Ozgiray, Erkin; Sogutlu, Fatma; Biray Avci, Cigir published the artcile< Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide>, Safety of (9Z,12Z)-Methyl octadeca-9,12-dienoate, the main research area is AZD7762; DNA damage response; IDH-mutant glioma; Polploidy; Temozolomide.
Abstract: The IDH mutation initially exhibits chemosensitive properties, progression-free survival cannot be achieved in the later grades, and malignant transformation occurs as a result of TMZ-induced hypermutation profile and adaptation to this profile. In this study, we evaluated the potential of the combination of TMZ and AZD7762 at mol. level, to increase the anticancer activity of TMZ in IDH-mutant U87-mg cells. We used the WST-1 test to evaluate cytotoxic effect of TMZ and AZD7762 combination with dose-effect and isobologram curves. The effects of the inhibitory and effective concentrations of the combination on apoptosis, cell cycle and γ-H2AX phosphorylation were analyzed with flow cytometry. The expression of genes responsible for the DNA damage response was analyzed with qRT-PCR. The combination showed a synergistic effect with high dose reduction index. Single and combined administrations of TMZ and AZD7762 increased in G2/M arrest from 24 to 48 h, and cells in the G2/M phase shifted towards octaploidy at 72 h. While no double-strand breaks were detected after TMZ treatment, AZD7762 and combination treatments caused a significant increase in γ-H2AX phosphorylation and increased apoptotic stimulation towards 72 h although TMZ did not cause apoptotic effect in IDH-mutant U87-mg cells. The genes controlling the apoptosis were determined to be upregulated in all three groups, and genes regarding cell cycle checkpoints were downregulated. Targeting Chk1/2 with AZD7762 simultaneously with TMZ may be a potential therapeutic strategy for both increasing the sensitivity of IDH-mutant glioma cells to TMZ and reducing the dose of TMZ. Graphical abstract: In IDH-mutant glioma cells, AZD7762, the Chk1/2 inhibitor, can increase the efficacy of Temozolomide by (i) increasing mitotic chaos, and (ii) inhibiting double-strand break repair, (iii) thereby inducing cell death. [graphic not available: see fulltext]
Medical Oncology (New York, NY, United States) published new progress about 112-63-0. 112-63-0 belongs to class esters-buliding-blocks, and the molecular formula is C19H34O2, Safety of (9Z,12Z)-Methyl octadeca-9,12-dienoate.
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