title: Nelfinavir inhibits proliferation and induces DNA damage in thyroid cancer cells.
abstract: The HIV protease inhibitor Nelfinavir (NFV) inhibits PI3K/AKT and MAPK/ERK signaling pathways, emerging targets in thyroid cancers. We examined the effects of NFV on cancer cells that derived from follicular (FTC), papillary (PTC) and anaplastic (ATC) thyroid cancers. NFV (1-20 µM) was tested in FTC133, BCPAP and SW1736 cell lines. The effects of NFV on cell proliferation were determinedin vitrousing real-time microscopy and by flow cytometry. DNA damage, apoptotic cell death and expression of molecular markers of epithelial-mesenchymal transition (EMT) were determined by Western blot and real-time PCR. Real-time imaging demonstrated that NFV (10 µM) increased the time required for the cell passage through the phases of cell cycle and induced DNA fragmentation. Growth inhibitory effects of NFV were associated with the accumulation of cells in G0/G1 phase, downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4). NFV also induced the expression of γH2AX and p53BP1 indicating DNA damage. Treatment with NFV (20 µM) resulted in caspase-3 cleavage in all examined cells. NFV (20 µM) decreased the levels of total and p-AKT in PTEN-deficient FTC133 cells. NFV had no significant effects on total ERK and p-ERK in BRAF-positive BCPAP and SW1736 cells. NFV had no effects on the expression of EMT markers (Twist, Vimentin, E- and N-Cadherin), but inhibited the migration and decreased the abilities of thyroid cancer cells to survive in non-adherent conditions. We conclude that NFV inhibits proliferation and induces DNA damage in thyroid cancer cell lines. Ourin vitrodata suggest that NFV has a potential to become a new thyroid cancer therapeutic agent.
authors.affiliation: Department of PediatricsUniformed Services University of the Health Sciences, Bethesda, Maryland, USA kirk.jensen@usuhs.edu.
authors.forename: Kirk
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Department of Internal MedicineGeorgetown University Hospital MedStar, Washington Hospital Center Internal Medicine Residency Program, Washington, District of Columbia, USA.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Bikas
authors.affiliation: Department of PediatricsUniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Aneeta
authors.initials: A
authors.lastname: Patel
authors.affiliation: National Institutes of HealthNIDDK, Bethesda, Maryland, USA.
authors.forename: Yevgeniya
authors.initials: Y
authors.lastname: Kushchayeva
authors.affiliation: Department of PediatricsUniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: John
authors.initials: J
authors.lastname: Costello
authors.affiliation: Uniformed Services University of the Health SciencesBiomedical Instrumentation Center, Bethesda, Maryland, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: McDaniel
authors.affiliation: MedStar Washington Hospital CenterEndocrinology, Washington, District of Columbia, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Burman
authors.affiliation: Department of PediatricsUniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Vasyl
authors.initials: V
authors.lastname: Vasko
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D019888:Nelfinavir / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D017320:HIV Protease Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019888:Nelfinavir
keywords: carcinoma; thyroid