title: Metformin selectively affects human glioblastoma tumor-initiating cell viability: A role for metformin-induced inhibition of Akt.
abstract: Cancer stem cell theory postulates that a small population of tumor-initiating cells is responsible for the development, progression and recurrence of several malignancies, including glioblastoma. In this perspective, tumor-initiating cells represent the most relevant target to obtain effective cancer treatment. Metformin, a first-line drug for type II diabetes, was reported to possess anticancer properties affecting the survival of cancer stem cells in breast cancer models. We report that metformin treatment reduced the proliferation rate of tumor-initiating cell-enriched cultures isolated from four human glioblastomas. Metformin also impairs tumor-initiating cell spherogenesis, indicating a direct effect on self-renewal mechanisms. Interestingly, analyzing by FACS the antiproliferative effects of metformin on CD133-expressing subpopulation, a component of glioblastoma cancer stem cells, a higher reduction of proliferation was observed as compared with CD133-negative cells, suggesting a certain degree of cancer stem cell selectivity in its effects. In fact, glioblastoma cell differentiation strongly reduced sensitivity to metformin treatment. Metformin effects in tumor-initiating cell-enriched cultures were associated with a powerful inhibition of Akt-dependent cell survival pathway, while this pathway was not affected in differentiated cells. The specificity of metformin antiproliferative effects toward glioblastoma tumor-initiating cells was confirmed by the lack of significant inhibition of normal human stem cells (umbilical cord-derived mesenchymal stem cells) in vitro proliferation after metformin exposure. Altogether, these data clearly suggest that metformin exerts antiproliferative activity on glioblastoma cells, showing a higher specificity toward tumor-initiating cells, and that the inhibition of Akt pathway may represent a possible intracellular target of this effect.
authors.affiliation: Department of Internal Medicine, University of Genova, Genoa, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Würth
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pattarozzi
authors.forename: Monica
authors.initials: M
authors.lastname: Gatti
authors.forename: Adirano
authors.initials: A
authors.lastname: Bajetto
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corsaro
authors.forename: Alessia
authors.initials: A
authors.lastname: Parodi
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Sirito
authors.forename: Michela
authors.initials: M
authors.lastname: Massollo
authors.forename: Cecilia
authors.initials: C
authors.lastname: Marini
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zona
authors.forename: Daniela
authors.initials: D
authors.lastname: Fenoglio
authors.forename: Gianmario
authors.initials: G
authors.lastname: Sambuceti
authors.forename: Gilberto
authors.initials: G
authors.lastname: Filaci
authors.forename: Antonio
authors.initials: A
authors.lastname: Daga
authors.forename: Federica
authors.initials: F
authors.lastname: Barbieri
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
mesh_terms: D000071916:AC133 Antigen; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D008687:Metformin / Q000627:therapeutic use / Q000633:toxicity*; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D008687:Metformin; D051057:Proto-Oncogene Proteins c-akt