Anticancer research · 2025
Effects of Azelastine on Glioblastoma Cells.
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Uemichi Yuki, Yasuda Seina, Mabuchi Miyuki, Nakao Shuhei, Nagano Shuji, Shimizu Tadashi
Аннотация
BACKGROUND/AIM: Glioblastoma is an aggressive brain tumor with poor prognosis and limited treatment options. Azelastine (AZL), a histamine H1 receptor antagonist known to cross the blood-brain barrier, has shown anticancer activity in other malignancies. This study investigated the anti-proliferative effects of AZL on glioblastoma cells and its potential to enhance the efficacy of standard anticancer agents.
MATERIALS AND METHODS: Human glioblastoma cell lines U251 and T98G were treated with AZL. Cell viability was assessed via WST-8 assay. The impact of AZL on actin cytoskeleton and cell cycle was analyzed using fluorescent staining and flow cytometry. We further assessed the impact of four cell death pathway inhibitors - Z-VAD-fmk (pan-caspase inhibitor), necrostatin-1 (necroptosis inhibitor), ferrostatin-1 (ferroptosis inhibitor), and IM-54 (oxidative stress induced necrosis inhibitor) - on AZL-induced growth suppression and tested AZL in combination with temozolomide (TMZ) or doxorubicin (DOX).
RESULTS: AZL inhibited cell proliferation in a dose-dependent manner (IC50: 9.5 μM for U251, 31.0 μM for T98G). Cell death inhibitors did not substantially reverse the effects of AZL, suggesting that its primary mode of action involves growth inhibition rather than the induction of cell death. AZL induced G1 phase arrest in both cell lines and disrupted actin filament organization, particularly in U251 cells. Combination treatment with AZL and either TMZ or DOX significantly enhanced the anti-proliferative effects compared to monotherapy.
CONCLUSION: AZL inhibits glioblastoma cell growth primarily through G1 arrest and cytoskeletal remodeling, with minimal contribution from classical cell death pathways. Its ability to enhance TMZ and DOX efficacy, coupled with favorable BBB permeability and low toxicity, supports its potential as a repositioned therapeutic for glioblastoma, both as a monotherapy and as an adjuvant to overcome TMZ resistance.
MATERIALS AND METHODS: Human glioblastoma cell lines U251 and T98G were treated with AZL. Cell viability was assessed via WST-8 assay. The impact of AZL on actin cytoskeleton and cell cycle was analyzed using fluorescent staining and flow cytometry. We further assessed the impact of four cell death pathway inhibitors - Z-VAD-fmk (pan-caspase inhibitor), necrostatin-1 (necroptosis inhibitor), ferrostatin-1 (ferroptosis inhibitor), and IM-54 (oxidative stress induced necrosis inhibitor) - on AZL-induced growth suppression and tested AZL in combination with temozolomide (TMZ) or doxorubicin (DOX).
RESULTS: AZL inhibited cell proliferation in a dose-dependent manner (IC50: 9.5 μM for U251, 31.0 μM for T98G). Cell death inhibitors did not substantially reverse the effects of AZL, suggesting that its primary mode of action involves growth inhibition rather than the induction of cell death. AZL induced G1 phase arrest in both cell lines and disrupted actin filament organization, particularly in U251 cells. Combination treatment with AZL and either TMZ or DOX significantly enhanced the anti-proliferative effects compared to monotherapy.
CONCLUSION: AZL inhibits glioblastoma cell growth primarily through G1 arrest and cytoskeletal remodeling, with minimal contribution from classical cell death pathways. Its ability to enhance TMZ and DOX efficacy, coupled with favorable BBB permeability and low toxicity, supports its potential as a repositioned therapeutic for glioblastoma, both as a monotherapy and as an adjuvant to overcome TMZ resistance.