affected cells will undergo apoptosis. Both cell cycle arrest and apoptosis are normally mediated by p53 activities. In general, cells expressing wildtype p53 arrest in G1, whereas cells that do not express p53 or express a mutant p53 arrest mainly in G2.

Although the effects of caffeine have been heavily investigated, much of the research data regarding caffeine's effects on cell cycle and proliferation seem ambiguous. One important factor may be that caffeine has been used experimentally in numerous cell types under a variety of conditions at concentrations ranging from micromolar to high mM. Physiologically, achieving a 2 mM blood level of caffeine would require the simultaneous consumption of over 100 cups of coffee [11]. Therefore, the relevance of experimental data obtained by using greater than 1 mM caffeine is not clear and may account for some of the discrepancies in the literature. This review will attempt to reconcile data regarding the cellular effects of caffeine by examining reported effects on cell cycle, proliferation and apoptosis with careful attention to differences in experimental conditions and caffeine concentration utilized.

Section snippets

Regulation of cell cycle: brief overview

A review of the cell cycle and its various components will facilitate an understanding of the reported effects of caffeine on cell cycle function, proliferation and apoptosis. The cell cycle consists of four distinct phases that include the S phase where DNA duplication occurs, the M phase or mitosis during which the DNA is separated and the cell divides, and two gap phases. Gap1 or G1 is the phase before DNA synthesis and G2 is the period before mitosis begins. Progression through the cell

G1/S

When DNA damage occurs, p53 is phosphorylated (Ser15) by the ataxia telangiectasia mutated (ATM) protein and the AT-related homolog, ATR (Fig. 2A) [21], which results in p53 stabilization and accumulation [22]. ATM and ATR also prevent p53 degradation through their phosphorylation of mouse double minute 2 (MDM2) [23], which disrupts MDM2's association with p53 thereby preventing p53 ubiquitination and degradation. In addition, ATM phosphorylates Chk2, which in turn phosphorylates p53 (Ser20),

ATM and ATR

Initiating the appropriate checkpoint responses to double-strand DNA breaks requires the function of ATM and ATR [68]. This is supported by studies in ataxia telangiectasia (AT) patients and cells in which DNA damage cannot induce cell cycle arrest [69]. The cellular effects of caffeine resemble some defects observed in AT cells [70]. Although somewhat controversial, ATM (IC50 0.2 mM) and ATR (IC50 1.1 mM) have been identified as the primary molecular targets of caffeine in vitro [70]. ATM and

Some controversies on the effects of caffeine on cell cycle

Earlier studies suggested that caffeine was a teratogen in rabbits, mice and rats, and placental blood flow and embryonic growth were also severely reduced by caffeine [114], [119]. Others have also observed that in contrast to enhancing the killing of cells by IR and other DNA damaging agents, caffeine may have the opposite effect on the cytotoxic effect of certain chemotherapeutic agents such as paclitaxel [120]. Paclitaxel (Taxol) induces G2/M arrest and has been used in several clinical

Concluding remarks

Caffeine may very well be the most frequently ingested neuroactive drug in the world. Mechanistically, caffeine has been reported to affect cell cycle function, induce programmed cell death or apoptosis and perturb key cell cycle regulatory proteins. Although the effects of caffeine have been heavily investigated, much of the research data regarding caffeine's effects on cell cycle and proliferation seem ambiguous. One important factor may be that caffeine has been used experimentally in

References (128)

  • D.P. Brazil et al.

    Advances in protein kinase b signalling: aktion on multiple fronts

    Trends Biochem. Sci.

    (2004)
  • J. Li et al.

    Regulation of chk2 by DNA-dependent protein kinase

    J. Biol. Chem.

    (2005)
  • A. Blasina et al.

    Caffeine inhibits the checkpoint kinase atm

    Curr. Biol.

    (1999)
  • B.B. Zhou et al.

    Caffeine abolishes the mammalian g(2)/m DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity

    J. Biol. Chem.

    (2000)
  • D. Cortez

    Caffeine inhibits checkpoint responses without inhibiting the ataxia-telangiectasia-mutated (atm) and atm- and rad3-related (atr) protein kinases

    J. Biol. Chem.

    (2003)
  • R.U. Janicke et al.

    Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis

    J. Biol. Chem.

    (1998)
  • Y. Minemoto et al.

    Characterization of adriamycin-induced g2 arrest and its abrogation by caffeine in fl-amnion cells with or without p53

    Exp. Cell Res.

    (2001)
  • T. Ando et al.

    Involvement of the interaction between p21 and proliferating cell nuclear antigen for the maintenance of g2/m arrest after DNA damage

    J. Biol. Chem.

    (2001)
  • Coffee, tea, mate, methylxanthines and methylglyoxal, IARC working group on the evaluation of carcinogenic risks to...
  • F. Levi-Schaffer et al.

    Xanthines inhibit 3T3 fibroblast proliferation

    Skin Pharmacol.

    (1991)
  • L.J. Tolmach et al.

    The action of caffeine on x-irradiated Hela cells. I. Delayed inhibition of DNA synthesis

    Radiat. Res.

    (1977)
  • C.C. Lau et al.

    Mechanism by which caffeine potentiates lethality of nitrogen mustard

    Proc. Natl Acad. Sci. USA

    (1982)
  • P.M. Busse et al.

    The action of caffeine on x-irradiated hela cells. Ii. Synergistic lethality

    Radiat. Res.

    (1977)
  • P.M. Busse et al.

    The action of caffeine on x-irradiated hela cells. Iii. Enhancement of x-ray-induced killing during g2 arrest

    Radiat. Res.

    (1978)
  • Y.R. Lou et al.

    Effects of oral administration of tea, decaffeinated tea, and caffeine on the formation and growth of tumors in high-risk skh-1 mice previously treated with ultraviolet b light

    Nutr. Cancer

    (1999)
  • M. Nomura et al.

    Inhibition of epidermal growth factor-induced cell transformation and akt activation by caffeine

    Mol. Carcinog.

    (2005)
  • Z. He et al.

    Induction of apoptosis by caffeine is mediated by the p53, bax, and caspase 3 pathways

    Cancer Res.

    (2003)
  • K. Ito et al.

    Caffeine induces g2/m arrest and apoptosis via a novel p53-dependent pathway in nb4 promyelocytic leukemia cells

    J. Cell Physiol.

    (2003)
  • A. Lelo et al.

    Assessment of caffeine exposure: caffeine content of beverages, caffeine intake, and plasma concentrations of methylxanthines

    Clin. Pharmacol. Ther.

    (1986)
  • A.B. Pardee

    A restriction point for control of normal animal cell proliferation

    Proc. Natl Acad. Sci. USA

    (1974)
  • M. Ohtsubo et al.

    Human cyclin e, a nuclear protein essential for the g1-to-s phase transition

    Mol. Cell Biol.

    (1995)
  • N. Mailand et al.

    Rapid destruction of human cdc25a in response to DNA damage

    Science

    (2000)
  • C.Y. Peng et al.

    Mitotic and g2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of cdc25c on serine-216

    Science

    (1997)
  • K.J. Russell et al.

    Abrogation of the g2 checkpoint results in differential radiosensitization of g1 checkpoint-deficient and g1 checkpoint-competent cells

    Cancer Res.

    (1995)
  • S.N. Powell et al.

    Differential sensitivity of p53(−) and p53(+) cells to caffeine-induced radiosensitization and override of g2 delay

    Cancer Res.

    (1995)
  • H.J. Fingert et al.

    Cytotoxic, cell cycle, and chromosomal effects of methylxanthines in human tumor cells treated with alkylating agents

    Cancer Res.

    (1986)
  • J.P. Murnane

    Cell cycle regulation in response to DNA damage in mammalian cells: a historical perspective

    Cancer Metastasis Rev.

    (1995)
  • S. Banin et al.

    Enhanced phosphorylation of p53 by atm in response to DNA damage

    Science

    (1998)
  • M.B. Kastan et al.

    Participation of p53 protein in the cellular response to DNA damage

    Cancer Res.

    (1991)
  • R. Maya et al.

    Atm-dependent phosphorylation of mdm2 on serine 395: role in p53 activation by DNA damage

    Genes Dev.

    (2001)
  • A. Hirao et al.

    DNA damage-induced activation of p53 by the checkpoint kinase chk2

    Science

    (2000)
  • Y. Xiong et al.

    P21 is a universal inhibitor of cyclin kinases

    Nature

    (1993)
  • J.W. Harper et al.

    The p21 cdk-interacting protein cip1 is a potent inhibitor of g1 cyclin-dependent kinases

    Cell

    (1993)
  • A.B. Pardee et al.

    Selective killing of transformed baby hamster kidney (bhk) cells

    Proc. Natl Acad. Sci. USA

    (1975)
  • W. Qi et al.

    Caffeine induces tp53-independent g(1)-phase arrest and apoptosis in human lung tumor cells in a dose-dependent manner

    Radiat. Res.

    (2002)
  • J. Gong et al.

    Threshold expression of cyclin e but not d type cyclins characterizes normal and tumour cells entering s phase

    Cell Prolif.

    (1995)
  • T. Hashimoto et al.

    Caffeine inhibits cell proliferation by g0/g1 phase arrest in jb6 cells

    Cancer Res.

    (2004)
  • J. Qin et al.

    Down-regulation of cyclin e expression by caffeine promotes cancer cell entry into the s-phase of the cell cycle

    Anticancer Res.

    (2004)
  • M. Kitagawa et al.

    The consensus motif for phosphorylation by cyclin d1-cdk4 is different from that for phosphorylation by cyclin a/e-cdk2

    Eur Mol. Biol. Org. J.

    (1996)
  • J.A. Diehl et al.

    Glycogen synthase kinase-3beta regulates cyclin d1 proteolysis and subcellular localization

    Genes Dev.

    (1998)
  • Cited by (155)

    • Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells

      2022, Toxicology and Applied Pharmacology
      Citation Excerpt :

      Caffeine has generally been reported to induce G1/S arrest and to reverse the G1/S as well as G2/M checkpoint delay periods. It was proved that caffeine was able to arrest G2 in p53-deficient cells and had variable effects on G1 through both p53-dependent and p53-independent mechanisms (Powell et al., 1995; Russell et al., 1995; Bode and Dong, 2007). When caffeine was combined with DNA-damage agents, the potency of DNA-damage agent was increased significantly (Bode and Dong, 2007).

    View all citing articles on Scopus
    View full text