Promising Cancer Drug Cordycepin Works by Inhibiting Protein Synthesis

A recent study provides new information regarding the mode of action of the promising anticancer drug cordycepin.

Cordycepin, or 3'-deoxyadenosine, is a derivative of the nucleoside adenosine, differing from the latter by the absence of an oxygen atom in the 3' position of its ribose moiety. It was initially extracted from fungi of genus Cordyceps, but is now produced synthetically. Since cordycepin is similar to adenosine, some enzymes cannot discriminate between the two. Therefore, it can mimic adenosine in certain biochemical reactions (for example, be incorporated into an RNA molecule, thus causing the premature termination of its synthesis).

Investigators from the University of Nottingham (UK) studied the effect of cordycepin on cells growing in tissue culture. They reported in the November 23, 2009, online edition of the Journal of Biological Chemistry that low doses of cordycepin interfered with RNA synthesis, which reduced the proliferation of NIH3T3 fibroblasts. Higher doses of the drug inhibited cell attachment and reduced focal adhesions. Furthermore, high doses of the drug strongly inhibited total protein synthesis that correlated with the inhibition of mammalian target of rapamycin (mTOR) signaling, as observed by reductions in Akt kinase and 4E-binding protein (4EBP) phosphorylation.

In cells lacking the gene for 4EBP, the effect of cordycepin on translation was strongly reduced, confirming the role of this modification. In addition, the adenosine monophosphate (AMP)-activated kinase (AMPK) was shown to be activated. Inhibition of AMPK prevented translation repression by cordycepin and abolished 4EBP1 dephosphorylation, indicating that the effect of cordycepin on mTOR signaling and protein synthesis was mediated by AMPK activation.

"Our discovery will open up the possibility of investigating the range of different cancers that could be treated with cordycepin,” said senior author Dr. Cornelia H. de Moor, lecturer in RNA biology at the University of Nottingham. "We have also developed a very effective method that can be used to test new, more efficient or more stable versions of the drug in the Petri dish. This is a great advantage, as it will allow us to rule out any nonrunners before anyone considers testing them in animals. Because of technical obstacles and people moving on to other subjects, it has taken a long time to figure out exactly how cordycepin works on cells. With this knowledge, it will be possible to predict what types of cancers might be sensitive and what other cancer drugs it may effectively combine with. It could also lay the groundwork for the design of new cancer drugs that work on the same principle.”

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