The scientific blog world is in Riot : 'Although there's no evidence at all of a link between caffeine and cancer, we're putting two and two together and saying: caffeine can induce these changes and it has been shown that these changes are elevated in leukemia patients, "added Dr Cooke.It is derived from the words absence of evidence the basis of his research and also equal to the matching result from? I cry because time equal to the Nobel Prize committee ...
What the blogging colleagues (with the exception of Neuroskeptic ), in their excitement, but not received, and "overlooked" Mr Cooke was well: the caffeine content, and genome stability is already understood quite well! Sorry, but not the way it is presented in the article. But first things first.
signaling of DNA damage
I have mentioned a few posts already on the repair of DNA damage, but an important part of it I have been embezzled. For before the cell actually repairs the damage, it must still decide whether the repair worthwhile. For with numerous damages there's always the risk that creep mutations. And then before cancer develops, the organism sacrifices rather have a cell. This programmed cell death follows a strict genetic program and is known as apoptosis. the cell has decided to repair the damage they do, first of all the numerous repair proteins be activated. Moreover, during the repair of the cell cycle should be stopped. It would be very bad if the cell is located in the repair process begins to replicate their DNA, or to divide.
ATM and ATR
play a central role in all these signals, two related proteins, called the human ATM and ATR. Both are kinases, ie enzymes that regulate the activity of other proteins by transferring phosphate groups to certain amino acids. In the case of ATM and ATR kinase activity that is now dependent on damage to DNA: Because they are activated, and transfer phosphates to proteins, the above-mentioned processes such as apoptosis, cell cycle, regulate or repair. Fallen ATM and ATR, this results in humans with inherited diseases such as Ataxia-telangiectasia (ATM, trying times to say it several times) or Seckel syndrome (ATR). Actually it should not surprise that people who suffer from Ataxia-telangiectasia, are very sensitive to radiation. Ionizing radiation produces DNA damage, finally, and by the loss of ATM function then the regulation of repair is not everything, etc.. This point is important for another reason, as we shall see.
image of ATM signaling pathway in the cell from the gene assist TM Pathway Atlas of Ambion / Applied Biosystems. Shown are the most important processes that are regulated by ATM. Target protein can be activated by ATM by attaching phosphate groups represented by the circles with "P" on the proteins.
caffeine inhibits ATM and ATR
A few years ago then took a few research groups, an interesting discovery: The activity of ATM (and ATR) can be inhibited by administration of caffeine. The group of Zhou et al. With luck, her in the Journal of Biological Chemistry published articles may also be used online free for educational purposes. Working through with cell cultures, they showed that the addition of caffeine activated more of ATM signaling pathways were suppressed, such as a stop signal in the cell cycle, which is to prevent the initiation of cell division when DNA damage (the G2/M-Checkpoint). This effect mimics the behavior of AT cells (cells of patients suffering from Ataxia-telangiectasia and in which ATM is inactive) to see how nice to see in Figure 5 of the article.
Figure 5 in Zhou et al. (2000)
Chk2 is also a kinase that is regulated but the main repair pathway and are activated by ATM needs. Without big now, the principle behind electrophoretic methods to explain do you see after irradiation the cells, the activation of Chk2 by ATM in the higher band at 2 (compare with 1) because the Chk2 molecule is by attaching a Phosphatgrupppe grown. This activation occurs after treatment with caffeine no longer take place (the band is at 4 on the same level as the inactive control at 1, so we were a phosphate group turn hanged). This result is comparable with the behavior of AT cells without caffeine treatment (numbers 5 / 6).
Figure 7 from Zhou et al. (2000)
In Figure 7, Zhou and colleagues have another ATM-regulated way regarded apoptosis. Very important for initiating apoptosis (programmed cell death) is the protein p53, which can also be activated by attaching a phosphate group from ATM. As you can see very beautiful, p53 is activated with increasing caffeine concentration less and less, and even without irradiation (ausgeüllte circles: + irradiation, open squares: irradiation)! This means that in a few cells whose DNA was not severely damaged by irradiation, occurring spontaneous damage resulting in activation of p53 (and perhaps the triggering of apoptosis). And caffeine can be suppressed by inhibition of ATM.
The medical application
Earlier I said in the description of the disease ataxia-telangiectasia that patients are very sensitive to radiation, and the data have also shown why: ATM as a central regulator of many cellular processes after DNA damage can these processes not activate, the damage is not repaired and the cells cheerfully try to divide anyway. Since caffeine can mimic this appearance of AT cells, it has been used for several years in cancer medicine: Tumor cells are more sensitive to radiation therapy when administered to the patient receives additional caffeine. And this beneficial effect was also for several chemotherapeutics be shown (such as cisplatin ).
not forget: the concentration!
What in the Daily Mirror article is unfortunately omitted: To achieve these effects of caffeine in humans, concentrations of about 10 mM are necessary. After drinking a cup of strong coffee, the concentration in the blood but at about 50 microns [1], so it is about 200 times lower. In other words, caffeine is after more than five hours in blood taken down, we would have to at least 200 cups of strong coffee in less than five hours drinking in order to achieve an effect of caffeine on ATM!
The conclusion of the story: The Daily Mirror should be ashamed, pregnant women scare, and Mr. Cooke should research before his next project, at least five minutes brauchts namely, not more. And the literature is shown at least partially accessible.
[1] Calculated from a caffeine plasma concentration of 10 mg / l and the assumption of 8 mg / kg caffeine after drinking a cup of coffee.
[2] Sorry for the title, but I could not help me ;-)
Zhou, BB, Chaturvedi, P., Spring, K., Scott SP, Johanson RA, Mishra, R. Mattern, MR, Winkler JD, Khanna, KK (2000). Caffeine abolishes the mammalian G (2) / M DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity J Biol Chem, 275 (14), 10342-10348 my
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