A common drug that is usually prescribed to treat diarrhea may also be a powerful weapon against an aggressive type of brain cancer, suggests a new study published in the journal Autophagy. Loperamide, sold under the brand name Imodium, has previously been shown to induce cell death of glioblastoma cells, but the mechanism remained unknown until now. In this latest study, the researchers found a pathway by which the drug induces the cells to self-destruct, called autophagy which means "self-eating". By upregulating a gene that promotes cell death of glioblastoma cell lines, loperamide may be a promising drug candidate, which they now hope will open up new avenues to combat the deadly form of cancer. “Our experiments with cell lines show that autophagy could support the treatment of glioblastoma brain tumours,” says lead author Dr Sjoerd van Wijk in a statement. The researchers from the Institute of Experimental Cancer Research in Paediatrics at Goethe University hope to utilize a normal cellular process to combat over-replicating brain cancer cells. Autophagy occurs constantly within the body as a necessary means of removing damaged or malignant cells. However, through a variety of mechanisms, cancer can sometimes evade this system and rapidly grow out of control. If researchers could target cancer cells and induce autophagy specifically within them, cancer could be stopped in its tracks. When loperamide is administered to some cancer cells, it can trigger a stress response within the endoplasmic reticulum (ER). This cell organelle is incredibly important for the production of proteins. When stress markers are noticed by the cell in parts of the ER, the cell destroys these parts to prevent abnormal protein production – this is called reticulophagy. In normal cells, reticulophagy can be managed and the cell can survive. However, in cancer cells, autophagy can go into overdrive, and the entire cell is degraded. Targeting this pathway is exactly the plan of van Wijk and his team. The researchers identified a gene called ATF4 that is upregulated in the presence of loperamide and could be involved in the autophagy of glioblastoma cells. To understand the role of ATF4 in loperamide-triggered autophagy, the researchers knocked out ATF4 expression in glioblastoma cells. After stopping the production of ATF4, loperamide did not trigger reticulophagy within the cells, suggesting the drug requires the action of ATF4 to have a cancer-killing effect. Upon further investigation, the researchers found that by upregulating ATF4, the loperamide appeared to induce stress markers that ultimately led to the cancer cells’ demise. Alongside ATF4, the study also highlighted more receptors involved in the loperamide-triggered autophagy pathway that could be extremely useful in fighting glioblastoma. Furthermore, van Wijk also explains that the pathway could be applicable to the treatment of other serious neurological diseases. “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,” says van Wijk. The drug still requires more study before it can be verified as a treatment option for glioblastoma, and a delivery method would also need to be found that would allow loperamide to cross the blood-brain barrier and reach the tumors. The researchers now hope to further understand the loperamide pathway and identify other drug candidates that could have a similar effect. Source
