Page last updated at 00:01 GMT, Tuesday, 29 December 2009
Scientists discover how wild mushroom cancer drug works
Cordyceps militaris growing on a moth pupa
The drug was first isolated from a parasitic mushroom
Scientists have discovered how a promising cancer drug, first discovered in a wild mushroom, works.
The University of Nottingham team believe their work could help make the drug more effective, and useful for treating a wider range of cancers.
Cordycepin, commonly used in Chinese medicine, was originally extracted from a rare kind of parasitic mushroom that grows on caterpillars.
The study will appear in the Journal of Biological Chemistry.
The cordyceps mushroom has been studied by medical researchers for some time - the first scientific publication on cordycepin was in 1950.
However, although the drug showed great promise, it was quickly degraded in the body.
It can be given with another drug to combat this - but the second drug can produce side effects that limit its potential use.
As a result, researchers turned their interest to other potential candidate drugs, and exactly how cordycepin worked on the body's cells remained unclear.
It could lay the groundwork for the design of new cancer drugs that work on the same principle
Dr Cornelia de Moor
University of Nottingham
Researcher Dr Cornelia de Moor said: "Our discovery will open up the possibility of investigating the range of different cancers that could be treated with cordycepin.
"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."
The researchers have also developed a method to test how effective the drug is in new preparations, and combinations with other drugs, which might solve the problem of degradation more satisfactorily.
Dr De Moor said: "This is a great advantage as it will allow us to rule out any non-runners before anyone considers testing them in animals."
The Nottingham team observed two effects on the cells - at a low dose cordycepin inhibits the uncontrolled growth and division of the cells, and at high doses it stops cells from sticking together, which also inhibits growth.
The knowledge generated by this research demonstrates the mechanisms of drug action and could have an impact on one of the most important challenges to health
Professor Janet Allen
Biotechnology and Biological Sciences Research Council
Both of these effects probably have the same underlying mechanism - that cordycepin interferes with how cells make proteins.
At low doses cordycepin interferes with the production of mRNA, the molecule that gives instructions on how to assemble a protein.
And at higher doses it has a direct impact on the making of proteins.
Professor Janet Allen is director of research at the Biotechnology and Biological Sciences Research Council, which funded the study.
She said: "This project shows that we can always return to asking questions about the fundamental biology of something in order to refine the solution or resolve unanswered questions.
"The knowledge generated by this research demonstrates the mechanisms of drug action and could have an impact on one of the most important challenges to health."
Cordycepin inhibits protein synthesis and cell adhesion through effects on signal transduction
J. Biol. Chem. jbc.M109.071159First Published on November 23, 2009, doi:10.1074/jbc.M109.071159
* Ying Ying Wong,
* Alice Moon,
* Ruth Duffin,
* Adeline Barthet-Barateig,
* Hedda A. Meijer,
* Michael J. Clemens,
* and Cornelia H. de Moor
3' Deoxyadenosine, also known as cordycepin, is a known polyadenylation inhibitor with a large spectrum of biological activities, including anti-proliferative, pro-apoptotic and anti-inflammatory effects. In this study we confirm that cordycepin reduces the length of poly(A) tails, with some mRNAs being much more sensitive than others. The low doses of cordycepin that cause poly(A) changes also reduce the proliferation of NIH3T3 fibroblasts. At higher doses of the drug we observed inhibition of cell attachment and a reduction of focal adhesions. Furthermore, we observed a strong inhibition of total protein synthesis that correlates with an inhibition of mammalian target of rapamycin (mTOR) signalling, as observed by reductions in Akt kinase and 4E binding protein (4EBP) phosphorylation. In 4EBP knockout cells, the effect of cordycepin on translation is strongly reduced, confirming the role of this modification. In addition, the 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 signalling and protein synthesis is mediated by AMPK activation. We conclude that many of the reported biological effects of cordycepin are likely to be due to its effects on mTOR and AMPK signalling.
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