Metformin and simvastatin exert additive antitumour effects in glioblastoma via senescence-state: clinical and translational evidence.

Autor:	Fuentes-Fayos AC; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain. Electronic address: b22fufaa@uco.es., G-García ME; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., Pérez-Gómez JM; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., Montero-Hidalgo AJ; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., Martín-Colom J; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Department of Neurosurgery, Reina Sofia University Hospital, 14004, Cordoba, Spain., Doval-Rosa C; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Department of Neurosurgery, Reina Sofia University Hospital, 14004, Cordoba, Spain., Blanco-Acevedo C; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Department of Neurosurgery, Reina Sofia University Hospital, 14004, Cordoba, Spain., Torres E; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., Toledano-Delgado Á; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Department of Neurosurgery, Reina Sofia University Hospital, 14004, Cordoba, Spain., Sánchez-Sánchez R; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Pathology Service, Reina Sofia University Hospital, 14004, Cordoba, Spain., Peralbo-Santaella E; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Flow Cytometry Unit, Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), 14004, Cordoba, Spain., Ortega-Salas RM; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Pathology Service, Reina Sofia University Hospital, 14004, Cordoba, Spain., Jiménez-Vacas JM; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., Tena-Sempere M; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., López M; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain; NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain., Castaño JP; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., Gahete MD; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., Solivera J; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Department of Neurosurgery, Reina Sofia University Hospital, 14004, Cordoba, Spain., Luque RM; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Cordoba, Spain; Department of Cell Biology, Physiology, Immunology, University of Cordoba, 14004, Cordoba, Spain; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain. Electronic address: raul.luque@uco.es.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2023 Apr; Vol. 90, pp. 104484. Date of Electronic Publication: 2023 Mar 10.
DOI:	10.1016/j.ebiom.2023.104484
Abstrakt:	Background: Glioblastoma is one of the most devastating and incurable cancers due to its aggressive behaviour and lack of available therapies, being its overall-survival from diagnosis ∼14-months. Thus, identification of new therapeutic tools is urgently needed. Interestingly, metabolism-related drugs (e.g., metformin/statins) are emerging as efficient antitumour agents for several cancers. Herein, we evaluated the in vitro/in vivo effects of metformin and/or statins on key clinical/functional/molecular/signalling parameters in glioblastoma patients/cells. Methods: An exploratory-observational-randomized retrospective glioblastoma patient cohort (n = 85), human glioblastoma/non-tumour brain human cells (cell lines/patient-derived cell cultures), mouse astrocytes progenitor cell cultures, and a preclinical xenograft glioblastoma mouse model were used to measure key functional parameters, signalling-pathways and/or antitumour progression in response to metformin and/or simvastatin. Findings: Metformin and simvastatin exerted strong antitumour actions in glioblastoma cell cultures (i.e., proliferation/migration/tumoursphere/colony-formation/VEGF-secretion inhibition and apoptosis/senescence induction). Notably, their combination additively altered these functional parameters vs. individual treatments. These actions were mediated by the modulation of key oncogenic signalling-pathways (i.e., AKT/JAK-STAT/NF-κB/TGFβ-pathways). Interestingly, an enrichment analysis uncovered a TGFβ-pathway activation, together with AKT inactivation, in response to metformin + simvastatin combination, which might be linked to an induction of the senescence-state, the associated secretory-phenotype, and to the dysregulation of spliceosome components. Remarkably, the antitumour actions of metformin + simvastatin combination were also observed in vivo [i.e., association with longer overall-survival in human, and reduction in tumour-progression in a mouse model (reduced tumour-size/weight/mitosis-number, and increased apoptosis)]. Interpretation: Altogether, metformin and simvastatin reduce aggressiveness features in glioblastomas, being this effect significantly more effective (in vitro/in vivo) when both drugs are combined, offering a clinically relevant opportunity that should be tested for their use in humans. Funding: Spanish Ministry of Science, Innovation and Universities; Junta de Andalucía; CIBERobn (CIBER is an initiative of Instituto de Salud Carlos III, Spanish Ministry of Health, Social Services and Equality). Competing Interests: Declaration of interests The authors declare that no-competing financial and/or non-financial interests concerning the work exist. (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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