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Could the Anti-Chaperone VER155008 Replace Temozolomide for Glioma Treatment
Leroy Shervington1, Harshada Patil1, Amal Shervington1
1Brain Tumour North West, Faculty of Science and Technology, University of Central Lancashire, Preston, PR1 2HE. UK.
Abstract:
Cancer inducible molecular chaperone HSP90 is of great importance as an anticancer target. Proteomic analysis showed that inhibiting HSP90 by the geldanamycin derivative, 17-AAG elevated the expression of the co-chaperone Hsp70. In this study we used HSP90 selective inhibitor 17-AAG and HSP70/90 dual inhibitor, VER155008 (VER) in U87-MG glioma cells. miRNAs microarray technology was used to evaluate the efficacy of these inhibitory drugs compared with temozolomide (TMZ), used as a standard treatment for glioma. Microarrays data identified 154 differentially expressed miRNAs using stringent or unstringent parameters. 16 miRNAs were overlapped between treatments, 13 upregulated and one downregulated miRNA were overlapped between TMZ and VER. The miRNA target prediction software was used for these overlapped miRNAs and identified 6 of the 13 upregulated miRNAs target methyltransferase genes. The IC50, together with Akt and HSP70 and 90 protein level data favour VER and TMZ to 17-AAG, however due to the selectivity of VER to cancer cells as a potent antichaperon, it may be more favourable to the standard TMZ.
Insights
HSP90 inhibitors, 17-AAG and VER155008 (VER), were tested in glioma cells. VER and temozolomide (TMZ) showed better efficacy, with VER potentially offering advantages due to its cancer cell selectivity.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Heat shock protein 90 (HSP90) is a crucial cancer target.
- Inhibiting HSP90 can alter co-chaperone expression, like Hsp70.
- Glioblastoma treatment involves agents like temozolomide (TMZ).
Purpose of the Study:
- To compare the efficacy of HSP90 inhibitor 17-AAG and a dual HSP70/90 inhibitor VER155008 (VER) in U87-MG glioma cells.
- To evaluate drug effects on miRNA expression compared to standard glioma treatment (TMZ).
- To identify potential therapeutic targets based on miRNA expression changes.
Main Methods:
- Utilized U87-MG glioma cells.
- Administered HSP90 inhibitor 17-AAG and dual HSP70/90 inhibitor VER155008 (VER).
- Employed miRNA microarray technology and miRNA target prediction software, comparing results with temozolomide (TMZ).
Main Results:
- Identified 154 differentially expressed miRNAs; 16 miRNAs overlapped between treatments.
- Found 13 upregulated and 1 downregulated miRNA overlapped between TMZ and VER treatments.
- Predicted that 6 of the 13 upregulated miRNAs target methyltransferase genes, with VER and TMZ showing better IC50 and protein level data than 17-AAG.
Conclusions:
- VER155008 (VER) and temozolomide (TMZ) demonstrate superior efficacy compared to 17-AAG in U87-MG glioma cells.
- VER's selectivity for cancer cells suggests it may be a favorable alternative or adjunct to TMZ.
- MiRNA expression profiling reveals potential mechanisms and targets for glioma therapy.
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