Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer.

Animals Biperiden / pharmacology Carcinoma, Pancreatic Ductal / drug therapy Cell Growth Processes / drug effects Cell Line, Tumor Humans Mice Mice, Knockout Models, Molecular Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / antagonists & inhibitors NF-kappa B / metabolism Pancreatic Neoplasms / drug therapy Phenothiazines / pharmacology Proto-Oncogene Proteins c-rel / metabolism Random Allocation Xenograft Model Antitumor Assays

biperiden cancer therapy mepazin pancreatic cancer pharmacology

Journal

International journal of cancer

ISSN: 1097-0215

Titre abrégé: Int J Cancer

Pays: United States

ID NLM: 0042124

Informations de publication

Date de publication:
15 03 2020

Historique:

received: 12 02 2019

revised: 31 05 2019

accepted: 21 06 2019

pubmed: 11 7 2019

medline: 13 2 2020

entrez: 11 7 2019

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1002/ijc.32567 PMID: 31291468

pubmed: 31291468

doi: 10.1002/ijc.32567

doi:

Substances chimiques

NF-kappa B 0

Phenothiazines 0

Proto-Oncogene Proteins c-rel 0

REL protein, human 0

Biperiden 0FRP6G56LD

mepazine 60-89-9

MALT1 protein, human EC 3.4.22.-

Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein EC 3.4.22.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1618-1630

Informations de copyright

Références

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