Metformin Treatment Inhibits Motility and Invasion of Glioblastoma Cancer Cells

Hassan, Marwa Al; Fakhoury, Isabelle; Masri, Zeinab El; Ghazale, Noura; Dennaoui, Rayane; Atat, Oula El; Kanaan, Amjad; El‐Sibai, Mirvat

doi:10.1155/2018/5917470

Cited by 32 publications

(25 citation statements)

References 52 publications

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“…This has encouraged clinical development, and several trials are ongoing (ClinicalTrials.gov Identifiers: NCT03243851, NCT02780024, NCT01430351, and NCT02149459). A further potential benefit of metformin treatment is a reduction in GBM cell invasion [62,63], one of the consequences of tumor hypoxia.…”

Section: Discussionmentioning

confidence: 99%

An Experimentally Defined Hypoxia Gene Signature in Glioblastoma and Its Modulation by Metformin

Tardón

Marinari

Migliorini³

et al. 2020

Biology

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Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, characterized by a high degree of intertumoral heterogeneity. However, a common feature of the GBM microenvironment is hypoxia, which can promote radio- and chemotherapy resistance, immunosuppression, angiogenesis, and stemness. We experimentally defined common GBM adaptations to physiologically relevant oxygen gradients, and we assessed their modulation by the metabolic drug metformin. We directly exposed human GBM cell lines to hypoxia (1% O2) and to physioxia (5% O2). We then performed transcriptional profiling and compared our in vitro findings to predicted hypoxic areas in vivo using in silico analyses. We observed a heterogenous hypoxia response, but also a common gene signature that was induced by a physiologically relevant change in oxygenation from 5% O2 to 1% O2. In silico analyses showed that this hypoxia signature was highly correlated with a perinecrotic localization in GBM tumors, expression of certain glycolytic and immune-related genes, and poor prognosis of GBM patients. Metformin treatment of GBM cell lines under hypoxia and physioxia reduced viable cell number, oxygen consumption rate, and partially reversed the hypoxia gene signature, supporting further exploration of targeting tumor metabolism as a treatment component for hypoxic GBM.

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Section: Discussionmentioning

confidence: 99%

An Experimentally Defined Hypoxia Gene Signature in Glioblastoma and Its Modulation by Metformin

Tardón

Marinari

Migliorini³

et al. 2020

Biology

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“…Phase-contrast images of the wounded area were captured at 0 and 72 h after wounding. Wound widths were measured at 11 different points for each wound, and the average rate of wound closure was calculated (in μm/h) (described in [49,50]). The assay was done using infinity-corrected optics on a Zeiss Observer Z1 microscope supplemented with a computer-driven Roper cooled CCD camera and operated by Zen software (Zeiss).…”

Section: Methodsmentioning

confidence: 99%

Human Recombinant Arginase I [HuArgI (Co)-PEG5000]-Induced Arginine Depletion Inhibits Colorectal Cancer Cell Migration and Invasion

Al-Koussa

Haddad

Abi-Habib

et al. 2019

IJMS

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Purpose: Colorectal cancer (CRC) is the third most common type of cancer worldwide, and it represents over half of all gastrointestinal cancer deaths. Knowing that cancer cells have a high proliferation rate, they require high amounts of amino acids, including arginine. In addition, several tumor types have been shown to downregulate ASS-1 expression, becoming auxotrophic for arginine. Therefore, Arginine deprivation is one of the promising therapeutic approaches to target cancer cells. This can be achieved through the use of a recombinant human arginase, HuArgI(Co)-PEG5000, an arginine degrading enzyme. Methods: In this present study, the cytotoxic effect of HuArgI(Co)-PEG5000 on CRC cell lines (HT-29, Caco-2, Sw837) is examined though cytotoxicity assays. Wound healing assays, invasion assays, and adhesion assays were also performed to detect the effect on metastasis. Results: Wound healing and invasion assays revealed a decrease in cell migration and invasion after treatment with arginase. Cells that were treated with arginase also showed a decrease in adhesion, which coincided with a decrease in RhoA activation, demonstrated though the use of a FRET biosensor to detect RhoA activation in a single cell assay, and a decrease in MMP-9 expression. Treating cells with both arginase and L-citrulline, which significantly restores intracellular arginine levels, reversed the effect of HuArgI(Co)-PEG5000 on cell viability, migration, and invasion. Conclusion: We can, therefore, conclude that colorectal cancer is partially auxotrophic to arginine and that arginine depletion is a potential selective inhibitory approach for motility and invasion in colon cancer cells.

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“…Repurposing drugs, including anti-depressants, anti-convulsants, anti-hypertensives, statins, singly or in combination for the treatment of GB was recently reviewed [109] with positive effects. The understanding of the regulation of the RAS and CSCs in GB, in particular the expression and function of cathepsin B [110] and the IGF/IGFR-1 pathway [111], leads us to propose modulating the RAS, a singular systemic homeostatic pathway, using a combination of drugs (Figure 1), to simultaneously inhibit key steps of the RAS, its bypass loops and crosstalk signaling pathways interacting with the RAS. This may offer a novel therapeutic approach for patients with GB [76] to potentially increase overall survival while preserving their quality of life and avoiding drug toxicities.…”

Section: Repurposing Drugs That Target the Rasmentioning

confidence: 99%

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-Angiotensin System

Tan

Roth

Wickremesekera

et al. 2019

Cells

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Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection and adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs can be identified by embryonic stem cell markers, express components of the renin-angiotensin system (RAS) and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB patients rarely develop distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the RAS to improve overall symptom-free survival and maintain quality of life.

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Metformin Treatment Inhibits Motility and Invasion of Glioblastoma Cancer Cells

Cited by 32 publications

References 52 publications

An Experimentally Defined Hypoxia Gene Signature in Glioblastoma and Its Modulation by Metformin

An Experimentally Defined Hypoxia Gene Signature in Glioblastoma and Its Modulation by Metformin

Human Recombinant Arginase I [HuArgI (Co)-PEG5000]-Induced Arginine Depletion Inhibits Colorectal Cancer Cell Migration and Invasion

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-Angiotensin System

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