Caffeine and Apoptosis - Caffeine: Chemistry, Analysis, Function and Effects - page 385

Studies on the mechanism(s) of the inhibitory effect of caffeine on UVB-
induced carcinogenesis indicated a stimulatory effect on UVB-induced
apoptosis in the epidermis (Lu et al 2000; Lu et al 2002a) and apoptosis in
tumors (Lu et al 2002b) as well as a sunscreen effect (Lu et al 2007).
Mechanistic studies indicate that administration of caffeine enhances UVB-
induced apoptosis in mouse epidermis by increasing wild-type p53 (Lu et al
2000) as well as by a p53- and Bax-independent mechanism (Lu et al 2004).
Oral administration of caffeine to mice during chronic UVB irradiation
inhibited the formation of patches with p53 mutation (Lu et al 2005). In
addition, topical application of caffeine after stopping UVB in UVB-
pretreated high risk mice decreased the number of patches when compared
with control mice treated with acetone. It was of interest that patches from
caffeine-treated mice had fewer types of mutations than patches from mice
treated with water or tea (Kramata et al 2005). Whether there is a difference
among cells harboring various homozygous p53 mutations in their sensitivity
to caffeine remains to be investigated.

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21.3 Caffeine and ATR-Chk1
Caffeine exposure sensitizes tumor cells to ionizing radiation and other
genotoxic agents by inhibiting both ATR and ATR (Sarkaria et al 1999;
Cortez 2003; Alao and Sunnerhagen 2009). Caffeine (in amounts in the
millimolar range) can inhibit both ATR and the related ataxia-telangiectasia-
mutated (ATM) kinase, both of which are central components of the DNA
damage response. ATM is activated by DNA double-strand breaks, whereas
ATR is preferentially activated by single-stranded regions of DNA, which can
occur at stalled DNA replication forks or as intermediates during nucleotide
excision repair of UV photoproducts (O'Driscoll et al 2003).
Caffeine is reported to inhibit the catalytic activity of both ATM and ATR
at drug concentrations similar to those that induce radiosensitization (Hall-
Jackson et al 1999). The kinase activity of ATR in the presence and absence of
DNA is suppressed by caffeine. Cortez suggests that although caffeine is an
inhibitor of ATM-ATR kinase activity in vitro, it can block checkpoints
without inhibiting ATM-ATR activation in vivo (Cortez 2003).
The combined impact of caffeine and UVB radiation on keratinocytes has
attracted great attention. Administration of caffeine enhances the removal of
DNA-damaged cells by inhibiting the ATR-mediated phosphorylation of
Chk1 and prematurely increasing the number of cyclin B1-containing cells that
undergo lethal mitosis (Lu et al 2008b). UVB irradiation of mouse skin
activated the ataxia-telangiectasia mutated- and Rad3-related (ATR) pathway,
causing a several-fold increase in keratinocytes with phospho-Chk1 (Ser345)
and a marked decrease in mitotic keratinocytes with cyclin B1. Caffeine
administration reduced this mitotic delay to only 4 h and caused a marked
increase in apoptosis by 6 to 10 h after UVB (Lu et al 2008b). Chk1-345
phosphorylation activated by UVB was attenuated by caffeine (Figure 21.2).