title: A Novel Aziridine-based Bruton's Tyrosine Kinase Inhibitor Induces Apoptosis Through Down-regulation of p65/RelA Phosphorylation on Serine 536 and ERK1/2 in Mantle Cell Lymphoma.
abstract: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin's lymphoma characterized by hyperactive neoplastic B-cells and extended tumor cell survival. Bruton's tyrosine kinase (BTK), a crucial kinase in the B-cell antigen receptor signaling pathway, has emerged as a novel target of MCL therapy. A novel BTK-targeting inhibitor, JuSt-23F was prepared.
  
  
  
  The WST-8 assay was used to determine cytotoxicity and half-maximal inhibitory concentration (IC50) values for JuSt-23F against the MCL cell lines Mino and Maver-1. JuSt-23F-mediated apoptosis was assessed using the annexin V assay. We detected phosphorylation of p65/RelA on serine 536 in whole Jurkat, Mino and Maver-1 cells treated with JuSt-23F and stimulated with tumor necrosis factor (TNFα). We assessed JuSt-23F-mediated phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in T-cell lymphoma and MCL cells stimulated by phorbol-12-myristate-13-acetate (PMA).
  
  
  
  Our study suggests that JuSt-23F inhibits apoptosis selectively in B-cell lymphoma cells. JuSt-23F exerts its antiproliferative effects on MCL cells through targeting the downstream BTK signaling cascade via down-regulation of nuclear factor kappa-light-chain-enhancer of activated B-cells and ERK1/2 pathways. Thus, our findings propose the novel BTK inhibitor JuSt-23F as an attractive potential agent for investigation and treatment of MCL.
authors: Latvian Institute of Organic Synthesis, Riga, Latvia nadezhda@farm.osi.lv.
authors: Nadezhda
authors: N
authors: Romanchikova
authors: Latvian Biomedical Research and Study Centre, Riga, Latvia.
authors: Arnis
authors: A
authors: Strods
authors: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors: Julija
authors: J
authors: Strazdina
authors: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors: Boriss
authors: B
authors: Strumfs
authors: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors: Peteris
authors: P
authors: Trapencieris
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001388:Aziridines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012694:Serine / Q000737:chemistry; D051996:Transcription Factor RelA / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D047428:Protein Kinase Inhibitors; D051996:Transcription Factor RelA; D012694:Serine; C033132:aziridine; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human
keywords: Bruton's tyrosine kinase inhibitor; ERK1/2; Mantle cell lymphoma; NF-κB; apoptosis; drug discovery