Argyrin: natural substance raises hope for new cancer therapies

Scientists at HZI, MHH and LUH publish previously-unknown chemical mechanism

Ronald Frank  Nisar Malek  Markus KalesseThe effective treatment of many forms of cancer continues to pose a major problem for medicine. Many tumours fail to respond to standard forms of chemotherapy or become resistant to the medication. Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, the Hannover Medical School (MHH) and Leibniz-Universität (LUH) in Hanover have now discovered a chemical mechanism with which a natural substance - argyrin - destroys tumours. Today, the researchers publish their findings in the renowned scientific journal "CancerCell".

The basis for this breakthrough was an observation made by the MHH scientist Prof. Nisar Malek: he had been studying the role of a certain protein - a so-called cyclin-kinase inhibitor - in the development of cancer. In the process, Malek noted that mice in which the breakdown of the kinase inhibitor was suppressed by genetic change have a significantly lower risk of suffering from intestinal cancer. "I needed a substance that would prevent the breakdown of the protein that I was investigating in the cancer cells," says Nisar Malek: "This molecule, in all likelihood, would make a good anti-cancer agent."

Nisar Malek approached Dr. Ronald Frank, a chemist at HZI, with his considerations. Ronald Frank has established extensive collections of chemical substances at the HZI that can be tested for their biological activity in a fast, automated procedure. The two agreed to develop a special cell line in which the quantity of the cyclin kinase inhibitor can be measured using simple optical methods. Ronald Frank: "We adapted this cell based assay system to allow automated screening of large numbers of different chemical substances.”

“Myxobacteria provide another potential cancer medicine

Malek and Frank found what they were looking for in a collection of natural substances which had originally been isolated from microorganisms which live in soil – the so called Myxobacteria. Myxobacteria have proven to be a treasure trove of potential medicines, also being used in the production of epothilone, an active agent identified at the HZI. This drug has been approved as a cancer medicine in the USA last year. "The myxobacterial agent for our purposes is argyrin," says Ronald Frank.

With this knowledge, Ronald Frank and Nisar Malek joined up with the chemist Prof. Markus Kalesse of the LUH to launch an extensive research programme to discover how argyrin can be produced chemically and how it functions. In the process they stumbled upon a completely new mechanism, which was subsequently revealed in a publication in the non plus ultra of oncology journals, "CancerCell". "Argyrin blocks the molecular machinery of the cell which breakdowns proteins that are no longer required," explains Malek, "and thereby naturally also prevents the breakdown of the kinase inhibitor in question, the lack of which triggers cancer."

The research team has already conducted detailed studies of the effects of argyrin on mice: "When we treat animals with cancer with argyrin," says Nisar Malek, "the tumour ceases growing, it decreases by up to 50 percent and it begins to breakdown internally." Scarcely any side effects have been noted. Although the findings published in CancerCell are viewed by the scientists as an important result, it is merely the first step of a longer journey: "Research into argyrin continues at a fast pace," says Markus Kalesse: "We are already altering the argyrin molecule in all details and looking to see if it is possible to improve its performance further. Our goal is to submit such an optimised structure for clinical testing in the near future."

Title of the Original Publication:
Irina Nickeleit, Steffen Zender, Florenz Sasse, Robert Geffers, Gudrun Brandes, Inga Sörensen, Heinrich Steinmetz, Stefan Kubicka, Teresa Carlomagno, Dirk Menche, Ines Gütgemann, Jan Buer, Achim Gossler, Michael P. Manns, Markus Kalesse, Ronald Frank, and Nisar P. Malek: Argyrin A Reveals a Critical Role for the Tumor Suppressor Protein p27kip1 in Mediating Antitumor Activities in Response to Proteasome Inhibition; Cancer Cell 2008 14: 23-35.

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