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Nagel, D. ; Spranger, S. ; Vincendeau, M. ; Grau, M.* ; Raffegerst, S.H. ; Kloo, B. ; Hlahla, D. ; Neuenschwander, M.* ; von Kries, J.P.* ; Hadian, K. ; Dörken, B.* ; Lenz, P.* ; Lenz, G.* ; Schendel, D.J. ; Krappmann, D.

Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL.

Cancer Cell 22, 825-837 (2012)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords B-CELL LYMPHOMA; PARACASPASE MALT1; RNA INTERFERENCE; ACTIVATION; THIORIDAZINE; SURVIVAL; CLEAVAGE; CANCER; PROLIFERATION; METACASPASES
Language english
Publication Year 2012
HGF-reported in Year 2012
ISSN (print) / ISBN 1535-6108
e-ISSN 1878-3686
Journal Cancer Cell
Quellenangaben Volume: 22, Issue: 6, Pages: 825-837 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Research Unit Signaling and Translation (SAT)
Institute of Molecular Immunology (IMI)
Institute of Molecular Toxicology and Pharmacology (TOX)
POF-Topic(s) 30203 - Molecular Targets and Therapies
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Enabling and Novel Technologies
Immune Response and Infection
PSP Element(s) G-509800-002
G-501700-002
G-501790-001
G-505293-001
PubMed ID 23238017
DOI 10.1016/j.ccr.2012.11.002
WOS ID WOS:000312467000013
Scopus ID 84870769441
Erfassungsdatum 2012-12-31
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