title: Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1.
abstract: The variable manifestation of phenotypes that occur in patients with neurofibromatosis type 1 (NF1) includes benign and malignant neurocutaneous tumors for which no adequate treatment exists. Cell-based screening of known bioactive compounds library identified the protein phosphatase 2A (PP2A) inhibitor Cantharidin and the L-type calcium channel blocker Nifedipine as potential candidates for NF1 pharmacotherapy. Validation of screening results using human NF1-associated malignant peripheral nerve sheath tumor (MPNST) cells showed that Cantharidin effectively impeded MPNST cell growth, while Nifedipine treatment significantly decreased local tumor growth in an MPNST xenograft animal model. These data suggest that inhibitors of PP2A, as well as calcium channel blockers, might be used in broader MPNST preclinical studies as single agents or in combinatorial therapeutic strategies.
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA. Electronic address: Galina.Semenova@fccc.edu.
authors.forename: Galina
authors.initials: G
authors.lastname: Semenova
authors.affiliation: Russian National Research Medical University, Moscow, Russia; Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Dina S
authors.initials: DS
authors.lastname: Stepanova
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; National Research Tomsk Polytechnic University, Tomsk, Russia.
authors.forename: Sergey M
authors.initials: SM
authors.lastname: Deyev
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002193:Cantharidin / Q000009:adverse effects / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy; D009456:Neurofibromatosis 1; D009543:Nifedipine / Q000009:adverse effects / Q000627:therapeutic use*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D002121:Calcium Channel Blockers; D054648:Protein Phosphatase 2; D009543:Nifedipine; D002193:Cantharidin
keywords: Cantharidin; Chemical screening; Neurofibromatosis type 1; Nifedipine