title: Synergistic Cytotoxicity of Bendamustine and the BTK Inhibitor in a Mantle Cell Lymphoma Cell Line.
abstract: BACKGROUND
  Bendamustine is effective in B-cell malignancies, including mantle cell lymphoma (MCL), alone and in combination with other agents. This study investigated the combination effect of bendamustine and the Bruton tyrosine kinase (BTK) inhibitor PCI-32765 on MCL cell death and the underlying mechanisms.
  
  
  METHODS
  Cytotoxicity was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MIT) assay. Apoptosis was assessed by annexin V/propidium iodide staining and protein expression was analyzed by western blotting.
  
  
  RESULTS
  When combined with bendamustine, PCI-32765 showed a synergistic effect on growth inhibition of the MCL cell line Jeko-1. Cleavage of caspase-3 and poly-(ADP-ribose) polymerase was increased, indicating enhanced apoptosis induction. In addition, this combination decreased the protein expression of cyclin D1. Phosphorylated v-akt murine thymoma viral oncogene homolog 1 (AKT) (Ser473) was also down-regulated, suggesting a suppression of the phosphatidylinositol 3-kinase/AKT signaling pathway.
  
  
  CONCLUSIONS
  Combination treatment with bendamustine and a BTK inhibitor may be effective in MCL therapy.
authors.affiliation: Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Hagiwara
authors.affiliation: Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokunaga
authors.affiliation: Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Hiroatsu
authors.initials: H
authors.lastname: Iida
authors.affiliation: Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan nagaih@nnh.hosp.go.jp.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Nagai
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000069461:Bendamustine Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D010880:Piperidines; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000069461:Bendamustine Hydrochloride; D000225:Adenine
keywords: BCR signaling; BTK inhibitor; Mantle cell lymphoma; apoptosis; bendamustine