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Histone deacetylase inhibitors sensitize glioblastoma models to temozolomide and reprogram immunosuppressive myeloid
Golnaz Asaadi Tehrani1, Becca Kubick1, Maksym Zarodniuk1
1University of Notre Dame.
Abstract:
Histone deacetylase inhibitors (HDACis) are promising anti-cancer agents but remain underexplored in glioblastoma (GBM). This study evaluated the effects of three HDACis-CAY10603, vorinostat (SAHA), and valproic acid (VPA)-on human GBM cell lines (U87, MGG8) with immortalized human astrocytes (IHAs) as healthy controls. HDACis were tested alone or in combination with temozolomide (TMZ), the standard chemotherapy for GBM, in both 2D (monolayer) and 3D (neurosphere) cultures. Additionally, co-culture of GBM cells with macrophages (M0, biochemically differentiated from THP-1 human monocytes) was used to examine the impact of HDACis on cancer-immune interactions. Results demonstrated that all three HDACis significantly reduced cell viability and synergistically enhanced the effect of TMZ. CAY10603 and SAHA induced early apoptosis and upregulated caspase 3 (CASP3) expression, whereas VPA primarily induced late apoptosis and necrosis in GBM cultures. VPA induced both G0/G1 and G2/M cell cycle arrest, while SAHA and CAY10603 only induced G2/M arrest. mRNA expression analysis following HDACi treatment in U87 neurospheres revealed that HDACis inhibited expression of markers for epithelial-to-mesenchymal transition (EMT), proliferation, and stemness pathways. In U87-M0 co-cultures, we observed significant upregulation of stemness markers and the pro-inflammatory cytokine TNF-α following CAY10603 and VPA treatments. In contrast, TMZ monotherapy upregulated the expression of the immunosuppressive cytokine TGF-β. These findings suggest that HDAC inhibition-including the novel small molecule CAY10603-sensitizes GBM to temozolomide and confers potent anti-tumor effects that combat GBM (e.g., reducing proliferation, EMT, stemness). Our in vitro findings-e.g., with 3D neurospheres that better mimic physiological tumor growth than 2D monolayers-warrant future in vivo testing of HDACis alone or in combination with chemotherapy.
Insights
Histone deacetylase inhibitors (HDACis) show promise against glioblastoma (GBM) by reducing cell viability and enhancing chemotherapy. These HDACis, including novel CAY10603, combat GBM by inhibiting proliferation, EMT, and stemness.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Glioblastoma (GBM) remains a challenging cancer with limited treatment options.
- Histone deacetylase inhibitors (HDACis) are emerging as potent anti-cancer agents.
- The efficacy of HDACis in GBM, particularly in combination therapies, is underexplored.
Purpose of the Study:
- To evaluate the anti-cancer effects of three HDACis (CAY10603, vorinostat, valproic acid) on human GBM cell lines.
- To investigate the synergistic effects of HDACis with temozolomide (TMZ), the standard GBM chemotherapy.
- To examine the impact of HDACis on glioblastoma cell proliferation, apoptosis, cell cycle, and cancer-immune interactions.
Main Methods:
- Utilized human GBM cell lines (U87, MGG8) and immortalized human astrocytes (IHAs) in 2D and 3D cultures.
- Assessed HDACis alone and in combination with temozolomide (TMZ).
- Co-cultured GBM cells with macrophages (M0) to study cancer-immune interactions and analyzed mRNA expression.
Main Results:
- All tested HDACis significantly reduced GBM cell viability and synergistically enhanced TMZ efficacy.
- CAY10603 and vorinostat induced early apoptosis and upregulated caspase 3 (CASP3), while valproic acid induced late apoptosis and necrosis.
- HDACis inhibited markers of epithelial-to-mesenchymal transition (EMT), proliferation, and stemness, and modulated pro-inflammatory and immunosuppressive cytokines.
Conclusions:
- HDAC inhibition, including novel CAY10603, sensitizes glioblastoma to temozolomide, demonstrating potent anti-tumor effects.
- HDACis combat GBM by reducing proliferation, EMT, and stemness, and modulating the tumor immune microenvironment.
- These in vitro findings support further in vivo investigation of HDACis as a therapeutic strategy for glioblastoma.
