Metformin selectively affects human glioblastoma tumor-initiating cell viability: A role for metformin-induced inhibition of Akt
| Autor: | Roberto Würth, Gianluigi Zona, Antonio Daga, Alessandra Pattarozzi, Daniela Fenoglio, Alessia Parodi, Monica Gatti, Alessandro Corsaro, Michela Massollo, Rodolfo Sirito, Federica Barbieri, Cecilia Marini, Tullio Florio, Adirana Bajetto, Gilberto Filaci, Gianmario Sambuceti |
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| Rok vydání: | 2012 |
| Předmět: |
Male
cancer stem cell medicine.medical_specialty Cell Survival Cellular differentiation Cell Transplantation Heterologous Antineoplastic Agents Mice SCID Biology Mice Cancer stem cell Antigens CD Internal medicine Report medicine Tumor Cells Cultured Animals Humans AC133 Antigen Phosphorylation Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Aged Glycoproteins AMPk AKT Mesenchymal stem cell Cell Differentiation Mesenchymal Stem Cells Cell Biology Middle Aged Fetal Blood Metformin medicine.anatomical_structure Endocrinology Cancer research Neoplastic Stem Cells Female Stem cell Glioblastoma Peptides Proto-Oncogene Proteins c-akt Developmental Biology medicine.drug |
| Zdroj: | Cell cycle (Georget. Tex.) 12 (2013): 145–156. doi:10.4161/cc.23050 info:cnr-pdr/source/autori:Wuerth, Roberto; Pattarozzi, Alessandra; Gatti, Monica; Bajetto, Adriana; Corsaro, Alessandro; Parodi, Alessia; Sirito, Rodolfo; Massollo, Michela; Marini, Cecilia; Zona, Gianluigi; Fenoglio, Daniela; Sambuceti, Gianmario; Filaci, Gilberto; Daga, Antonio; Barbieri, Federica; Florio, Tullio/titolo:Metformin selectively affects human glioblastoma tumor-initiating cell viability A role for metformin-induced inhibition of Akt/doi:10.4161%2Fcc.23050/rivista:Cell cycle (Georget. Tex.)/anno:2013/pagina_da:145/pagina_a:156/intervallo_pagine:145–156/volume:12 |
| ISSN: | 1551-4005 |
| DOI: | 10.4161/cc.23050 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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