Identification of Mitoxantrone as a TRAIL-sensitizing agent for Glioblastoma Multiforme

Senbabaoglu, Filiz; Cingöz, Ahmet; Kaya, Emre Can; Kazancioglu, Selena; Lack, Nathan A.; Acılan, Ceyda; Bagcı-Önder, Tugba

doi:10.1080/15384047.2016.1167292

Cited by 29 publications

(37 citation statements)

References 54 publications

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“…TRAIL has entered into phase II clinical trial in non-small cell lung cancer (NCT00508625) because it has the merits of inducing apoptosis in varieties of malignant tumors sparing normal tissues [14][15][16][17][18]22]. However, these two commonly used treatments do not work for GSLCs.…”

Section: Discussionmentioning

confidence: 99%

“…TRAIL has been demonstrated to have killing effects on malignant tumors [14][15][16][17][18][19]. TRAIL receptors include death receptor 4, 5 (DR4 and DR5) and decoy receptor 1, 2 (DcR1 and DcR2).…”

mentioning

confidence: 99%

“…Because of such merits, TRAIL has long been studied as a potential anticancer drug. However, many tumor cells including GSLCs are resistant to TRAIL [14,[16][17][18]23]. Consequently, the researchers should focus on the mechanisms of TRAIL resistance and pursue a strategy to increase the sensitivity of GSLCs toward TRAIL.…”

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confidence: 99%

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Synergistic effect of TRAIL and irradiation in elimination of glioblastoma stem-like cells

et al. 2018

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Glioblastoma multiforme (GBM) is the most common malignancy in central nervous system. A small subpopulation of GBM cells known as GBM stem-like cells (GSLCs) were supposed to be the most malignant cells among GBM cells as they are resistant to multiple therapies including radiotherapy. In this study, we set up two GSLCs cell lines from the two parental U87 and U251 glioma cell lines, and studied the expression of apoptosis-related genes alteration in GSLCs before and after irradiation. We found that one of the receptors of TNF-related apoptosis-inducing ligand (TRAIL), DR5, was dramatically up-regulated in GSLCs after irradiation (IR). Although GSLCs are resistant to both TRAIL and radiation treatment alone, the combined treatment with TRAIL and irradiation achieved maximum killing effect of GSLCs due to inducing the expression of DR5 and inhibiting the expression of cFLIP. Therefore, TRAIL and IR combined treatment would be a simple but practical therapeutic strategy for clinical application.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Synergistic effect of TRAIL and irradiation in elimination of glioblastoma stem-like cells

et al. 2018

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“…MTN has been reported to have DNA-damaging effects on cancer cells [8]. MTN-induced DNA damage is known to induce the expression of the p53 protein and result in cellular apoptosis [9].…”

Section: Introductionmentioning

confidence: 99%

High Concentration of Glial Cell Line-Derived Neurotrophic Factor Protects Primary Astrocytes from Apoptosis

et al. 2018

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Background: Studies have shown that astrocytes play an important role in a variety of biological processes, so damage to astrocytes can cause a series of related diseases. Glial cell line-derived neurotrophic factor (GDNF) has always been considered a protective factor for dopamine neurons. However, it remains unclear whether GDNF has a protective effect on glial cells, especially astrocytes. In this study, we put forward the hypothesis that a high concentration of GDNF in the microenvironment of astrocytes exerts an inhibitory effect on the apoptosis of astrocytes by DNA-damaging reagents. Methods: We isolated, purified, and identified primary astrocytes from neonate rats. Astrocytes were exposed to mitoxantrone (MTN, a DNA-damaging compound) for 24 h. The effects of MTN on astrocytes were tested by Hoechst 33342 staining, CCK-8 assay, and flow cytometry assay. One of the concentrations of MTN was applied to construct an apoptotic model of astrocytes. The astrocytes were then treated with GDNF together with a selected concentration of MTN for 24 h. The cell viability, cell nucleus morphology, and apoptosis ratio of the cells was assessed by Hoechst 33342 staining, CCK-8 assay, and flow cytometry assay, respectively. RNA sequencing (RNA-Seq), quantitative PCR analysis, and KEGG pathway mapping were performed to examine the genes involved in the procedure. Finally, Western blot analysis was applied to confirm the expression levels of the proteins of interest. Results: Hoechst 33342 staining revealed a one-tenth change in the percentage of Hoechst-positive cells after the addition of 500 ng/mL GDNF combined with 1,000 nM MTN for 24 h. The viability of the cells treated the same as described above was 1.4-fold that of the control group. Flow cytometry assays indicated that the apoptotic rates were 17.67, 8.67, and 4.34% for 0, 200, and 500 ng/mL GDNF, respectively. Birc2, Birc3, and Gadd45b were linked to the antiapoptotic process induced by GDNF in astrocytes. Western blot analysis confirmed the elevated expression of Birc2 and Gadd45b. Conclusions: Our studies revealed that GDNF has a noticeable antiapoptotic effect on gene-injured astrocytes. This may provide critical clues for the treatment of a series of diseases in which damaged astrocytes are involved.

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“…Although GBMs constitute only 1% of adult cancers, these are considered as grade 4 due to the poor patient survival rate of 12–15 months . Tumor necrosis factor (TNF) α‐related apoptosis‐inducing ligand (TRAIL), or apoptosis inducing ligand 2, is a promising antitumor agent for GBM . TRAIL is a member of the TNF cytokine family secreted by mostly immune cells that can specifically induce apoptotic cell death in cancer cells rather than healthy cells .…”

Section: Introductionmentioning

confidence: 99%

Quinacrine Mediated Sensitization of Glioblastoma (GBM) Cells to TRAIL through MMP-Sensitive PEG Hydrogel Carriers

et al. 2016

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Overcoming drug resistance is a major challenge for cancer therapy. Tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) is a potent therapeutic as an activator of apoptosis, particularly in tumor but not in healthy cells. However, its efficacy is limited by the resistance of tumor cell populations to the therapeutic substance. Here, we have addressed this limitation through the development of a controlled release system, matrix-metalloproteinase (MMP)-sensitive and arg-gly-asp-ser (RGDS) peptide functionalized poly (ethylene-glycol) (PEG) particles which are synthesized via visible-light-induced water-in-water emulsion polymerization. Quinacrine (QC), a recently discovered TRAIL sensitizer drug, is loaded into the hydrogel carriers and the influence of this system on the apoptosis of a malignant type of brain cancer, glioblastoma multiforme (GBM), has been investigated in detail. The results suggest that MMP-sensitive particles are cytocompatible and superior to promote TRAIL-induced apoptosis in GBM cells when loaded with QC. Compared to QC and TRAIL alone, combination of QC-loaded PEG hydrogel and TRAIL demonstrates synergistic apoptotic inducing behavior. Furthermore, QC-loaded particles, but not QC or PEG-hydrogels alone, enhance apoptosis as is measured through expression of apoptosis-related genes. This system is promising to significantly improve the efficacy of chemotherapeutic drugs and suggests a combination treatment for GBM therapy.

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Identification of Mitoxantrone as a TRAIL-sensitizing agent for Glioblastoma Multiforme

Cited by 29 publications

References 54 publications

Synergistic effect of TRAIL and irradiation in elimination of glioblastoma stem-like cells

Synergistic effect of TRAIL and irradiation in elimination of glioblastoma stem-like cells

High Concentration of Glial Cell Line-Derived Neurotrophic Factor Protects Primary Astrocytes from Apoptosis

Quinacrine Mediated Sensitization of Glioblastoma (GBM) Cells to TRAIL through MMP-Sensitive PEG Hydrogel Carriers

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