Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL.
Cancer Cell, 2012/12/11;22(6):825-37.
Nagel D[1], Spranger S, Vincendeau M, Grau M, Raffegerst S, Kloo B, Hlahla D, Neuenschwander M, Peter von Kries J, Hadian K, Dörken B, Lenz P, Lenz G, Schendel DJ, Krappmann D
Affiliations
PMID: 23238017
Impact factor: 38.585
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.
MeSH terms
Apoptosis; B-Lymphocytes; Caspases; Cell Line, Tumor; Humans; Interleukin-2; Lymphoma, Large B-Cell, Diffuse; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; NF-kappa B; Neoplasm Proteins; Phenothiazines; Signal Transduction
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