Mini-reviewThe enigmatic effects of caffeine in cell cycle and cancer
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
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