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- Title
Therapeutic potential of the metabolic modulator Metformin on osteosarcoma cancer stem-like cells.
- Authors
Paiva-Oliveira, Daniela I.; Martins-Neves, Sara R.; Abrunhosa, Antero J.; Fontes-Ribeiro, Carlos; Gomes, Célia M. F.
- Abstract
<bold>Purpose: </bold>Osteosarcoma is the most common primary bone tumour appearing in children and adolescents. Recent studies demonstrate that osteosarcoma possesses a stem-like cell subset, so-called cancer stem-like cells, refractory to conventional chemotherapeutics and pointed out as responsible for relapses frequently observed in osteosarcoma patients. Here, we explored the therapeutic potential of Metformin on osteosarcoma stem-like cells, alone and as a chemosensitizer of doxorubicin.<bold>Methods: </bold>Stem-like cells were isolated from human osteosarcoma cell lines, MNNG/HOS and MG-63, using the sphere-forming assay. Metformin cytotoxicity alone and combined with doxorubicin were evaluated using MTT/BrdU assays. Protein levels of AMPK and AKT were evaluated by Western Blot. Cellular metabolic status was assessed based on [18F]-FDG uptake and lactate production measurements. Sphere-forming efficiency and expression of pluripotency transcription factors analysed by qRT-PCR were tested as readout of Metformin effects on stemness features.<bold>Results: </bold>Metformin induced a concentration-dependent decrease in the metabolic activity and proliferation of sphere-forming cells and improved doxorubicin-induced cytotoxicity. This drug also down-regulated the expression of master regulators of pluripotency (OCT4, SOX2, NANOG), and decreased spheres' self-renewal ability. Metformin effects on mitochondria led to the activation and phosphorylation of the energetic sensor AMPK along with an upregulation of the pro-survival AKT pathway in both cell populations. Furthermore, Metformin-induced mitochondrial stress increased [18F]-FDG uptake and lactate production in parental cells but not in the quiescent stem-like cells, suggesting the inability of the latter to cope with the energy crisis induced by metformin.<bold>Conclusions: </bold>This preclinical study suggests that Metformin may be a potentially useful therapeutic agent and chemosensitizer of osteosarcoma stem-like cells to doxorubicin.
- Subjects
OSTEOSARCOMA; BONE tumors; CANCER stem cells; DOXORUBICIN; PHOSPHORYLATION; THERAPEUTICS; ANTINEOPLASTIC antibiotics; CELL lines; CELL physiology; CELLULAR signal transduction; COMPARATIVE studies; DRUG synergism; ENERGY metabolism; RESEARCH methodology; MEDICAL cooperation; MITOCHONDRIA; POLYMERASE chain reaction; RESEARCH; RESEARCH funding; STEM cells; TRANSCRIPTION factors; TRANSFERASES; EVALUATION research; METFORMIN; REVERSE transcriptase polymerase chain reaction; PHARMACODYNAMICS
- Publication
Cancer Chemotherapy & Pharmacology, 2018, Vol 81, Issue 1, p49
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-017-3467-6