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

Official URL:https://doi.org/10.1016/j.ccr.2012.11.002
PubMed:View item in PubMed
Creators Name:Nagel, D. and Spranger, S. and Vincendeau, M. and Grau, M. and Raffegerst, S. and Kloo, B. and Hlahla, D. and Neuenschwander, M. and von Kries, J.P. and Hadian, K. and Doerken, B. and Lenz, P. and Lenz, G. and Schendel, D.J. and Krappmann, D.
Journal Title:Cancer Cell
Journal Abbreviation:Cancer Cell
Page Range:825-837
Date:11 December 2012
Keywords:Apoptosis, B-Lymphocytes, Caspases, Diffuse Lymphoma, Large B-Cell, NF-{kappa} B, Neoplasm Proteins, Phenothiazines, Signal Transduction
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-{kappa}B 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.
Publisher:Cell Press / Elsevier (U.S.A.)
Item Type:Article

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