Methylxanthines, inflammation, and cancer: fundamental mechanisms

Methylxanthines are an integral part of everyday food and drink consumption even though the majority of humans do not identify them by their chemical name. The breakthrough in understanding the action(s) of methylxanthines was in large part due to the understanding that methylxanthines can function as antagonists of adenosine receptors. This represented an example of scientific search and was instructive in view of both new therapeutic options and alarming realizations. It was the subsequent demonstration of the in vivo critical role of A2A adenosine receptors in controlling excessive collateral inflammatory damage that attracted the attention of immunologists to the A2A-adenosine-receptor-antagonizing methylxanthines. We summarize here data showing that caffeine is capable of preventing the inhibition of antitumor T cells in a hypoxic tumor microenvironment. On the other hand, caffeine may exacerbate liver damage by weakening the tissue-protecting A2A adenosine receptor signaling during episodes of acute liver inflammation. However, methylxanthines may also prevent the excessive hepatic connective tissue deposition that is associated with the progression of chronic hepatitis to cirrhosis, which is one of the common causes of mortality.