Research ArticleExperimental Studies
Open Access

Effects of Azelastine on Glioblastoma Cells

YUKI UEMICHI, SEINA YASUDA, MIYUKI MABUCHI, SHUHEI NAKAO, SHUJI NAGANO and TADASHI SHIMIZU
Anticancer Research July 2025, 45 (7) 2763-2771; DOI: https://doi.org/10.21873/anticanres.17645

Abstract

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.

Keywords:

Introduction

Glioblastoma, an aggressive brain tumor with poor prognosis, is characterized by an average survival of only 12-15 months and a 5-year survival rate of <10% (1, 2). The invasive nature of glioblastoma allows it to spread extensively within brain tissue, making complete surgical removal nearly impossible (3). Postoperative treatment typically involves a combination of radiation therapy and chemotherapy; however, tumor recurrence is almost inevitable (4).

Standard chemotherapy for glioblastoma involves temozolomide (TMZ), an oral alkylating prodrug that methylates DNA purine bases to induce tumor cell death (5). In patients with glioblastoma, a combination of radiotherapy and TMZ has been shown to improve survival compared to radiotherapy alone; however, the median survival increase is only 2.5 months (1). Moreover, patients often develop resistance to TMZ, diminishing the effectiveness of chemotherapy (6). A key mechanism underlying TMZ resistance may be the increased expression of O(6)-methylguanine-DNA methyltransferase (MGMT) in resistant glioblastoma cells (6, 7). Therefore, it is crucial to identify new anti-tumor agents that are more effective than TMZ and capable of overcoming such drug resistance.

Drug repositioning involves identifying new pharmacological effects of approved or discontinued drug candidates and extending their application to the treatment of diseases beyond their original indications (8). In our previous studies, we reported that bronanserin and lomerizine, both capable of crossing the blood–brain barrier, inhibited glioblastoma cell proliferation (9, 10). In this study, we focused on azelastine hydrochloride (AZL), which is a compound that is structurally similar to bronanserin according to the structural similarity screening with SICOMP program (11).

AZL is a histamine H1 antagonist that is widely used to treat allergic conditions (12). Clinical studies using positron emission tomography (PET) have demonstrated that AZL crosses the blood–brain barrier (13). Our literature review indicated that AZL reportedly exhibits anticancer effects on human colorectal, cervical, and breast cancer cells (14-16). However, its anti-proliferative effects and impact on the human glioblastoma phenotype remain largely unexplored. AZL has been reported to restore doxorubicin (DOX) sensitivity in multidrug-resistant rat glioma models by increasing intracellular drug accumulation via P-glycoprotein (P-gp) inhibition (17).

In this study, we examined the anti-proliferative effects of AZL on human glioblastoma cells and investigated its influence on cytoskeletal organization and cell cycle progression. Furthermore, we assessed the potential of AZL in combination with TMZ and DOX in enhancing the therapeutic efficacy.

Materials and Methods

Chemicals. Azelastine hydrochloride (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan), Z-VAD-Fmk (Z-VAD, Peptide Institute Inc., Osaka, Japan), necrostatin-1 (Nec-1; Cayman Chemical, Ann Arbor, MI, USA), and ferrostatin-1 (Fer-1; Tokyo Chemical Industry Co., Ltd., Tokyo, Japan) were used. IM-54 was synthesized according to a previously reported literature (18).

Cell culture. Human glioblastoma cell line U251 was obtained from Dr. T. Sasayama (Kobe University, Japan). Human glioblastoma cell line T98G was purchased from the JCRB Cell Bank (Osaka, Japan). U251 cells were maintained in Dulbecco’s modified Eagle medium (DMEM; FUJIFILM Wako Pure Chemical, Osaka, Japan) supplemented with 10% fetal bovine serum (FBS; Sigma-Aldrich, Tokyo, Japan). T98G cells were maintained in Eagle’s Minimum Essential Medium (EMEM) with L-glutamine, phenol red, pyruvate, non-essential amino acids, and 1,500 mg/l sodium bicarbonate (FUJIFILM Wako Pure Chemical) supplemented with 10% FBS, 100 U of penicillin, and 100 μg/ml streptomycin (Nacalai Tesque, Kyoto, Japan). The cells were maintained at 37°C under a humidified atmosphere containing 5% CO2.

Cell proliferation assay. We prepared test solutions at final concentrations of 0, 1, 5, 10, 20, 30, 40, and 50 μM by diluting a solution of AZL in dimethyl sulfoxide (DMSO) to 1/1,000 in culture medium. U251 (3,000 cells/well) and T98G (2,000 cells/well) cells were seeded in 96-well plates in 100 μl cultured medium and incubated at 37°C in a humidified atmosphere containing 5% CO2. After 24 h, the cells were treated with 100 μl test compounds in medium solution including 0.1% DMSO (final concentrations of 0, 1, 5, 10, 20, and 30 μM for U251 and 0, 10, 20, 30, 40, and 50 μM for T98G) and incubated for 48 h. Thereafter, 10 μl of Cell Counting Kit-8 (CCK-8) (Dojindo Laboratories, Yoshida, Kumamoto, Japan) was added to each well, and the plates were incubated at 37°C for approximately 2 h. Absorbance was measured at 450 nm (test wavelength) and 630 nm (reference wavelength) using VersaMax microplate reader (Molecular Devices, San Jose, CA, USA). Cell viability at each AZL concentration was calculated as a percentage of that of the 0.1% DMSO-treated control group.

Chemical rescue by cell death inhibitors. U251 (3,000 cells/well) and T98G (2,000 cells/well) cells were seeded in 96-well plates in 100 μl cultured medium and incubated at 37°C for 24 h in a humidified atmosphere containing 5% CO2. Subsequently, the cells were treated with AZL (10 μM for U251 and 30 μM for T98G) combined with a caspase-dependent apoptosis inhibitor, Z-VAD-Fmk or a caspase- independent necrotic cell death inhibitor, Nec-1, Fer-1, or IM-54 in 100 μl cultured medium. After a 48-h incubation, 10 μl of CCK-8 solution was added to each well, and the plates were incubated at 37°C for approximately 2 h. Absorbance was measured as mentioned above.

Fluorescence imaging. U251 (80,000 cell density/dish) and T98G (60,000 cell density/dish) cells were seeded in 3-mm-wide glass-based dishes (AGC techno glass, Yoshida, Shizuoka, Japan) and incubated at 37°C. After a 24 h incubation, the cells were treated with AZL (10 μM for U251 and 30 μM for T98G) and incubated again for 48 h. The cells were then washed with phosphate-buffered saline (PBS; FUJIFILM Wako Pure Chemical). Thereafter, 4% paraformaldehyde in PBS (Nacalai Tesque) was added to the cells at room temperature for 30 min, followed by washing with PBS. The cells were incubated with 0.3% TritonTM X-100 in PBS at 4°C for 10 min. Subsequently, the cells were incubated with Phalloidin, Rhodamine X conjugated (FUJIFILM Wako Pure Chemical), and Deoxyribonuclease I, Alexa Fluor™ 488 Conjugate (Thermo Fisher Scientific, San Jose, MA, USA) in 0.03% Triton™ X-100 in PBS at 4°C for 24 h. Following which, the cells were washed with PBS and then observed under All-in-One Fluorescence Microscope BZ-X800 (Keyence, Osaka, Japan). Fluorescence intensity was quantified, and the filamentous actin (F-actin)/globular actin (G-actin) ratio (F/G ratio) was calculated from approximately five images.

Flow cytometry. U251 cells (6.0×105 cells/dish) were seeded in 100-mm-wide dishes and incubated at 37°C for 24 h. T98G cells (2.0×105 cells/dish) were seeded in 100-mm-wide dishes and incubated at 37°C for 48 h. After incubation, the cells were treated with AZL (10 μM for U251 and 30 μM for T98G) and incubated again for 24 h. After which, the cells were washed twice with PBS, trypsinized, and fixed with 300 μl of ice-cold PBS and 700 μl of ethanol for 24 h. The cells were centrifuged (520 × g for 5 min at 4°C) to remove the supernatant and washed with 1% bovine serum albumin (BSA; Merck, Darmstadt, Germany) in PBS. The cell pellet was resuspended in 1% BSA/PBS and stored at −30°C overnight. After washing, the cells were resuspended in 500 μl of 1% BSA/PBS and stained with 1 μl of 1 mg/ml propidium iodide. Cell cycle distribution was measured using a FACSAria™ III flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA).

Combined effect of AZL with TMZ or DOX on glioblastoma cells. U251 cells (3,000 cells/well) were seeded in 96-well plates in 100 μl cultured medium and incubated at 37°C for 24 h. After incubation, 5 μM AZL in combination with either TMZ (100 or 300 μM) or doxorubicin (50 or 100 nM) was added to 100 μl of culture medium containing 0.2% DMSO. After a 48 h incubation, 10 μl of CCK-8 solution was added to each well, and absorbance was measured.

Statistical analysis. In this study, data are presented as mean±SEM. JMP Pro® 16 (SAS Institute, Cary, NC, USA) was used to apply Student’s t-test or Dunnett’s multiple comparisons to determine the significance of differences between control and treated groups. The statistical significance was set at p<0.05.

Results

Inhibitory effect of AZL on the proliferation of glioblastoma cells. AZL inhibited glioblastoma cell proliferation in a dose-dependent manner. The half-maximal inhibitory concentration (IC50) values of AZL for U251 and T98G cell growth were 9.5±0.2 and 31.0±0.6 μM, respectively (Figure 1).

Figure 1.
Figure 1.

Inhibitory effects of azelastine on glioblastoma cells. U251 and T98G cells were treated with azelastine for 48 h, and cell viability (%) was calculated using the WST-8 assay with dimethyl sulfoxide-treated cells as the control (100%). Data are shown as the mean±SEM (n=4).

Chemical rescue by cell death inhibitors. None of the four cell death inhibitors −Z-VAD (pan-caspase, apoptosis), necrostatin-1 (necroptosis), ferrostatin-1 (ferroptosis), and IM-54 (oxidative stress-induced necrosis)− substantially altered the inhibitory effect of AZL on glioblastoma cell proliferation (Figure 2A and B). However, co-treatment with Z-VAD-Fmk slightly rescued the viability of T98G cells, increasing the viability from 45% with AZL alone to 52% (p<0.01) (Figure 2B).

Figure 2.
Figure 2.

Chemical rescue by cell death inhibitors. Cells were treated with azelastine and four cell death inhibitors (Z-VAD-fmk (Z-VAD): 20 μM, Necrostatin-1 (Nec-1): 10 μM, Ferrostatin-1 (Fer-1): 1 μM, and IM-54: 1 μM) for 48 h. Cell viability was evaluated using WST-8 assay. (A) U251 cells were treated with 10 μM azelastine. (B) T98G cells were treated with 30 μM azelastine. Data are shown as the mean±SEM (n=4). Significant differences at **p<0.01 vs. DMSO control, using Dunnett’s test. DMSO: Dimethyl sulfoxide.

Effect of AZL on filamentous actin morphology. In T98G cells treated with 30 μM AZL, no significant change was observed in the F/G-actin ratio compared with the control. However, fluorescent staining revealed altered F-actin distribution at the plasma membrane, as indicated by the white arrows in Figure 3. In contrast, 10 μM AZL-treated U251 cells showed a significant decrease in both the F/G ratio and F-actin localization at the plasma membrane compared with the control (Figure 3).

Figure 3.
Figure 3.

Effect of azelastine on filamentous actin morphology. (A) U251 cells were stained after a treatment with 10 μM azelastine for 48 h. (B) T98G cells were stained after a treatment with 30 μM azelastine for 48 h. Red fluorescence indicates F-actin labeled with conjugated phalloidin-rhodamine and green fluorescence indicates G-actin labeled with Alexa Fluor™ 488–conjugated deoxyribonuclease I. (C) The F/G actin ratio (F/G ratio) was calculated from five independent images. White arrows emphasize representative cells with F-actin localized at the plasma membrane. Data are shown as the mean±SEM (n=5). Significant differences at ***p<0.001 vs. DMSO control, using Student’s t-test.

Effect of AZL on cell cycle progression. In U251 cells, 10 μM AZL treatment significantly increased the proportion of cells in the G1 phase (control: 60%, AZL: 68%; p<0.01) and significantly decreased those in the S (control: 19%, AZL: 12%; p<0.01) and G2/M phases (control: 19%, AZL: 16%; p<0.001). Similarly, in T98G cells, 30 μM AZL treatment significantly increased the proportion of cells in the G1 phase (control: 70%, AZL: 78%; p<0.01) and significantly decreased those in the S (control: 9.0%, AZL: 6.7%; p<0.01) and G2/M phases (control: 17%, AZL: 14%; p<0.01) (Figure 4).

Figure 4.
Figure 4.

Effect of azelastine on cell cycle progression. After treatment with azelastine for 24 h, the cells were fixed and stained with 1 mg/ml propidium iodide to analyze the cell distribution using flow cytometry. Peaks represent the G1, S, and G2/M phases of the cell cycle. (A) U251 cells were treated with 10 μM azelastine. T98G cells were treated with 30 μM azelastine. (B) Quantitative analysis of the percentage distribution of cells in each cell cycle phase. Data are shown as the mean±SEM (n=3). Significant differences at **p<0.01, ***p <0.001 vs. DMSO control, using Student’s t-test.

Combined effect of AZL with TMZ or DOX on glioblastoma cells. Although TMZ alone reduced cell viability to 65% at 100 μM and 66% at 300 μM, its combination with 5 μM AZL significantly reduced the cell viability to 55% and 53%, respectively (Figure 5A). Similarly, the cell viability with DOX alone was 58% at 50 nM and 42% at 75 nM, whereas co-treatment with 5 μM AZL further reduced the cell viability to 18% and 14%, respectively (Figure 5B).

Figure 5.
Figure 5.

Combined effects of azelastine and DOX on glioblastoma cells. (A) U251 cells were treated with 5 μM azelastine alone, 100 or 300 μM TMZ alone, or a combination of AZL and TMZ for 48 h. (B) U251 cells were treated with 5 μM azelastine alone, 50 or 75 nM DOX alone, or a combination of AZL and DOX for 48 h. Data are shown as the mean±SEM (n=4). Significant differences at *p<0.05, ***p<0.001 vs. TMZ or DOX alone using Student’s t-test.

Discussion

In this study, AZL inhibited the proliferation of the glioblastoma cell lines U251 and T98G in a dose-dependent manner. Notably, its anti-proliferative activity was over 30-fold stronger in U251 cells and more than 10-fold stronger in T98G cells than that of TMZ (10). Although the anticancer activity of AZL has been demonstrated in several cancer cell lines (14-16), our findings suggest that AZL, which can penetrate the blood–brain barrier, may also exert antitumor effects against glioblastoma.

None of the four major cell death pathway-targeting inhibitors (Z-VAD, Nec-1, Fer-1, IM-54) dramatically reversed AZL-induced growth inhibition. Although the partial rescue by Z-VAD-Fmk in T98G cells implied a minor contribution of apoptosis, this may not be the major mechanism of action. These findings suggest that rather than cell death induction, the growth inhibitory effect is the predominant mechanism at approximately IC50.

AZL treatment significantly reduced the F/G-actin ratio and disrupted peripheral F-actin localization in U251 cells. In T98G cells, the F/G-actin ratio was not significantly changed; however, fluorescent staining revealed F-actin distribution at the plasma membrane, as indicated by the white arrows in Figure 3. In addition, AZL induced G1 phase cell cycle arrest in both glioblastoma cell lines. These observations are consistent with those of previous reports demonstrating that IQGAP1 plays a critical role in regulating actin cytoskeleton dynamics, cell adhesion, and proliferative signaling pathways (19). In colorectal cancer cells, AZL suppresses mitochondrial fission and tumor growth by inhibiting the ARF1–IQGAP1–ERK–Drp1 signaling axis (14). Furthermore, in gastric cancer cells, IQGAP1 overexpression promotes cell proliferation, whereas menin suppression leads to growth inhibition (20). Collectively, these findings suggest that AZL induces G1 phase arrest by modulating IQGAP1 function, thereby altering cytoskeletal organization and cell adhesion.

AZL significantly enhanced the cytotoxic effects of TMZ, a clinically used agent, and strongly potentiated the activity of DOX. Although previous studies have demonstrated that AZL can reverse DOX resistance in P-gp-overexpressing rat glioma cells (17), its efficacy and mechanistic effects in human glioblastoma models are yet to be fully characterized. Our findings suggest that AZL may similarly enhance DOX efficacy in human glioblastoma cells, potentially by inhibiting P-gp-mediated drug efflux.

Although higher doses of AZL may be required for anti-tumor efficacy than its conventional use as an anti-allergic agent, its known adverse effects are relatively mild, with drowsiness being the most common, and less severe than those associated with TMZ. Preclinical oral administration studies have reported non-toxic doses of up to 60 mg/kg in dogs and 30 mg/kg in rats (21), suggesting that doses higher than 300 times the standard clinical dose may not cause serious toxicity. Thus, AZL appears to be a suitable candidate for drug repositioning owing to its efficacy and favorable safety profile. In addition, intracranial implantation of AZL after a glioblastoma surgery as an alternative to highly toxic nitrosourea-based agents may allow for localized delivery while minimizing systemic exposure.

In summary, AZL suppressed the proliferation of both glioblastoma cell lines and TMZ-resistant cells, demonstrating superior efficacy compared with TMZ. Moreover, AZL enhanced the anti-proliferative effects of TMZ and DOX in glioblastoma cells. These findings indicate that AZL, a low-toxicity clinical drug, may be effective as a monotherapy and enhance the efficacy of standard treatments for TMZ-resistant glioblastoma.

Acknowledgements

The Authors would especially like to thank Prof. Takashi Sasayama (Kobe University) for providing glioblastoma cell lines and would also like to thank Editage (www.editage.com) for English language editing.

Footnotes

  • Authors’ Contributions

    Yuki Uemichi: Investigation, data curation, visualization, and writing – original draft preparation. Seina Yasuda: Investigation, data curation, visualization, and writing – reviewing and editing. Miyuki Mabuchi: Investigation and writing – reviewing and editing. Shuhei Nakao: Writing – reviewing and editing. Shuji Nagano: Writing – reviewing and editing. Tadashi Shimizu: Conceptualization, writing – original draft preparation, writing – reviewing and editing, funding acquisition, and supervision.

  • Conflicts of Interest

    All Authors declare no conflicts of interest in relation to this study.

  • Funding

    This work was supported in part by the JSPS KAKENHI (grant number 24K02559; to T.S.).

  • Artificial Intelligence (AI) Disclosure

    During the preparation of this manuscript, the authors used ChatGPT based on the GPT-4o model (OpenAI, San Francisco, CA, USA) to assist with English language editing, including improving clarity, tone, and readability. All content generated through this tool was critically reviewed and revised by the authors, who take full responsibility for the integrity and accuracy of the final manuscript.

  • Received April 25, 2025.
  • Revision received May 6, 2025.
  • Accepted May 7, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Stupp R,
    2. Mason WP,
    3. van den Bent MJ,
    4. Weller M,
    5. Fisher B,
    6. Taphoorn MJ,
    7. Belanger K,
    8. Brandes AA,
    9. Marosi C,
    10. Bogdahn U,
    11. Curschmann J,
    12. Janzer RC,
    13. Ludwin SK,
    14. Gorlia T,
    15. Allgeier A,
    16. Lacombe D,
    17. Cairncross JG,
    18. Eisenhauer E,
    19. Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group
    : Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10): 987-996, 2005. DOI: 10.1056/NEJMoa043330
    OpenUrlCrossRefPubMed
  2. ↵
    1. Price M,
    2. Ballard C,
    3. Benedetti J,
    4. Neff C,
    5. Cioffi G,
    6. Waite KA,
    7. Kruchko C,
    8. Barnholtz-Sloan JS,
    9. Ostrom QT
    : CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2017-2021. Neuro Oncol 26(Suppl_6): vi1-vi85, 2024. DOI: 10.1093/neuonc/noae145
    OpenUrlCrossRefPubMed
  3. ↵
    1. Giese A,
    2. Bjerkvig R,
    3. Berens ME,
    4. Westphal M
    : Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 21(8): 1624-1636, 2003. DOI: 10.1200/JCO.2003.05.063
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Omuro A
    : Glioblastoma and other malignant gliomas. JAMA 310(17): 1842, 2013. DOI: 10.1001/jama.2013.280319
    OpenUrlCrossRefPubMed
  5. ↵
    1. Hegi ME,
    2. Diserens AC,
    3. Gorlia T,
    4. Hamou MF,
    5. de Tribolet N,
    6. Weller M,
    7. Kros JM,
    8. Hainfellner JA,
    9. Mason W,
    10. Mariani L,
    11. Bromberg JE,
    12. Hau P,
    13. Mirimanoff RO,
    14. Cairncross JG,
    15. Janzer RC,
    16. Stupp R
    : MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10): 997-1003, 2005. DOI: 10.1056/NEJMoa043331
    OpenUrlCrossRefPubMed
  6. ↵
    1. Weller M,
    2. Stupp R,
    3. Reifenberger G,
    4. Brandes AA,
    5. van den Bent MJ,
    6. Wick W,
    7. Hegi ME
    : MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6(1): 39-51, 2010. DOI: 10.1038/nrneurol.2009.197
    OpenUrlCrossRefPubMed
  7. ↵
    1. Esteller M,
    2. Garcia-Foncillas J,
    3. Andion E,
    4. Goodman SN,
    5. Hidalgo OF,
    6. Vanaclocha V,
    7. Baylin SB,
    8. Herman JG
    : Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343(19): 1350-1354, 2000. DOI: 10.1056/NEJM200011093431901
    OpenUrlCrossRefPubMed
  8. ↵
    1. Siegelin MD,
    2. Schneider E,
    3. Westhoff MA,
    4. Wirtz CR,
    5. Karpel-Massler G
    : Current state and future perspective of drug repurposing in malignant glioma. Semin Cancer Biol 68: 92-104, 2021. DOI: 10.1016/j.semcancer.2019.10.018
    OpenUrlCrossRefPubMed
  9. ↵
    1. Tsuchiya N,
    2. Okamoto K,
    3. Nakao S,
    4. Ohmori S,
    5. Shimizu T
    : Effect of Blonanserin on the proliferation and migration of glioblastoma cells. Pharmazie 78(5): 37-41, 2023. DOI: 10.1691/ph.2023.1821
    OpenUrlCrossRefPubMed
  10. ↵
    1. Uemichi Y,
    2. Mabuchi M,
    3. Tsuchiya N,
    4. Yasuda S,
    5. Nakao S,
    6. Shimizu T
    : Effects of lomerizine and its metabolite on glioblastoma cells. Anticancer Res 44(7): 2943-2952, 2024. DOI: 10.21873/anticanres.17106
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Hattori M,
    2. Okuno Y,
    3. Goto S,
    4. Kanehisa M
    : Development of a chemical structure comparison method for integrated analysis of chemical and genomic information in the metabolic pathways. J Am Chem Soc 125(39): 11853-11865, 2003. DOI: 10.1021/ja036030u
    OpenUrlCrossRefPubMed
  12. ↵
    1. McNeely W,
    2. Wiseman LR
    : Intranasal azelastine. A review of its efficacy in the management of allergic rhinitis. Drugs 56(1): 91-114, 1998. DOI: 10.2165/00003495-199856010-00011
    OpenUrlCrossRefPubMed
  13. ↵
    1. Yanai K,
    2. Yoshikawa T,
    3. Yanai A,
    4. Nakamura T,
    5. Iida T,
    6. Leurs R,
    7. Tashiro M
    : The clinical pharmacology of non-sedating antihistamines. Pharmacol Ther 178: 148-156, 2017. DOI: 10.1016/j.pharmthera.2017.04.004
    OpenUrlCrossRefPubMed
  14. ↵
    1. Hu HF,
    2. Xu WW,
    3. Li YJ,
    4. He Y,
    5. Zhang WX,
    6. Liao L,
    7. Zhang QH,
    8. Han L,
    9. Yin XF,
    10. Zhao XX,
    11. Pan YL,
    12. Li B,
    13. He QY
    : Anti-allergic drug azelastine suppresses colon tumorigenesis by directly targeting ARF1 to inhibit IQGAP1-ERK-Drp1-mediated mitochondrial fission. Theranostics 11(4): 1828-1844, 2021. DOI: 10.7150/thno.48698
    OpenUrlCrossRefPubMed
    1. Trybus E,
    2. Król T,
    3. Trybus W
    : The Multidirectional effect of azelastine hydrochloride on cervical cancer cells. Int J Mol Sci 23(11): 5890, 2022. DOI: 10.3390/ijms23115890
    OpenUrlCrossRefPubMed
  16. ↵
    1. Moraca F,
    2. Arciuolo V,
    3. Marzano S,
    4. Napolitano F,
    5. Castellano G,
    6. D’Aria F,
    7. Di Porzio A,
    8. Landolfi L,
    9. Catalanotti B,
    10. Randazzo A,
    11. Pagano B,
    12. Malfitano AM,
    13. Amato J
    : Repurposing FDA-approved drugs to target G-quadruplexes in breast cancer. Eur J Med Chem 285: 117245, 2025. DOI: 10.1016/j.ejmech.2025.117245
    OpenUrlCrossRefPubMed
  17. ↵
    1. Hu YP,
    2. Robert J
    : Azelastine and flezelastine as reversing agents of multidrug resistance: pharmacological and molecular studies. Biochem Pharmacol 50(2): 169–175, 1995. DOI: 10.1016/0006-2952(95)00130-R
    OpenUrlCrossRefPubMed
  18. ↵
    1. Dodo K,
    2. Katoh M,
    3. Shimizu T,
    4. Takahashi M,
    5. Sodeoka M
    : Inhibition of hydrogen peroxide-induced necrotic cell death with 3-amino-2-indolylmaleimide derivatives. Bioorg Med Chem Lett 15(12): 3114-3118, 2005. DOI: 10.1016/j.bmcl.2005.04.016
    OpenUrlCrossRefPubMed
  19. ↵
    1. Le Clainche C,
    2. Schlaepfer D,
    3. Ferrari A,
    4. Klingauf M,
    5. Grohmanova K,
    6. Veligodskiy A,
    7. Didry D,
    8. Le D,
    9. Egile C,
    10. Carlier MF,
    11. Kroschewski R
    : IQGAP1 stimulates actin assembly through the N-Wasp-Arp2/3 pathway. J Biol Chem 282(1): 426-435, 2007. DOI: 10.1074/jbc.M607711200
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Ren F,
    2. Guo Q,
    3. Zhou H
    : Menin represses the proliferation of gastric cancer cells by interacting with IQGAP1. Biomed Rep 18(4): 27, 2023. DOI: 10.3892/br.2023.1609
    OpenUrlCrossRefPubMed
  21. ↵
    1. Nakao K,
    2. Wakabayashi T,
    3. Sugiyama K,
    4. Taki T,
    5. Sumigama S,
    6. Chiba T
    : Subacute and chronic toxicity studies in rats and dose range finding study in dogs by oral administration of azelastine. Arzneimittelforschung 31(8): 1220-1225, 1981.
    OpenUrlPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Effects of Azelastine on Glioblastoma Cells
YUKI UEMICHI, SEINA YASUDA, MIYUKI MABUCHI, SHUHEI NAKAO, SHUJI NAGANO, TADASHI SHIMIZU
Anticancer Research Jul 2025, 45 (7) 2763-2771; DOI: 10.21873/anticanres.17645
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords