title: Metformin and Ara-a Effectively Suppress Brain Cancer by Targeting Cancer Stem/Progenitor Cells.
abstract: BACKGROUND
  Gliomas and neuroblastomas pose a great health burden worldwide with a poor and moderate prognosis, respectively. Many studies have tried to find effective treatments for these primary malignant brain tumors. Of interest, the AMP-activated protein kinase (AMPK) pathway was found to be associated with tumorigenesis and tumor survival, leading to many studies on AMPK drugs, especially Metformin, and their potential role as anti-cancer treatments. Cancer stem cells (CSCs) are a small population of slowly-dividing, treatment-resistant, undifferentiated cancer cells that are being discovered in a multitude of cancers. They are thought to be responsible for replenishing the tumor with highly proliferative cells and increasing the risk of recurrence.
  
  
  METHODS
  Metformin and 9-β-d-Arabinofuranosyl Adenine (Ara-a) were used to study the role of the AMPK pathway in vitro on U251 (glioblastoma) and SH-SY5Y (neuroblastoma) cell lines.
  
  
  RESULTS
  We found that both drugs are able to decrease the survival of U251 and SH-SY5Y cell lines in a 2D as well as a 3D culture model. Metformin and Ara-a significantly decreased the invasive ability of these cancer cell lines. Treatment with these drugs decreased the sphere-forming units (SFU) of U251 cells, with Ara-a being more efficient, signifying the extinction of the CSC population. However, if treatment is withdrawn before all SFUs are extinguished, the CSCs regain some of their sphere-forming capabilities in the case of Metformin but not Ara-a treatment.
  
  
  CONCLUSIONS
  Metformin and Ara-a have proved to be effective in the treatment of glioblastomas and neuroblastomas, in vitro, by targeting their cancer stem/progenitor cell population, which prevents recurrence.
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut Beirut, Lebanon.
authors.forename: Tarek H
authors.initials: TH
authors.lastname: Mouhieddine
authors.affiliation: Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut Beirut, Lebanon.
authors.forename: Amaly
authors.initials: A
authors.lastname: Nokkari
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut Beirut, Lebanon.
authors.forename: Muhieddine M
authors.initials: MM
authors.lastname: Itani
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut Beirut, Lebanon.
authors.forename: Farah
authors.initials: F
authors.lastname: Chamaa
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut Beirut, Lebanon.
authors.forename: Hisham
authors.initials: H
authors.lastname: Bahmad
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut Beirut, Lebanon.
authors.forename: Alissar
authors.initials: A
authors.lastname: Monzer
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut Beirut, Lebanon.
authors.forename: Rabih
authors.initials: R
authors.lastname: El-Merahbi
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut Beirut, Lebanon.
authors.forename: Georges
authors.initials: G
authors.lastname: Daoud
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut Beirut, Lebanon.
authors.forename: Assaad
authors.initials: A
authors.lastname: Eid
authors.affiliation: Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut Beirut, Lebanon.
authors.forename: Firas H
authors.initials: FH
authors.lastname: Kobeissy
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut Beirut, Lebanon.
authors.forename: Wassim
authors.initials: W
authors.lastname: Abou-Kheir
keywords: AMPK pathway; Ara-A; cancer stem cell; glioblastoma; metformin; neuroblastoma