Person:
Lorente Pérez, María Del Mar

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First Name
María Del Mar
Last Name
Lorente Pérez
URI
https://hdl.handle.net/20.500.14352/76270
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Ciencias Químicas
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
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2018 - 20202
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Author: Hernández-Tiedra, Sonia × Subject: 577.2 ×

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Now showing 1 - 2 of 2
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    Targeting Glioma Initiating Cells with A combined therapy of cannabinoids and temozolomide
    (Biochemical Pharmacology, 2018) López-Valero, Israel; Saiz-Ladera, Cristina; Torres, Sofía; Hernández-Tiedra, Sonia; García-Taboada, Elena; Rodríguez-Fornés, Fátima; Barba, Marina; Dávila, David; Salvador-Tormo, Nélida; Guzmán Pastor, Manuel; Sepúlveda, Juan Manuel; Sánchez-Gómez, Pilar; Lorente Pérez, María Del Mar; Velasco Díez, Guillermo
    Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor due, at least in part, to its poor response to current anticancer treatments. These features could be explained, at least partially, by the presence within the tumor mass of a small population of cells termed Glioma Initiating Cells (GICs) that has been proposed to be responsible for the relapses occurring in this disease. Thus, the development of novel therapeutic approaches (and specifically those targeting the population of GICs) is urgently needed to improve the survival of the patients suffering this devastating disease. Previous observations by our group and others have shown that Δ9-Tetrahydrocannabinol (THC, the main active ingredient of marijuana) and other cannabinoids including cannabidiol (CBD) exert antitumoral actions in several animal models of cancer, including gliomas. We also found that the administration of THC (or of THC + CBD at a 1:1 ratio) in combination with temozolomide (TMZ), the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts. In this work we investigated the effect of the combination of TMZ and THC:CBD mixtures containing different ratios of the two cannabinoids in preclinical glioma models, including those derived from GICs. Our findings show that TMZ + THC:CBD combinations containing a higher proportion of CDB (but not TMZ + CBD alone) produce a similar antitumoral effect as the administration of TMZ together with THC and CBD at a 1:1 ratio in xenografts generated with glioma cell lines. In addition, we also found that the administration of TMZ + THC:CBD at a 1:1 ratio reduced the growth of orthotopic xenografts generated with GICs derived from GBM patients and enhanced the survival of the animals bearing these intracranial xenografts. Remarkably, the antitumoral effect observed in GICs-derived xenografts was stronger when TMZ was administered together with cannabinoid combinations containing a higher proportion of CBD. These findings support the notion that the administration of TMZ together with THC:CBD combinations – and specifically those containing a higher proportion of CBD – may be therapeutically explored to target the population of GICs in GBM.
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    Midkine signaling maintains the self-renewal and tumorigenic capacity of glioma initiating cells
    (Theranostics, 2020) López Valero, Israel; Dávila, David; González Martínez, José; Salvador-Tormo, Nélida; Lorente Pérez, María Del Mar; Saiz Ladera, Cristina; Torres Pabón, Norma Sofía; Gabicagogeascoa Corta, Estíbaliz; Hernández-Tiedra, Sonia; García Taboada, Elena; Mendiburu Eliçabe, Marina; Rodríguez Fornés, Fátima; Sánchez Domínguez, Rebeca; Segovia Martínez, Juan Carlos; Sánchez Gómez, Pilar; Matheu Fernández, Ander; Sepúlveda Salas, Juan Miguel; Velasco Díez, Guillermo
    Glioblastoma (GBM) is one of the most aggressive forms of cancer. It has been proposed that the presence within these tumors of a population of cells with stem-like features termed Glioma Initiating Cells (GICs) is responsible for the relapses that take place in the patients with this disease. Targeting this cell population is therefore an issue of great therapeutic interest in neuro-oncology. We had previously found that the neurotrophic factor MIDKINE (MDK) promotes resistance to glioma cell death. The main objective of this work is therefore investigating the role of MDK in the regulation of GICs. Methods: Assays of gene and protein expression, self-renewal capacity, autophagy and apoptosis in cultures of GICs derived from GBM samples subjected to different treatments. Analysis of the growth of GICs-derived xenografts generated in mice upon blockade of the MDK and its receptor the ALK receptor tyrosine kinase (ALK) upon exposure to different treatments. Results: Genetic or pharmacological inhibition of MDK or ALK decreases the self-renewal and tumorigenic capacity of GICs via the autophagic degradation of the transcription factor SOX9. Blockade of the MDK/ALK axis in combination with temozolomide depletes the population of GICs in vitro and has a potent anticancer activity in xenografts derived from GICs. Conclusions: The MDK/ALK axis regulates the self-renewal capacity of GICs by controlling the autophagic degradation of the transcription factor SOX9. Inhibition of the MDK/ALK axis may be a therapeutic strategy to target GICs in GBM patients.