title: Metformin inhibition of neuroblastoma cell proliferation is differently modulated by cell differentiation induced by retinoic acid or overexpression of NDM29 non-coding RNA.
abstract: BACKGROUND
  Metformin is a widely used oral hypoglycemizing agent recently proposed as potential anti-cancer drug. In this study we report the antiproliferative effect of metformin treatment in a high risk neuroblastoma cell model, focusing on possible effects associated to different levels of differentiation and/or tumor initiating potential.
  
  
  METHODS
  Antiproliferative and cytotoxic effects of metformin were tested in human SKNBE2 and SH-SY5Y neuroblastoma cell lines and in SKNBE2 cells in which differentiation is induced by retinoic acid treatment or stable overexpression of NDM29 non-coding RNA, both conditions characterized by a neuron-like differentiated phenotype.
  
  
  RESULTS
  We found that metformin significantly inhibits the proliferation of NB cells, an effect that correlates with the inhibition of Akt, while AMPK activity resulted unchanged. Notably, metformin effects were modulated in a different ways by differentiating stimuli, being abolished after retinoic acid treatment but potentiated by overexpression of NDM29.
  
  
  CONCLUSIONS
  These data suggest the efficacy of metformin as neuroblastoma anticancer agent, and support the requirement of further studies on the possible role of the differentiation status on the antiproliferative effects of this drug.
authors.affiliation: Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy ; IRCCS-AOU San Martino-IST, Genova, Italy.
authors.forename: Delfina
authors.initials: D
authors.lastname: Costa
authors.affiliation: Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy ; IRCCS-AOU San Martino-IST, Genova, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Gigoni
authors.affiliation: Internal Medicine (DIMI), University of Genova, Genova, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Würth
authors.affiliation: Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy ; IRCCS-AOU San Martino-IST, Genova, Italy.
authors.forename: Ranieri
authors.initials: R
authors.lastname: Cancedda
authors.affiliation: Internal Medicine (DIMI), University of Genova, Genova, Italy ; Center of Excellence for Biomedical Research (CEBR), University of Genova, Genova, Italy.
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.affiliation: Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy ; IRCCS-AOU San Martino-IST, Genova, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Pagano
keywords: Anti-cancer therapy; Differentiation; Metformin; NDM29 ncRNA; Neuroblastoma