Pharmacologic Inhibition of MALT1 Protease by Phenothiazines as a Therapeutic Approach for the Treatment of Aggressive ABC-DLBCL

被引：194

作者：

Nagel, Daniel ^{[1
]}

Spranger, Stefani ^{[2
]}

Vincendeau, Michelle ^{[1
]}

Grau, Michael ^{[3
]}

Raffegerst, Silke ^{[2
]}

Kloo, Bernhard ^{[1
]}

Hlahla, Daniela ^{[1
]}

Neuenschwander, Martin ^{[4
]}

von Kries, Jens Peter ^{[4
]}

Hadian, Kamyar

Doeken, Bernd ^{[5
]}

Lenz, Peter ^{[3
]}

Lenz, Georg ^{[5
]}

Schendel, Dolores J. ^{[2
]}

Krappmann, Daniel ^{[1
]}

机构：

[1] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Mol Toxicol & Pharmacol, Res Unit Cellular Signal Integrat, D-85764 Neuherberg, Germany

[2] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Mol Immunol & Immune Monitoring Platform, D-81377 Munich, Germany

[3] Univ Marburg, Dept Phys, D-35032 Marburg, Germany

[4] Leibniz Inst Mol Pharmacol, D-13125 Berlin, Germany

[5] Charite, Mol Canc Res Ctr, Dept Hematol Oncol & Tumorimmunol, D-13353 Berlin, Germany

来源：

CANCER CELL | 2012年 / 22卷 / 06期

关键词：

B-CELL LYMPHOMA; THIORIDAZINE; CLEAVAGE; SURVIVAL; PROLIFERATION; METACASPASES; LYMPHOCYTES; METABOLITES; ACTIVATION; SIGNATURE;

D O I：

10.1016/j.ccr.2012.11.002

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：825 / 837

页数：13

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