title: In vitro anti-neuroblastoma activity of saquinavir and its association             with imatinib.
abstract: Neuroblastoma (NB) has a poor prognosis when in advanced stages, highlighting             the need for new therapeutic options. The human immunodeficiency virus (HIV) protease             inhibitor saquinavir is active in vitro against chronic myeloid leukaemia cells,             in synergy with the tyrosine kinase inhibitor imatinib. Here, we evaluated the             effects of saquinavir, alone or in association with imatinib, on cell proliferation             (count of viable cells after trypan blue exclusion), apoptosis (Annexin V binding)             and invasion (through a transwell membrane coated with Matrigel) in SJ-N-KP, IMR5,             AF-8, SK-N-SH and SK-N-BE NB lines, all expressing c-kit and PDGF-R (determined             by flow cytometry). Saquinavir showed a dose-dependent anti-proliferative and             anti-invasive activity on NB lines, increased by the association with imatinib             when the two drugs were utilized at clinically attainable concentrations. The             same low saquinavir concentrations inhibited in NB cells the nuclear activation             of NF-κB (Western immuno-blotting for nuclear NF-κB p50 and p65). Saquinavir at             high concentrations also exerted a pro-apoptotic activity on NB lines, significantly             increased by the association with imatinib. In conclusion, saquinavir and imatinib             are both drugs utilized for long-term therapies, with good oral bioavailability             and a well-known toxicity profile. The anti-NB activity of saquinavir and of its             association with imatinib suggests a potential usefulness in the treatment of             NB, particularly for remission maintenance.
authors.affiliation: Paediatric Haematology-Oncology, Regina Margherita Children's Hospital, and Department of Paediatrics, University of Turing, Piazza Polonia 94, I-10126 Turin, Italy. fabio.timeus@unito.it
authors.forename: Fabio
authors.initials: F
authors.lastname: Timeus
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Crescenzio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Doria
authors.forename: Luiselda
authors.initials: L
authors.lastname: Foglia
authors.forename: Sara
authors.initials: S
authors.lastname: Pagliano
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ricotti
authors.forename: Franca
authors.initials: F
authors.lastname: Fagioli
authors.forename: Pier Angelo
authors.initials: PA
authors.lastname: Tovo
authors.forename: Luca
authors.initials: L
authors.lastname: Cordero di Montezemolo
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D019258:Saquinavir / Q000008:administration & dosage
chemical_list: D001549:Benzamides; D016328:NF-kappa B; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019258:Saquinavir