Efficacy of rapamycin against glioblastoma cancer stem cells

Mendiburu-Eliçabe, Marina; Gil-Ranedo, Jon; Izquierdo, Marta López

doi:10.1007/s12094-013-1109-y

Cited by 35 publications

(28 citation statements)

References 30 publications

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“…Luciferase-transfected U87MG cells were kindly provided by Jari E. Heikkila, Department of Biochemistry and Pharmacy, Abo Akademi University, Turku, Finland. Six GBM patient-derived stem cell lines (BT12M, BT25M, BT48EF, BT50EF, BT53M), kindly provided by J. Gregory Cairncross and Samuel Weiss (Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada) [ 28 ] and GSCs-5 and CSCs-7 [ 29 ] from Marta Izquierdo (Departamento de Biología Molecular, Universidad Autónoma de Madrid, Spain) were maintained as neurosphere cultures in Neurocult medium (Stem Cell Technologies, Vancouver, BC, Canada) supplemented with epidermal growth factor (20 ng/ml) and fibroblast growth factor (10 ng/ml). GSCs-5 cells were transfected with pGL4.13 vector (Promega Italia, Milan) using jetPEI (Polyplus) to create a stable luciferase expression clone selected by limited dilution.…”

Section: Methodsmentioning

confidence: 99%

The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma

et al. 2018

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BackgroundThe use of alkylating agents such as temozolomide in association with radiotherapy (RT) is the therapeutic standard of glioblastoma (GBM). This regimen modestly prolongs overall survival, also if, in light of the still dismal prognosis, further improvements are desperately needed, especially in the patients with O6-methylguanine-DNA-methyltransferase (MGMT) unmethylated tumors, in which the benefit of standard treatment is less. Tinostamustine (EDO-S101) is a first-in-class alkylating deacetylase inhibitor (AK-DACi) molecule that fuses the DNA damaging effect of bendamustine with the fully functional pan-histone deacetylase (HDAC) inhibitor, vorinostat, in a completely new chemical entity.MethodsTinostamustine has been tested in models of GBM by using 13 GBM cell lines and seven patient-derived GBM proliferating/stem cell lines in vitro. U87MG and U251MG (MGMT negative), as well as T98G (MGMT positive), were subcutaneously injected in nude mice, whereas luciferase positive U251MG cells and patient-derived GBM stem cell line (CSCs-5) were evaluated the orthotopic intra-brain in vivo experiments.ResultsWe demonstrated that tinostamustine possesses stronger antiproliferative and pro-apoptotic effects than those observed for vorinostat and bendamustine alone and similar to their combination and irrespective of MGMT expression. In addition, we observed a stronger radio-sensitization of single treatment and temozolomide used as control due to reduced expression and increased time of disappearance of γH2AX indicative of reduced signal and DNA repair. This was associated with higher caspase-3 activation and reduction of RT-mediated autophagy. In vivo, tinostamustine increased time-to-progression (TTP) and this was additive/synergistic to RT. Tinostamustine had significant therapeutic activity with suppression of tumor growth and prolongation of DFS (disease-free survival) and OS (overall survival) in orthotopic intra-brain models that was superior to bendamustine, RT and temozolomide and showing stronger radio sensitivity.ConclusionsOur data suggest that tinostamustine deserves further investigation in patients with glioblastoma.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0576-6) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma

et al. 2018

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“…As GBM cells typically express p53 with a wild-type amino acid sequence, the re-activation of p53 functionality can be restored through the inhibition of the oncogenic block exerted by the AKT/mTOR pathway, which causes an excessive stimulation of MDM2. In this respect, while agents inhibiting either the AKT/mTOR pathway 13 14 15 or the MDM2/p53 interaction 16 17 18 have provided some survival benefit in GBM, the effects of a co-therapy have not been deeply investigated to date, either in GBMs or in their stem cells. In acute myeloid leukaemia, the PI3K/mTOR inhibitor PI-103 acts synergistically with the MDM2 inhibitor nutlin-3 to induce apoptosis in a wild-type p53-dependent fashion 19 , supporting the aforementioned mechanistic rationale.…”

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confidence: 99%

Combined inhibition of AKT/mTOR and MDM2 enhances Glioblastoma Multiforme cell apoptosis and differentiation of cancer stem cells

Daniele

Costa

Zappelli

et al. 2015

Sci Rep

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The poor prognosis of Glioblastoma Multiforme (GBM) is due to a high resistance to conventional treatments and to the presence of a subpopulation of glioma stem cells (GSCs). Combination therapies targeting survival/self-renewal signals of GBM and GSCs are emerging as useful tools to improve GBM treatment. In this context, the hyperactivated AKT/mammalian target of the rapamycin (AKT/mTOR) and the inhibited wild-type p53 appear to be good candidates. Herein, the interaction between these pathways was investigated, using the novel AKT/mTOR inhibitor FC85 and ISA27, which re-activates p53 functionality by blocking its endogenous inhibitor murine double minute 2 homologue (MDM2). In GBM cells, FC85 efficiently inhibited AKT/mTOR signalling and reactivated p53 functionality, triggering cellular apoptosis. The combined therapy with ISA27 produced a synergic effect on the inhibition of cell viability and on the reactivation of p53 pathway. Most importantly, FC85 and ISA27 blocked proliferation and promoted the differentiation of GSCs. The simultaneous use of these compounds significantly enhanced GSC differentiation/apoptosis. These findings suggest that FC85 actively enhances the downstream p53 signalling and that a combination strategy aimed at inhibiting the AKT/mTOR pathway and re-activating p53 signalling is potentially effective in GBM and in GSCs.

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“…The subcellular scale parameters, i.e., the production and degradation constants, are calibrated with the Western blot experiments from the literature using densitometric analysis [43–50]. …”

Section: Numerical Implementationmentioning

confidence: 99%

A fully coupled space–time multiscale modeling framework for predicting tumor growth

Rahman

Feng

Yankeelov

et al. 2017

Computer Methods in Applied Mechanics and Engineering

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Most biological systems encountered in living organisms involve highly complex heterogeneous multi-component structures that exhibit different physical, chemical, and biological behavior at different spatial and temporal scales. The development of predictive mathematical and computational models of multiscale events in such systems is a major challenge in contemporary computational biomechanics, particularly the development of models of growing tumors in humans. The aim of this study is to develop a general framework for tumor growth prediction by considering major biological events at tissue, cellular, and subcellular scales. The key to developing such multiscale models is how to bridge spatial and temporal scales that range from 10−3 to 103 mm in space and from 10−6 to 107 s in time. In this paper, a fully coupled space–time multiscale framework for modeling tumor growth is developed. The framework consists of a tissue scale model, a model of cellular activities, and a subcellular transduction signaling pathway model. The tissue, cellular, and subcellular models in this framework are solved using partial differential equations for tissue growth, agent-based model for cellular events, and ordinary differential equations for signaling transduction pathway as a network at subcellular scale. The model is calibrated using experimental observations. Moreover, this model is biologically-driven from a signaling pathway, volumetrically-consistent between cellular and tissue scale in terms of tumor volume evolution in time, and a biophysically-sound tissue model that satisfies all conservation laws. The results show that the model is capable of predicting major characteristics of tumor growth such as the morphological instability, growth patterns of different cell phenotypes, compact regions of the higher cell density at the tumor region, and the reduction of growth rate due to drug delivery. The predicted treatment outcomes show a reduction in proliferation at different rates in response to different drug dosages. Moreover, the results of several 3D applications to tumor growth and the evolution of cellular and subcellular events are presented.

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Efficacy of rapamycin against glioblastoma cancer stem cells

Abstract: We report the efficacy of rapamycin by reducing CSCs proliferation and tumorigenic potential in vitro. Despite these encouraging results, the efficacy in vivo was very poor. This finding confirms the limited use of rapamycin as a monotherapy for glioblastomas.

Cited by 35 publications

References 30 publications

The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma

The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma

Combined inhibition of AKT/mTOR and MDM2 enhances Glioblastoma Multiforme cell apoptosis and differentiation of cancer stem cells

A fully coupled space–time multiscale modeling framework for predicting tumor growth

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