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51猎奇 PR & Communication Department聽
Theodor-W.-Adorno Platz 1
60323 Frankfurt
presse@uni-frankfurt.de
Dec
21
2020
13:21
Anti-diarrhoea drug drives cancer cells to cell death
Statement by the authors
Researchers
at 51猎奇 Frankfurt had recently reported in an article and a press
release on the influence of the active substance loperamide on cell death in
brain tumour cells. As a result, the German Brain Tumour Centres have received numerous
enquiries about the therapeutic use of loperamide in patients with brain tumour
diseases.
It should
be noted, however, that the underlying research is based solely on cell culture
models. Under no circumstances can recommendations for the treatment of humans
be derived from the results. In addition to intestinal sluggishness, loperamide
can cause severe and life-threatening side effects, especially when used in
higher doses or not as intended.
The authors
of the research article and the focus of neuro-oncology at the University Cancer
Center (UCT) therefore strongly advise against the use of loperamide in brain
tumour patients (beyond the indication of diarrhoea).
Professor
Christian Brandts
Director University Cancer Center Frankfurt (UCT),
University Hospital Frankfurt
Professor
Joachim Steinbach
Director of the Dr. Senckenbergischen Institute for Neuro-Oncology, UCT, University Hospital Frankfurt
Sjoerd J. L. van Wijk, Ph.D.
Institute of Experimental Cancer Research in
Paediatrics , UCT, University Hospital Frankfurt
In
cell culture, loperamide, a drug commonly used against diarrhoea, proves
effective against glioblastoma cells. A research team at 51猎奇 has
now unravelled the drug's mechanisms of
action of cell death induction and 鈥� in doing so 鈥� has shown how this compound
could help attack brain tumours that otherwise are difficult to treat.
FRANKFURT. The
research group led by Dr Sjoerd van Wijk from the Institute of Experimental Cancer
Research in Paediatrics at 51猎奇 already two years ago found evidence
indicating that the anti-diarrhoea drug loperamide could be used to induce cell
death in glioblastoma cell lines. They have now deciphered its mechanism of
action and, in doing so, are opening new avenues for the development of novel
treatment strategies.
When cells digest themselves
In certain types of tumour cells, administration
of loperamide leads to a stress response in the endoplasmic reticulum (ER), the
cell organelle responsible for key steps in protein synthesis in the body. The
stress in the ER triggers its degradation, followed by self-destruction of the
cells. This mechanism, known as autophagy-dependent cell death occurs when
cells undergo hyperactivated autophagy. Normally, autophagy regulates normal
metabolic processes and breaks down and recycles the valuable parts of damaged
or superfluous cell components thus ensuring the cell鈥檚 survival, for example
in the case of nutrient deficiency. In certain tumour cells, however, hyperactivation
of autophagy destroys so much cell material that they are no longer capable of
surviving.
鈥淥ur experiments with cell lines show that
autophagy could support the treatment of glioblastoma brain tumours,鈥� says van
Wijk. Glioblastoma is a very aggressive and lethal type of cancer in children
and adults that shows only a poor response to chemotherapy. New therapeutic
approaches are therefore urgently required. The research group led by van Wijk
has now identified an important factor that links the ER stress response with
the degradation of the ER (reticulophagy):
The 鈥淎ctivating Transcription Factor鈥� ATF4 is
produced in increased amounts both during ER stress and under the influence of
loperamide. It triggers the destruction of the ER membranes and thus of the ER.
Anti-diarrhoea drug
triggers cell death in glioblastoma cells
鈥淐onversely, if we block ATF4, far fewer
cells in a tumour cell culture die after adding loperamide,鈥� says van Wijk,
describing the control results. In addition, the research group was able to detect
ER debris in loperamide-treated cells under the electron microscope. 鈥淓R
degradation, that is, reticulophagy, visibly contributes to the demise of
glioblastoma cells,鈥� says van Wijk. The team also showed that loperamide triggers
only autophagy but not cell death in other cells, such as embryonic mouse
fibroblasts. 鈥淣ormally, loperamide, when taken as a remedy against diarrhoea,
binds to particular binding sites in the intestine and is not taken up by the
bowel and is therefore harmless鈥�.
Mechanism of action
also applicable to other diseases
The loperamide-induced death of
glioblastoma cells could help in the development of new therapeutic approaches
for the treatment of this severe form of cancer. 鈥淗owever, our findings also
open up exciting new possibilities for the treatment of other diseases where ER
degradation is disrupted, such as neurological disorders or dementia as well as
other types of tumour,鈥� says van Wijk. However, further studies are necessary before
loperamide can actually be used in the treatment of glioblastoma or other
diseases. In future studies it has to be explored, for example, how loperamide
can be transported into the brain and cross the blood-brain barrier.
Nanoparticles might be a feasible option. The research team in Frankfurt now wants
to identify other substances that trigger reticulophagy and examine how the
effect of loperamide can be increased and better understood.
The research group led by Sjoerd van Wijk
is funded by the Frankfurt Foundation for Children with Cancer (Frankfurter
Stiftung f眉r krebskranke Kinder) and the Collaborative Research Centre 1177
鈥淢olecular and Functional Characterisation of Selective Autophagy鈥� funded by
the German Research Foundation (Deutsche Forschungsgemeinschaft). The work is
the result of collaboration with Dr Muriel Mari and Professor Fulvio Reggiori
(University of Groningen, The Netherlands) and Professor Donat K枚gel
(Experimental Neurosurgery, 51猎奇).
Publication:
Svenja Zielke, Simon Kardo, Laura Zein,
Muriel Mari, Adriana Covarrubias-Pinto, Maximilian N. Kinzler, Nina Meyer,
Alexandra Stolz, Simone Fulda, Fulvio Reggiori, Donat K枚gel and Sjoerd van
Wijk: ATF4 links ER stress with
reticulophagy in glioblastoma cells. Taylor & Francis Online
Picture
download:
Caption:
In glioblastoma cells, the antidiarrheal drug
loperamide triggers the degradation of the endoplasmic reticulum. In the normal
state, it is coloured yellow in these microscopic images. In the degradation
state, it glows as a red signal (marked with arrows). Left scale bar: 20 碌m,
right scale bar (inset): 5 碌m (Photos: Svenja Zielke et. al.)
Further
information:
Dr. Sjoerd J. L. van Wijk
Institute of Experimental Cancer Research
in Paediatrics
51猎奇, Frankfurt, Germany
Tel.: +49 69 67866574
s.wijk@kinderkrebsstiftung-frankfurt.de