title: Bortezomib Treatment can Overcome Glucocorticoid Resistance in Childhood B-cell Precursor Acute Lymphoblastic Leukemia Cell Lines.
abstract: BACKGROUND
  The response to initial glucocorticoid (gc) treatment is a reliable stratification factor in childhood acute lymphoblastic leukemia (ALL) and may predict the response to multi-agent chemotherapy. In a former study we detected that the valosin-containing protein (VCP, cdc48), a member of the ubiquitin proteasome degradation system (UPS), is altered in gc-resistant leukemic cells suggesting that the associated pathways might be involved in chemotherapy resistance in childhood ALL.
  
  
  METHODS
  Human B-cell precursor leukemia cell lines, gc-resistant MHH-cALL-2 and gc-sensitive MHH-cALL-3, were treated with prednisolone and various concentrations of bortezomib. Viability and apoptosis rates were determined.
  
  
  RESULTS
  Both cell lines showed a dose-dependent increase in caspase activity after bortezomib single treatment. The gc-sensitive cells showed an additive effect after combined treatment with prednisolone and bortezomib. In contrast, both cell lines showed a reduced viability and enhanced propidium iodide positivity after combined treatment as determined by flow cytometry. Western blot analyses of poly-(ADP-ribose) polymerase 1 (PARP-1) suggested that combined treatment promote necrotic cleavage of PARP-1 in gc-resistant cells. Furthermore, after prednisolone treatment the UPS associated proteins VCP and NFκB-inhibitor IκBα were differentially modulated in gc-resistant cells.
  
  
  CONCLUSIONS
  The proteasome inhibitor bortezomib seems to sensitize gc-resistant childhood ALL cells for prednisolone-induced cell death.
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Junk
authors.affiliation: Department of Pediatrics, Christian-Albrechts-University of Kiel, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Cario
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Wittner
authors.affiliation: Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: Institute for Biometry, Hannover Medical School, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Scherer
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schlegelberger
authors.affiliation: Department of Pediatrics, Christian-Albrechts-University of Kiel, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: N
authors.initials: N
authors.lastname: von Neuhoff
authors.affiliation: Department of Pediatrics, University of Lübeck, University Medical Center Schleswig-Holstein, Lübeck, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Lauten
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000069286:Bortezomib / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects*; D002648:Child; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D000072000:NF-KappaB Inhibitor alpha; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D011239:Prednisolone / Q000494:pharmacology; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D005938:Glucocorticoids; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; D011239:Prednisolone; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein