Press release

Prof. Dr. Jindrich Cinatl

First steps on the way to a new cancer drug

Researchers from Frankfurt and Kent successful in finding ways to overcome resistance

FRANKFURT. Researchers from Goethe University and the University of Kent (UK) have found the first step towards a new generation of cancer drugs capable of inhibiting drug resistance.

With its research, the international team led by Professor Jindrich Cinatl of Goethe University and Professor Martin Michaelis of Kent’s School of Biosciences has paved the way for tailored drug combinations that could increase the effectiveness of treatments, especially for patients with treatment-resistant cancers.

Drug resistance is a common reason for the failure of cancer therapies, and is thus responsible for the death of many patients. Despite great advances in the treatment of cancer over the past decades, cures are still mainly achieved when cancer is detected early and treated locally in the form of surgery and radiotherapy. Once the cancer cells have spread throughout the body and formed metastases (secondary tumours), the prognosis is bleak: the survival rate after five years is then less than 20 percent.

Therefore, effective drugs are urgently sought to help improve the chances of patients with metastatic cancer systemically. However, many cancers carry resistance and do not respond to any therapy from the time of diagnosis, others initially respond to therapies, but then the cancer cells become resistant.

The most important resistance mechanism in cancer cells is probably the function of so-called ATP-binding cassette (ABC) transporters. These are drug pumps that transport cancer drugs out of cancer cells. ABCB1 (also called multi-drug resistance gene 1 (MDR1) or P-glycoprotein) is the most significant of these. However, previous attempts to target ABCB1 as part of cancer therapy have failed.

One important reason for this is that ABCB1 is found in many places in the body, but especially at tissue boundaries such as the junction of the stomach and intestine and the bloodstream and brain. This used to mean that drugs that inhibited ABCB1 were not suitable for the desired interaction of cancer drugs with ABCB1 on cancer cells. Instead, the distribution of many different drugs and dietary components in the body was affected, leading to toxic side effects.

The research presented here shows that certain inhibitors of ABCB1 (produced in the research group of Prof. Manfred Schubert-Zsilavecz, Goethe University) interact in a special way with the ABCB1-mediated transport of certain cancer drugs. This represents a first step towards the development of customised combinations of anticancer drugs and ABCB1 inhibitors that specifically induce the accumulation of anticancer drugs in ABCB1-expressing cancer cells but have no effect on the distribution of other drugs or food components in the body.

In addition to Professor Michaelis and Professor Cinatl and their colleagues, the team also included Prof. Manfred Schubert-Zsilavecz (Goethe University), Professor Michael Wiese (University of Bonn), Dr Mark Wass (University of Kent) and Dr Taravat Ghafourian (University of Sussex) and their research groups.

Prof. Cinatl’s research group was additionally supported by the association “Hilfe für krebskranke Kinder” and its foundation “Frankfurter Stiftung für krebskranke Kinder”.

A tumour cell (here the neuroblastoma cell UKF-NB-3) is treated with a cytostatic drug (here with vincristine [VCR]) and dies.
Here, a chemoresistant neuroblastoma cell (UKF-NB-3 resistant to vincristine) is also treated with vincristine. However, the chemoresistant cell has the ABC transporter P-glycoprotein (green circles). The result is that vincristine is pumped out of the cell by Pglycoprotein, so that vincristine cannot take effect and the chemoresistant tumour cell does not die.
If the function of the P-glycoprotein in the chemoresistant cell is disturbed by specific inhibitors (here red crosses), the P-glycoprotein can no longer transport vincristine out of the cell, vincristine takes effect and the chemoresistant tumour cell dies.

 

Publication: Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport, in: Oncotarget.

See here: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=7345&author-preview=5o1

Explanatory graphics for download at  www.uni-frankfurt.de/60434613

Information:
Prof. Dr. Jindrich Cinatl, Institut für Medizinische Virologie, Goethe-Universität Frankfurt; cinatl@em.uni-frankfurt.de; +49 69 6301 6409; Dr. Florian Rothweiler; f.rothweiler@kinderkrebsstiftung-frankfurt.de; +49 69 6786 6572.

Press release in English:
http://www.goethe-university-frankfurt.de/60434202/11

 

Goethe University is a strong research university in the European financial metropolis of Frankfurt. Founded in 1914 with purely private funds by free-minded citizens of Frankfurt, it is still committed to the motto “Science for Society” in research and teaching. Many of the men and women who founded the university in the early days were Jewish donors. In the last 100 years, Goethe University has made pioneering achievements in the fields of social and economic sciences, chemistry, quantum physics, brain research and labour law. On 1 January 2008, it gained a unique degree of autonomy by returning to its historical roots as a foundation university. Today it is one of the ten universities with the most third-party funding and three largest universities in Germany, with three clusters of excellence in medicine, life sciences and the humanities.

Publisher: The President
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Internet: www.uni-frankfurt.de

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