Improving the Response of High-Grade Glioma (HGG) Cells to Temozolomide Treatment Through Combination With Imatinib

TL;DR

This study explores combining temozolomide and imatinib to improve treatment outcomes for high-grade gliomas in a lab setting.

Contribution

The study evaluates the synergistic potential of temozolomide and imatinib in high-grade glioma treatment using in vitro experiments.

Findings

Combination therapy showed synergistic effects in 31.9% of cases.

Monotherapy with both drugs exhibited dose-dependent cytotoxicity.

Approximately one-third of combinations showed subadditive effects.

Abstract

Background: High-grade gliomas (HGGs), the most common adult brain tumors, have always posed a dreaded prognosis to patients and difficulties to medical professionals due to their high heterogeneity and resistance to treatment. In terms of standard of care, maximal surgical resection along with temozolomide (TMZ) and radiotherapy (RT) has remained the current first-line treatment for HGG for decades. Surgical resection has experienced improvements due to neuronavigation and novel imaging sequences, which facilitate a more precise tumor removal while decreasing morbidity. TMZ remains the only approved first-line therapy with limited efficiency, in part because of the developing resistance and side effects. One of the characteristics of HGGs is the presence of multiple receptor tyrosine kinase (RTK) pathways that are aberrantly activated; thus, resistance to treatment as well as uncontrolled proliferation might be attributed in part to these pathways. Our current study aims to evaluate the potential cytotoxic effects of an alkylating cytostatic, TMZ, in combination with a multitarget tyrosine kinase inhibitor (TKI), namely imatinib mesylate (IMT), in comparison to their effects in monotherapy in an in vitro environment.

Methods: HGG cells growing in Roswell Park Memorial Institute Medium (RPMI) standard medium were treated with TMZ and IMT in both monotherapy and combined therapy, and the in vitrocytotoxicity was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Drug interaction (I) was classified by the multiplicative method.

Results: In the in vitro conditions, each drug exhibited cytotoxic effects in monotherapy in a dose-dependent manner. TMZ and IMT combined regimens were synergistic in 31.9%, additive in 31.9%, and subadditive in 36.1% of the combinations.

Conclusions: TMZ and IMT demonstrated cytotoxic effects in both monotherapy and combination therapy. Dual therapy yielded predominantly synergistic and additive effects, with subadditive results in approximately one-third of the combinations. Overall, combination therapy produced a better cytotoxic behavior than its individual effects in an in vitro setting.

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