title: Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL.
abstract: Proteolytic activity of the mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) paracaspase is required for survival of the activated B cell subtype of diffuse large B cell lymphoma (ABC-DLBCL). We have identified distinct derivatives of medicinal active phenothiazines, namely mepazine, thioridazine, and promazine, as small molecule inhibitors of the MALT1 protease. These phenothiazines selectively inhibit cleavage activity of recombinant and cellular MALT1 by a noncompetitive mechanism. Consequently, the compounds inhibit anti-apoptotic NF-κB signaling and elicit toxic effects selectively on MALT1-dependent ABC-DLBCL cells in vitro and in vivo. Our data provide a conceptual proof for a clinical application of distinct phenothiazines in the treatment of ABC-DLBCL.
authors.affiliation: Research Unit Cellular Signal Integration, Helmholtz Zentrum München-German Research Center for Environmental Health, Institute of Molecular Toxicology and Pharmacology, Ingolstädter Landstrasse. 1, 85764 Neuherberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nagel
authors.forename: Stefani
authors.initials: S
authors.lastname: Spranger
authors.forename: Michelle
authors.initials: M
authors.lastname: Vincendeau
authors.forename: Michael
authors.initials: M
authors.lastname: Grau
authors.forename: Silke
authors.initials: S
authors.lastname: Raffegerst
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kloo
authors.forename: Daniela
authors.initials: D
authors.lastname: Hlahla
authors.forename: Martin
authors.initials: M
authors.lastname: Neuenschwander
authors.forename: Jens
authors.initials: J
authors.lastname: Peter von Kries
authors.forename: Kamyar
authors.initials: K
authors.lastname: Hadian
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Peter
authors.initials: P
authors.lastname: Lenz
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Schendel
authors.forename: Daniel
authors.initials: D
authors.lastname: Krappmann
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D010640:Phenothiazines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D007376:Interleukin-2; D016328:NF-kappa B; D009363:Neoplasm Proteins; D010640:Phenothiazines; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein