Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

In vitro tests show clinically tested drug overcomes resistance to potential new cancer therapy

03.04.2014

Results from laboratory experiments carried out by a team of molecular biologists at Saarland University have identified a strategy for overcoming resistance to a new therapeutic opportunity for prostate cancer patients and for potentially suppressing the migration of cancer cells.

The new therapeutic approach, which is currently being studied by numerous research groups, aims to destroy cancer cells by influencing cellular calcium distribution. However, the research team, supervised by Professor Richard Zimmermann and Dr Markus Greiner, found that in about half of the patients examined, a cellular mechanism was present that could impede the efficacy of the new therapy.

The molecular biologists discovered that this resistance was caused by an increased concentration of the protein Sec62 in the tumour cells. Results from their laboratory cell line experiments indicate that a pharmaceutically active agent previously used in the treatment of psychotic disorders can counteract the observed cellular resistance as well as supress cell migration. The research team has published its findings in the medical journal BMC Cancer.

Prostate cancer is the most common malignant tumour in men. A new therapeutic approach to combating the disease is currently the subject of international research. In recent years, US scientists have developed a number of analogues of thapsigargin that are capable of selectively killing tumour cells by emptying the calcium stores in these cells.

But recent research by scientists at Saarland University’s Faculty of Medicine in Homburg has demonstrated that in approximately half of the patients suffering from prostate cancer, the tumour cells can be expected to show a resistance to this new form of therapy.

‘The resistance mechanism is due to a higher concentration of the protein Sec62,’ explains Professor Richard Zimmermann. As a result of increased Sec62 levels the protein calmodulin can close the calcium leak channels more efficiently in the membrane of the important intracellular calcium store known as the endoplasmic reticulum. ‘This is why tumour cells with a higher concentration of Sec62 show greater resistance to treatment regimens based on thapsigargin analogues,’ says Zimmermann.

Working with tumour cell cultures in the laboratory, Zimmermann’s group at the Department of Medical Biochemistry and Molecular Biology has found a possible solution to the problem and their results have been published in the journal BMC Cancer. ‘Using tumour cell lines, we were able to show that a substance called trifluoperazine (TFP) was able to counteract the observed resistance. TFP has been used as an antipsychotic and was marketed in Germany under the brand Jatroneutral® where it was used in the treatment of psychotic disorders,’ explains Dr Markus Greiner, a member of Professor Zimmermann’s research team. ‘TFP binds directly to the protein calmodulin and thus impairs the calmodulin-mediated closure of the calcium channels,’ explains Greiner.

Sec62 has been shown to be an important tumour marker, i.e. a protein that occurs at enhanced concentrations in tumour cells, not only in prostate carcinomas, but also in thyroid and lung carcinomas. The Homburg researchers see a correlation between the presence of Sec62 protein and a more aggressive tumour and hence lower patient survival rates. The research team also measured increased Sec62 concentrations in tumours that had already metastasized.

‘Calcium is an important signalling molecule that regulates cell migration, which is itself an important contributor to tumour metastasis,’ says Markus Greiner. The calcium in the cells ensures that the cells can detect the direction in which they are migrating. If these tumour cells are treated with TFP, the calcium store will be emptied and the cells essentially lose their orientation. ‘This leads to an almost complete cessation of cellular migration,’ explains Greiner.

‘We propose a therapeutic approach based on TFP in combination with thapsigargin analogues. In future, this may be a therapeutic option for those many patients whose tumours have a high cellular concentration of Sec62, which might make them unsuitable for treatment with thapsigargin,’ says Greiner. The results obtained by the Homburg research team will now be evaluated in tumour model studies before any clinical trials can be proposed.

Original publication: Linxweiler M., Schorr S., Schäuble N., Jung M., Linxweiler J., Langer F., Schäfers H.-J., Cavaliè A., Zimmermann R., and Greiner M.: Targeting cell migration and Endoplasmic Reticulum stress response with calmodulin antagonists: Mimicking Sec62-depletion phenotypes by small molecule treatment, BMC Cancer, 2013, 13:574;
doi: 10.1186/1471-2407-13-574

Contact: Prof. Dr. Richard Zimmermann: +49 (0)6841 162-6511
E-mail: richard.zimmermann@uks.eu
Dr. Markus Greiner: +49 (0)6841 162-6515 E-mail: m.greiner@uks.eu

Press photographs are available at http://www.uni-saarland.de/pressefotos and can be used free of charge.

Claudia Ehrlich | Universität des Saarlandes

Further reports about: BMC Cancer TFP analogues calmodulin carcinomas concentration disorders mechanism resistance therapy tumour

More articles from Life Sciences:

nachricht Pathogenic bacteria hitchhiking to North and Baltic Seas?
22.07.2016 | Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung

nachricht Unconventional quasiparticles predicted in conventional crystals
22.07.2016 | Max-Planck-Institut für Chemische Physik fester Stoffe

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Mapping electromagnetic waveforms

Munich Physicists have developed a novel electron microscope that can visualize electromagnetic fields oscillating at frequencies of billions of cycles per second.

Temporally varying electromagnetic fields are the driving force behind the whole of electronics. Their polarities can change at mind-bogglingly fast rates, and...

Im Focus: Continental tug-of-war - until the rope snaps

Breakup of continents with two speed: Continents initially stretch very slowly along the future splitting zone, but then move apart very quickly before the onset of rupture. The final speed can be up to 20 times faster than in the first, slow extension phase.phases

Present-day continents were shaped hundreds of millions of years ago as the supercontinent Pangaea broke apart. Derived from Pangaea’s main fragments Gondwana...

Im Focus: A Peek into the “Birthing Room” of Ribosomes

Scaffolding and specialised workers help with the delivery – Heidelberg biochemists gain new insights into biogenesis

A type of scaffolding on which specialised workers ply their trade helps in the manufacturing process of the two subunits from which the ribosome – the protein...

Im Focus: New protocol enables analysis of metabolic products from fixed tissues

Scientists at the Helmholtz Zentrum München have developed a new mass spectrometry imaging method which, for the first time, makes it possible to analyze hundreds of metabolites in fixed tissue samples. Their findings, published in the journal Nature Protocols, explain the new access to metabolic information, which will offer previously unexploited potential for tissue-based research and molecular diagnostics.

In biomedical research, working with tissue samples is indispensable because it permits insights into the biological reality of patients, for example, in...

Im Focus: Computer Simulation Renders Transient Chemical Structures Visible

Chemists at the University of Basel have succeeded in using computer simulations to elucidate transient structures in proteins. In the journal Angewandte Chemie, the researchers set out how computer simulations of details at the atomic level can be used to understand proteins’ modes of action.

Using computational chemistry, it is possible to characterize the motion of individual atoms of a molecule. Today, the latest simulation techniques allow...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

GROWING IN CITIES - Interdisciplinary Perspectives on Urban Gardening

15.07.2016 | Event News

SIGGRAPH2016 Computer Graphics Interactive Techniques, 24-28 July, Anaheim, California

15.07.2016 | Event News

Partner countries of FAIR accelerator meet in Darmstadt and approve developments

11.07.2016 | Event News

 
Latest News

Hey robot, shimmy like a centipede

22.07.2016 | Information Technology

New record in materials research: 1 terapascals in a laboratory

22.07.2016 | Physics and Astronomy

University of Graz researchers challenge 140-year-old paradigm of lichen symbiosis

22.07.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>