Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer |
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| Authors: | Leonie Konczalla Daniel R Perez Nadine Wenzel Gerrit Wolters-Eisfeld Clarissa Klemp Johanna Lüddeke Annika Wolski Dirk Landschulze Chris Meier Anika Buchholz Dichao Yao Bianca T Hofmann Julia K Graß Sarah L Spriestersbach Katharina Grupp Udo Schumacher Christian Betzel Svetlana Kapis Theresa Nuguid Pablo Steinberg Klaus Püschel Guido Sauter Maximillian Bockhorn Faik G Uzunoglu Jakob R Izbicki Cenap Güngör Alexander T El Gammal |
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| Institution: | 1. Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;2. Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany;3. Institute of Organic Chemistry, University of Hamburg, Hamburg, Germany;4. Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;5. Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;6. Laboratory for Structural Biology of Infection and Inflammation, Department of Chemistry, c/o DESY, University of Hamburg, Hamburg, Germany;7. Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;8. Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany |
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| Abstract: | MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms. |
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| Keywords: | cancer therapy pharmacology pancreatic cancer biperiden mepazin |
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