title: The dual kinase inhibitor NVP-BEZ235 in combination with cytotoxic drugs exerts anti-proliferative activity towards acute lymphoblastic leukemia cells.
abstract: BACKGROUND
  Inhibition of signal transduction pathways has been successfully introduced into cancer treatment. The dual phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 has antitumor activity in vitro against solid tumors. Here, we examined the activity of NVP-BEZ235 in acute lymphoblastic leukemia (ALL) cells and the best modalities for combination approaches.
  
  
  METHODS
  ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were treated with NVP-BEZ235 alone, or in combination with cytarabine (AraC), doxorubicin (Doxo) or dexamethasone (Dexa).
  
  
  RESULTS
  NVP-BEZ235 potently inhibited the proliferation and metabolic activity of ALL cells. Antiproliferative effects were associated with G(0)/G(1) arrest and reduced levels of cyclin-dependent kinase 4 (CDK4) and cyclin D3. Inhibition of PI3K and mTOR activity was detected at 10 and 100 nM. NVP-BEZ235 combined with AraC, Doxo or Dexa synergistically enhanced the cytotoxicity compared to single-drug treatment, even in glucocorticoid-resistant cells.
  
  
  CONCLUSIONS
  NVP-BEZ235 displays pronounced antiproliferative effects in ALL cells and might therefore be a useful drug in the treatment of ALL.
authors.affiliation: University of Rostock, Division of Medicine, Department of Hematology, Oncology and Palliative Medicine, Ernst Heydemann Str. 6, 18057 Rostock, Germany.
authors.forename: Catrin
authors.initials: C
authors.lastname: Schult
authors.forename: Meike
authors.initials: M
authors.lastname: Dahlhaus
authors.forename: Aenne
authors.initials: A
authors.lastname: Glass
authors.forename: Kristin
authors.initials: K
authors.lastname: Fischer
authors.forename: Sandra
authors.initials: S
authors.lastname: Lange
authors.forename: Mathias
authors.initials: M
authors.lastname: Freund
authors.forename: Christian
authors.initials: C
authors.lastname: Junghanss
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D019169:Jurkat Cells; D015448:Leukemia, B-Cell / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D003561:Cytarabine; D003907:Dexamethasone; D004317:Doxorubicin; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib