Anti-diarrheal drug causes cell death in glioblastoma cells

In cell culture, loperamide, a drug commonly used against diarrhea, proves to be effective against glioblastoma cells. A research team at Goethe University has now linked the drug’s action to cell death and – in doing so – shown how this fertilizer could help attack tumors. a brain that is difficult to handle otherwise.

The research group led by Dr Sjoerd van Wijk from Goethe University’s Institute for Experimental Cancer Research in Pediatrics already two years ago found evidence showing that loperamide could be used against anti-diarrheal drugs to cause cell death stimulated in glioblastoma cell lines. They have now improved their approach and, in doing so, are opening up new avenues for developing innovative treatment strategies.

When cells break down themselves

In certain types of tumor cells, administration of loperamide leads to a stress response in the endoplasmic reticulum (ER), the cell organelle that is responsible for major steps in protein synthesis in the body. The stress in the ER leads to degeneration, followed by self-destruction of the cells. This conditioning, called autophagy-dependent cell death, occurs when cells undergo hyperactivated autophagy. Autophagy usually regulates normal metabolic processes and breaks down and recycles the valuable parts of damaged or redundant cell parts and thus ensures the survival of the cell, for example in the case of malnutrition. In some tumor cells, however, mass autophagy destroys so much cell material that they can no longer survive.

Our experiments with cell lines show that autophagy may support the treatment of glioblastoma brain tumors. “

Dr. Sjoerd van Wijk, Institute of Cancer Experimental Research in Pediatrics, Goethe University

Glioblastoma is a very aggressive and deadly type of cancer in children and adults that shows just a poor response to chemotherapy. So new therapeutic methods are needed immediately. The van Wijk-led research group has now identified an important feature linking ER stress response with ER (reticulophagy) contamination: The “Active Transcription Factor” ATF4 has been produced in larger amounts both during ER stress and under the influence of loperamide. It removes the destruction of the ER organs and thus the ER.

Anti-diarrheal drug causes cell death in glioblastoma cells

“On the other hand, if we inhibit ATF4, far fewer cells in tumor cell culture die after adding loperamide,” van Wijk said, describing the control results. In addition, the research group was able to detect ER debris in cells treated with loperamide under the electron microscope. “ER contamination, i.e., reticulophagy, obviously contributes to the degeneration of glioblastoma cells,” van Wijk says. The team also showed that loperamide only triggers autophagy but not cell death in other cells, such as embryonic mouse fibroblasts. “Loperamide, when taken as a remedy for diarrhea, usually binds to specific binding sites in the abdomen and is not absorbed by the abdomen so it is without harm “.

Equipment action also relevant to other diseases

Loperamide-induced glioblastoma cell death may help develop new therapeutic approaches for the treatment of this very type of cancer. “However, our findings also open up exciting new opportunities for the treatment of other ER-contaminated diseases, such as brain disorders or depression as well as other types of dementia. tumors, “says van Wijk. However, more studies are needed before loperamide can be used in the treatment of glioblastoma or other diseases. In future studies it is necessary to study, for example, how loperamide can be treated. into the brain and cross the blood-brain barrier Nanoparticles may be a viable option The research team in Frankfurt is now looking to identify other products that promote reticulophagy and study how the effects of loperamide can be increased and better understood.