title: NVP-BEZ235 alone and in combination in mantle cell lymphoma: an effective therapeutic strategy.
abstract: OBJECTIVE
  Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma; the complete response rate for standard therapies in use today is 85 - 90%. NVP-BEZ235 inhibits the PI3K/Akt/mTOR signaling axis at the level of both PI3K and mTOR. In this study, we analyzed the inhibitory effects of NVP-BEZ235 on mantle cell lines and its effects in combination with enzastaurin, everolimus and perifosine.
  
  
  METHODS
  The effects of NVP-BEZ235 on cell proliferation and apoptosis were evaluated using MTT assay and flow cytometry analysis. The cell cycle analysis was performed applying BrdU incorporation. Western blot analysis was utilized for phosphorylation status evaluation of protein kinases. The interaction between NVP-BEZ235 and enzastaurin, everolimus and perifosine was examined by Chou-Talalay method.
  
  
  RESULTS
  NVP-BEZ235 induced significant increase of apoptosis, both via intrinsic and extrinsic pathways. We found that NVP-BEZ235 inhibited mantle cells growth by induction of G1 arrest. NVP-BEZ235 exerts its antitumor activity even when mantle cells were in contact with bone marrow microenvironment. Enzastaurin, everolimus and perifosine enhanced the cytotoxicity triggered by NVP-BEZ235.
  
  
  CONCLUSIONS
  The above results encourage clinical development of NVP-BEZ235 in combination and the possible inclusion of patients with mantle lymphoma in Phase I/II clinical trials.
authors.affiliation: University of Modena, 1-Program of Innovative Therapies in Oncology and Haematology, Centro Oncologico Modenese, Department of Oncology and Haematology, Largo del Pozzo 71, 41100 Modena, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Civallero
authors.forename: Maria
authors.initials: M
authors.lastname: Cosenza
authors.forename: Luigi
authors.initials: L
authors.lastname: Marcheselli
authors.forename: Samantha
authors.initials: S
authors.lastname: Pozzi
authors.forename: Stefano
authors.initials: S
authors.lastname: Sacchi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068338:Everolimus; D005434:Flow Cytometry; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D007093:Imidazoles; D007211:Indoles; D011804:Quinolines; D010767:Phosphorylcholine; C105905:perifosine; D000068338:Everolimus; D011494:Protein Kinases; C531198:dactolisib; C504878:enzastaurin; D020123:Sirolimus