Cytotoxic effect of accelerated carbon beams on glioblastoma cell lines with p53 mutation: clonogenic survival and cell-cycle analysis

Abstract Background The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ. Methods Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. Results Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. Conclusion Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.

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Differential Effects of Selective COX-2 Inhibitors on Cell Cycle Regulation and Proliferation of Glioblastoma Cell Lines

Cancer Biology & Therapy ◽

10.4161/cbt.3.1.571 ◽

2004 ◽

Vol 3 (1) ◽

pp. 55-62 ◽

Cited By ~ 58

Author(s):

Adel Kardosh ◽

Martina Blumenthal ◽

Wei Jun Wang ◽

Thomas C. Chen ◽

Axel H. Schonthal

Keyword(s):

Cell Cycle ◽

Cell Lines ◽

Cell Cycle Regulation ◽

Glioblastoma Cell ◽

Differential Effects ◽

Cox 2 ◽

Cycle Regulation ◽

Cox 2 Inhibitors ◽

Glioblastoma Cell Lines

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Moschamine inhibits proliferation of glioblastoma cells via cell cycle arrest and apoptosis

Tumor Biology ◽

10.1177/1010428317705744 ◽

2017 ◽

Vol 39 (5) ◽

pp. 101042831770574 ◽

Cited By ~ 5

Author(s):

George A Alexiou ◽

Diamanto Lazari ◽

Georgios Markopoulos ◽

Evrysthenis Vartholomatos ◽

Entela Hodaj ◽

...

Keyword(s):

Cell Cycle ◽

Flow Cytometry ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Indole Alkaloid ◽

Glioblastoma Cell ◽

Trypan Blue Exclusion ◽

Cycle Arrest ◽

Cd15 Expression ◽

Glioblastoma Cell Lines

Glioblastoma is the most common and most malignant primary brain tumor with a median survival of 15 months. Moschamine is an indole alkaloid that has a serotoninergic and cyclooxygenase inhibitory effect. In this study, we sought to determine whether moschamine could exert cytotoxic and cytostatic effects on glioma cells in vitro. Moschamine was tested for toxicity in zebrafish. We investigated the effect of moschamine on U251MG and T98G glioblastoma cell lines. Viability and proliferation of the cells were examined with trypan blue exclusion assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the xCELLigence system. Apoptosis (annexin–propidium iodide), cell cycle, and CD24/CD44/CD56/CD15 expression were tested with flow cytometry. Treatment with moschamine significantly reduced cell viability in both cell lines tested. Induction of cell death and cell cycle arrest was confirmed with flow cytometry in both cell lines. After treatment with moschamine, there was a dose-dependent decrease in CD24 and CD44 expression, whereas there was no change in CD56 and CD15 expression in T98G cell line. The zebrafish mortality on the fifth post-fertilization day was zero even for 1 mM of moschamine concentration. The treatment of glioblastoma cell lines with moschamine may represent a novel strategy for targeting glioblastoma.

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Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells

British Journal of Cancer ◽

10.1038/bjc.2012.442 ◽

2012 ◽

Vol 107 (9) ◽

pp. 1488-1497 ◽

Cited By ~ 157

Author(s):

P Liu ◽

S Brown ◽

T Goktug ◽

P Channathodiyil ◽

V Kannappan ◽

...

Keyword(s):

Cell Lines ◽

Cytotoxic Effect ◽

Glioblastoma Cell ◽

Human Glioblastoma ◽

Human Glioblastoma Cell ◽

Glioblastoma Cell Lines

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Dabigatran antagonizes growth, cell‐cycle progression, migration, and endothelial tube formation induced by thrombin in breast and glioblastoma cell lines

Cancer Medicine ◽

10.1002/cam4.857 ◽

2016 ◽

Vol 5 (10) ◽

pp. 2886-2898 ◽

Cited By ~ 12

Author(s):

Fabrizio Vianello ◽

Luisa Sambado ◽

Ashley Goss ◽

Fabrizio Fabris ◽

Paolo Prandoni

Keyword(s):

Cell Cycle ◽

Cell Lines ◽

Cell Cycle Progression ◽

Tube Formation ◽

Glioblastoma Cell ◽

Cycle Progression ◽

Endothelial Tube Formation ◽

Glioblastoma Cell Lines

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In Vitro Activity of Monofunctional Pt-II Complex Based on 8-Aminoquinoline against Human Glioblastoma

Pharmaceutics ◽

10.3390/pharmaceutics13122101 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2101

Author(s):

Valentina Coccè ◽

Isabella Rimoldi ◽

Giorgio Facchetti ◽

Emilio Ciusani ◽

Giulio Alessandri ◽

...

Keyword(s):

Cell Cycle ◽

Cell Lines ◽

Significant Activity ◽

Glioblastoma Cell ◽

Main Target ◽

Human Carcinomas ◽

A Minor ◽

Glioblastoma Cell Lines ◽

Minor Activity

A new cationic Pt(II) complex bearing 8-aminoquinoline as chelating ligand (called Pt-8AQ) was evaluated against two human carcinomas, one mesothelioma, and three glioblastoma cell lines. The in vitro comparison to the clinically approved CisPt showed a minor activity of Pt-8AQ against carcinoma and mesothelioma, whereas a significant activity of Pt-8AQ was observed on the proliferation of the three glioblastoma cell lines (U87-MG IC50 = 3.68 ± 0.69 µM; U373-MG IC50 = 11.53 ± 0.16 µM; U138-MG IC50 = 8.05 ± 0.23 µM) that was higher than that observed with the clinically approved CisPt (U87-MG IC50 = 7.27 + 1.80 µM; U373-MG IC50 = 22.69 ± 0.05 µM; U138-MG IC50 = 32.1 ± 4.44 µM). Cell cycle analysis proved that Pt-8AQ significantly affected the cell cycle pattern by increasing the apoptotic cells represented by the sub G0/G1 region related with a downregulation of p53 and Bcl-2. Moreover, an NMR investigation of Pt-8AQ interaction with 9-EtG, GSH, and Mets7 excluded DNA as the main target, suggesting a novel mechanism of action. Our study demonstrated the high stability of Pt-8AQ after incubation at 37 °C and a significant antineoplastic activity on glioblastomas. These features also make Pt-8AQ a good candidate for developing a new selective advanced cell chemotherapy approach in combination with MSCs.

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