title: Resistance to the atypical retinoid ST1926 in SK-N-AS cells selected the subline rAS-ST with enhanced sensitivity to ATRA mediated by not conventional mechanisms: DNA damage, G2 accumulation and late telomerase inhibition.
abstract: OBJECTIVE
  13-cis-Retinoic acid represents a well-established clinical strategy for the management of minimal residual disease of high risk neuroblastoma (NB) patients. However, the clinical efficacy on the overall survival of these patients remains limited, addressing the issue of better understanding the molecular mechanisms and intracellular pathways mediating Retinoic Acid (RA) clinical effects.
  
  
  METHODS
  This work investigates the mechanism underlying the sensitivity/resistance to RA in NB by taking advantage of the paired SK-N-AS/rAS-ST cells showing different responsivity to ATRA. The subline rAS-ST was selected by inducing resistance to the novel retinoid ST1926 in the NB SK-N-AS cell line.
  
  
  RESULTS
  Resistance to ST1926 was neither dependent on cellular uptake nor on multi-drug resistance phenotype. Rather, both delayed/lower DNA damage and apoptosis appeared involved in reduced sensitivity of rAS-ST cells to ST1926. This subline showed enhanced responsivity to ATRA compared to the wt counterpart, that was associated with enhanced RARα/β expression, DNA damage, G2 accumulation, PI3K/AKT pathway inhibition, cellular differentiation and delayed telomerase inhibition, without involvement of either p27/p53 or caspase-mediated apoptosis.
  
  
  CONCLUSIONS
  The present data add important information to the understanding of RA sensitivity in NB, providing further insights towards a more efficacious clinical use of this drug.
authors.affiliation: Division of Paediatric Oncology, Catholic University of Rome, Rome, Italy. Electronic address: angeladifrancesco@tin.it.
authors.forename: A M
authors.initials: AM
authors.lastname: Di Francesco
authors.affiliation: Division of Paediatric Oncology, Catholic University of Rome, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cusano
authors.affiliation: Department of Systems Medicine, Section of Pharmacology, University of Rome "Tor Vergata", Italy.
authors.forename: O
authors.initials: O
authors.lastname: Franzese
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Orienti
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Falconi
authors.affiliation: Research & Development, Sigma Tau, Pomezia, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Vesci
authors.affiliation: Division of Paediatric Oncology, Catholic University of Rome, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Riccardi
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology*; D020552:Comet Assay; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: C472791:3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid; D000970:Antineoplastic Agents; D002934:Cinnamates; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D051057:Proto-Oncogene Proteins c-akt; D019098:Telomerase; D000218:Adamantane
keywords: Differentiation; Neuroblastoma; Retinoic acid; ST1926; Telomerase