Histone deacetylase inhibitors sensitize glioblastoma models to temozolomide and reprogram immunosuppressive myeloid cells
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Golnaz Asaadi Tehrani1, Rebecca N Kubick2, Maksym Zarodniuk1
1Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN, USA.
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-[Formula: see text]. 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). Among the HDAC inhibitors tested, CAY10603 exhibited the most potent anti-tumor effect in 3D neurosphere and macrophage co-culture models, significantly enhancing apoptosis and disrupting pro-tumorigenic and anti-inflammatory signaling in GBM. 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) like CAY10603 show potent anti-cancer effects against glioblastoma (GBM). These HDACis enhance chemotherapy and reduce tumor growth, proliferation, and stemness, warranting further in vivo investigation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Glioblastoma (GBM) remains a challenging cancer with limited treatment options.
- Histone deacetylase inhibitors (HDACis) are emerging as promising anti-cancer agents but are underexplored in GBM.
- Temozolomide (TMZ) is the standard chemotherapy for GBM.
Purpose of the Study:
- To evaluate the efficacy of three HDACis (CAY10603, vorinostat, valproic acid) against human GBM cell lines.
- To assess the synergistic effects of HDACis in combination with TMZ in 2D and 3D cultures.
- To investigate the impact of HDACis on glioblastoma-macrophage interactions.
Main Methods:
- Utilized human GBM cell lines (U87, MGG8) and immortalized human astrocytes (IHAs).
- Assessed HDACis alone and with TMZ in 2D (monolayer) and 3D (neurosphere) cultures.
- Co-cultured GBM cells with macrophages (M0) to study cancer-immune interactions.
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); valproic acid induced late apoptosis and necrosis.
- HDACis inhibited epithelial-to-mesenchymal transition (EMT), proliferation, and stemness markers in GBM neurospheres.
- CAY10603 and valproic acid upregulated stemness markers and TNF-α in GBM-macrophage co-cultures, while TMZ alone upregulated TGF-β.
Conclusions:
- HDAC inhibition, particularly with CAY10603, sensitizes GBM to TMZ and exhibits potent anti-tumor effects.
- HDACis reduce GBM proliferation, EMT, and stemness, with CAY10603 showing the most potent effects in 3D and co-culture models.
- In vitro findings support further in vivo testing of HDACis alone or combined with chemotherapy for GBM treatment.
