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Abstract Histone deacetylase inhibitors (HDACi) have emerged as a new class of anti-tumor agents for various types of cancers, including glioblastoma (GBM). Recent studies have shown that targeting the GBM epigenome can enhance the effects of standard clinical therapies. Here, we utilized the human U87-GBM cell line to evaluate the cytotoxic properties of three blood-brain-barrier-penetrating HDACi, suberoylanilide hydroxamic acid (SAHA, or Vorinostat), valproic acid (VPA), and CAY10603, both as monotherapies and in combination with the chemotherapeutic agent temozolomide (TMZ). Combination Index (CI) was quantified by MTT assay and human normal astrocytes (HNAs, SV40T) were used as cytotoxic controls. We found that HDACi significantly reduced cell viability and increased cell death of human GBM cells, but not HNAs. Combination therapy of HDACi with TMZ generated increased cytotoxic activity in comparison to TMZ monotherapy, with the combination of VPA and TMZ having the strongest effect (30% viability following VPA/TMZ treatment, compared to 42% SAHA/TMZ, 45% CAY10603/TMZ, and 85% TMZ alone). In contrast, when evaluating epi-drugs as monotherapies, at intermediate concentrations, 1. 9 μM CAY10603 was most effective in decreasing U87-GBM cell viability (27%) particularly at micromolar concentrations, compared to 3. 7 μM SAHA (36%) and 1. 5 mM VPA (51%). In HNAs, CAY10603, SAHA, and VPA decreased cell viability to 80%, 87%, and 90%, respectively. These findings suggest that HDACi synergize with TMZ to enhance its cytotoxicity. The promising anti-tumor effects these HDACi-s warrant preclinical studies. Citation Format: Golnaz Asaadi Tehrani, Becca Kubick, Meenal Datta. Epigenetic targeting improves glioblastoma cell sensitivity to chemotherapy abstract. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₁): Abstract nr B018.
Tehrani et al. (Mon,) studied this question.