title: Efficacy and selectivity of nilotinib on NF1-associated tumors in vitro.
abstract: Neurofibromatosis type 1 is a tumor suppressor gene disorder which predisposes patients to cutaneous neurofibromas, plexiform neurofibromas (PNFs) and malignant peripheral nerve sheath tumors (MPNSTs) among other neoplasias and manifestation. In this study, we examined the efficiency of nilotinib on PNF-derived Schwann cells and on cells of established MPNST lines in vitro. Nilotinib treatment for 10 days led to decreased proliferation, viability and vitality of the cells with 50 % inhibitory concentration (IC50) for proliferation varying from 3.1 to 9.0 μM. We further addressed selectivity of the drug for tumor cells by simultaneously examining its efficacy on tumor cells (Schwann cells) and non-tumor cells (fibroblasts) from the same tumor. For four out of the six PNFs studied, IC50 was lower in Schwann cells than in fibroblasts for all parameters measured (proliferation, vitality and viability), indicating good drug selectivity. In addition, nilotinib induced apoptosis and suppressed collagenase activity. Our results suggest that nilotinib may provide a treatment option for some PNFs and MPNSTs and our in vitro model of comparative treatment on tumor and non-tumor cells may provide a prototype of preclinical drug screening system toward personalized treatment.
authors.affiliation: Laboratory for Tumor Genetics, Department of Neurology, University Medical Center Hamburg-Eppendorf, Building O48, 4th Floor, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Claudia
authors.initials: C
authors.lastname: Schnabel
authors.forename: Melanie
authors.initials: M
authors.lastname: Spyra
authors.forename: Victor-F
authors.initials: VF
authors.lastname: Mautner
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Friedrich
authors.forename: Christian
authors.initials: C
authors.lastname: Hagel
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Lan
authors.initials: L
authors.lastname: Kluwe
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D017364:Collagenases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D018317:Nerve Sheath Neoplasms / Q000235:genetics* / Q000473:pathology*; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D012583:Schwann Cells / Q000187:drug effects; D018800:Thy-1 Antigens / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D017304:Annexin A5; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D018800:Thy-1 Antigens; D017364:Collagenases; C498826:nilotinib