title: Combining CAL-101 with Celecoxib Enhances Apoptosis of EBV-transformed B-Cells Through MAPK-induced ER Stress.
abstract: BACKGROUND
  Phosphoinositide-3 kinase (PI3K) inhibition attenuates proliferation and survival in B-cell malignancies. Celecoxib induces endoplasmic reticulum (ER) stress-induced apoptosis via a cyclo-oxgenase-2 (COX2)-independent manner in certain types of cancer cells. In the present study, we assessed the effects of combinations of drugs with a p110δ-specific inhibitor, CAL-101, and celecoxib to induce apoptosis in Epstein-Barr virus (EBV)-transformed B-cells and non-Hodgkin's lymphoma (NHL) cells.
  
  
  METHODS
  The apoptotic effect of combination treatment with CAL-101 and celecoxib on B-cell malignancies was determined by flow cytometry and immunoblotting.
  
  
  RESULTS
  Exposure to CAL-101 and celecoxib significantly increased apoptosis, which was accompanied by the inactivation of AKT, Ras homolog gene family, member A (RHOA), Rho-associated coiled-coil containing protein kinase 1 (ROCK1), and ROCK2 as well as up-regulation of Phosphatase and tensin homolog (PTEN). Co-treatment with CAL-101 and celecoxib triggered the ER stress response and the down-regulation of BCL2 and BCL-XL. SB203580, SP600125, and salubrinal effectively inhibited apoptosis and attenuated expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK) and CCAAT-enhancer-binding protein homologous protein (CHOP). Levels of apoptosis signal-regulating kinase 1 (ASK1) were also increased after treatment with CAL-101 and celecoxib.
  
  
  CONCLUSIONS
  The apoptosis of EBV-transformed B-cells and NHL cells caused by CAL-101 and celecoxib might be related to inhibiting the RHOA/ROCK pathway and might also be associated with mitogen-activated protein kinase (MAPK)-mediated ER stress.
authors.affiliation: Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Ga Bin
authors.initials: GB
authors.lastname: Park
authors.affiliation: Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea kimdj@inje.ac.kr.
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Hur
authors.affiliation: Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea kimdj@inje.ac.kr.
authors.forename: Daejin
authors.initials: D
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D000068579:Celecoxib; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020928:Mitogen-Activated Protein Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D052999:Quinazolinones / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage*
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D052999:Quinazolinones; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D000068579:Celecoxib; C552946:idelalisib
keywords: CAL-101; Celecoxib; EBV-transformed B cells; ER stress