Synergistic inhibition of tumor growth by combination treatment with drugs against different subpopulations of glioblastoma cells

Chang, Chia Hsin; Liu, Wei Ting; Hung, Hui Chi; Gean, Chia Yu; Tsai, Hann-Huei; Su, Chun Li; Gean, Po Wu

doi:10.1186/s12885-017-3924-y

Cited by 15 publications

(16 citation statements)

References 36 publications

(34 reference statements)

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“…In general, glioblastoma cells are resistant to chemotherapy and radiotherapy as well as to most apoptotic stimuli. However, there are many published papers showing sensitivity of glioma cells to certain small molecules in vitro .…”

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confidence: 99%

LAMP‐1 gene is overexpressed in high grade glioma

Sarafian

Koev²,

Mehterov

et al. 2018

APMIS

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High-grade gliomas (HGG) are the most frequent brain tumors in adults. Glioblastoma multiforme (GBM) is their most aggressive form resistant to therapy. It was shown that inhibition of autophagy reduced GBM development and autophagy interfering agents are regarded as a new strategy to fight glioma cells. The lysosome-associated membrane proteins (LAMPs) display differential expression particularly in cancer. There are few data on their expression and especially on their molecular profile. The aim of the present study is to investigate the expression of LAMP-1 and LAMP-2 genes and proteins in HGG. Newly diagnosed patients with HGG and healthy controls were examined by immunohistochemistry and qPCR for both protein and mRNA levels of LAMP-1 and LAMP-2. The transcriptional activity of LAMP-1 in HGG was significantly higher compared to normal brain and to LAMP-2. The two glycoproteins were detected in the cytosol of tumor cells with varying intensity, LAMP-1 showing again enhanced expression. In conclusion, novel data on LAMP-1 overexpression in HGG are presented suggesting involvement of this gene and protein in cell adhesion and tumor progression. These findings might help the elucidation of the complex biological role of the multifunctional LAMPs proteins and to predict novel therapeutic targets in lysosomes.

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confidence: 99%

LAMP‐1 gene is overexpressed in high grade glioma

Sarafian

Koev²,

Mehterov

et al. 2018

APMIS

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“…CD133 has been reported as a marker of human neural and brain tumor stem cells (32,33). We previously have isolated cancer stem-like cells with CD133 from glioblastoma (GBM) cell lines using magnetic bead cell sorting (34). Then CD133 + and CD133 − cell populations were collected and cultured separately.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Sonic Hedgehog Signaling Suppresses Glioma Stem-Like Cells Likely Through Inducing Autophagic Cell Death

et al. 2020

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Glioblastoma (GBM) often recurs after radio-and chemotherapies leading to poor prognosis. Glioma stem-like cells (GSCs) contribute to drug resistance and recurrence. Thus, understanding cellular mechanism underlying the growth of GSCs is critical for the treatment of GBM. Here GSCs were isolated from human U87 GBM cells with magnetic-activated cell sorting (MACS) using CD133 as a marker. The CD133 + cells highly expressed sonic hedgehog (Shh) and were capable of forming tumor spheroids in vitro and tumor in vivo. Athymic mice received intracranial injection of luciferase transduced parental and CD133 + GBM cells was utilized as orthotopic GBM model. Inhibited Shh by LDE225 delayed GBM growth in vivo, and downregulated Ptch1 and Gli1. CD133 + cell proliferation was more sensitive to inhibition by LDE225 than that of CD133 − cells. Treatment with LDE225 significantly reduced CD133 +-derived tumor spheroid formation. Large membranous vacuoles appeared in the LDE225-treated cells concomitant with the conversion of LC3-I to LC3-II. In addition, LDE225-induced cell death was mitigated in the presence of autophagy inhibitor 3-methyladenine (3-MA). Tumor growth was much slower in Shh shRNA-knockdown mice than in control RNA-transfected mice. Conversely, tumor growth was faster in Shh overexpressed mice. Furthermore, combination of LDE225 and rapamycin treatment resulted in additive effect on LC3-I to LC3-II conversion and reduction in cell viability. However, LDE225 did not affect the phosphorylated level of mTOR. Similarly, amiodarone, an mTOR-independent autophagy enhancer, reduced CD133 + cell viability and tumor spheroid formation in vitro and exhibited anti-tumor activity in vivo. These results suggest that Shh inhibitor induces autophagy of CD133 + cells likely through mTOR independent pathway. Targeting Shh signal pathway may overcome chemoresistance and provide a therapeutic strategy for patients with malignant gliomas.

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“…Both MNL and NS models might be used for drug screening purposes. They are capable of representing all tumor cell subclones, combining self-renewal and tumor growth properties (Figure 5b) [24]. To go further, we developed a concomitant 2D/3D culture that preserved the differentiated and stem-like subpopulations after 10 passages (Figure 5c).…”

Section: Discussionmentioning

confidence: 99%

Hypoxic Environment and Paired Hierarchical 3D and 2D Models of Pediatric H3.3-Mutated Gliomas Recreate the Patient Tumor Complexity

Blandin

Durand

Litzler

et al. 2019

Cancers

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Background: Pediatric high-grade gliomas (pHGGs) are facing a very dismal prognosis and representative pre-clinical models are needed for new treatment strategies. Here, we examined the relevance of collecting functional, genomic, and metabolomics data to validate patient-derived models in a hypoxic microenvironment. Methods: From our biobank of pediatric brain tumor-derived models, we selected 11 pHGGs driven by the histone H3.3K28M mutation. We compared the features of four patient tumors to their paired cell lines and mouse xenografts using NGS (next generation sequencing), aCGH (array comparative genomic hybridization), RNA sequencing, WES (whole exome sequencing), immunocytochemistry, and HRMAS (high resolution magic angle spinning) spectroscopy. We developed a multicellular in vitro model of cell migration to mimic the brain hypoxic microenvironment. The live cell technology Incucyte© was used to assess drug responsiveness in variable oxygen conditions. Results: The concurrent 2D and 3D cultures generated from the same tumor sample exhibited divergent but complementary features, recreating the patient intra-tumor complexity. Genomic and metabolomic data described the metabolic changes during pHGG progression and supported hypoxia as an important key to preserve the tumor metabolism in vitro and cell dissemination present in patients. The neurosphere features preserved tumor development and sensitivity to treatment. Conclusion: We proposed a novel multistep work for the development and validation of patient-derived models, considering the immature and differentiated content and the tumor microenvironment of pHGGs.

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Synergistic inhibition of tumor growth by combination treatment with drugs against different subpopulations of glioblastoma cells

Cited by 15 publications

References 36 publications

LAMP‐1 gene is overexpressed in high grade glioma

LAMP‐1 gene is overexpressed in high grade glioma

Inhibition of Sonic Hedgehog Signaling Suppresses Glioma Stem-Like Cells Likely Through Inducing Autophagic Cell Death

Hypoxic Environment and Paired Hierarchical 3D and 2D Models of Pediatric H3.3-Mutated Gliomas Recreate the Patient Tumor Complexity

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