Obesity, metabolism & miscellaneous endocrinology
Antonio C. Fuentes-Fayos 1 , Jesús M. Pérez-Gómez 1 , Miguel E. García-García 1 , Juan M. Jimenez-Vacas 1 , Julia Martín-Colom 2 , Carlos Doval-Rosa 2 , Cristóbal Blanco-Acevedo 2 , Manuel D. Gahete 1 , Justo P. Castaño 1 , Juan Solivera 2 & Raúl M. Luque 1
1Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Córdoba; Reina Sofia University Hospital (HURS), Cordoba; Department of Cell Biology, Physiology and Immunology, University of Cordoba (UCO), Córdoba; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Córdoba. [email protected]; 2Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Córdoba; Reina Sofia University Hospital (HURS), Cordoba; Neurology Service, HURS, Cordoba
Background: Glioblastomas (GBMs) remain the deadliest human brain tumors, with a poor prognosis despite years of research. Currently, standard therapeutic strategies to treat GBM are not efficient, and the overall survival is ˜14 months. Thus, the identification of new therapeutic tools to battle GBMs is crucial. In this sense, many metabolic drugs (e.g., metformin (MF) and simvastatin (SVT)) have emerged as putative antitumor agents for certain endocrine-related cancers, demonstrating antitumor effects.
Objectives: We aimed to evaluate the putative in vivo association between MF and/or SVT treatment and key clinical parameters in GBM patients, and the direct effects of MF, SVT, and their combination, on key functional endpoints and associated signaling mechanisms in GBM.
Methods: An exploratory/observational retrospective patient cohort with GBM (n=61) was analyzed. Human GBM cell lines and patient-derived GBM cells were used to measure a set of key functional parameters and signaling pathways in response to MF, SVT, and their combination.
Results: MF/SVT combination showed an association to longer overall survival in GBM patients. Moreover, MF and SVT exerted strong antitumor actions in terms of proliferation, migration, tumorsphere, VEGF secretion, and apoptosis in vitro. Remarkably, their combination further decreased these parameters. These combined actions were mediated through the modulation of key oncogenic signaling pathways (AKT/JAK-STAT/NFkB/TGFβ pathways). Interestingly, an enrichment analysis uncovered an activation of the TGFβ pathway together with the AKT inactivation after combination treatment, which might be strongly linked with induction of senescence-associated secretory phenotype and a senescence state transition.
Conclusion: Therefore, given the demonstrated clinical safety of MF and SVT, and their antitumor effects observed in GBM, our results suggest a potential therapeutic role for these drugs, especially their combination, in GBMs.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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