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Article Open Access

Doxazosin inhibits vasculogenic mimicry in human non‑small cell lung cancer through inhibition of the VEGF‑A/VE‑cadherin/mTOR/MMP pathway

  • Authors:
    • Jui-Ling Hsu
    • Wohn-Jenn Leu
    • Lih-Ching Hsu
    • Chia-Hsun Hsieh
    • Jih-Hwa Guh
  • View Affiliations / Copyright

    Affiliations: Department of Nursing, Division of Basic Medical Sciences, Chang‑Gung University of Science and Technology, Taoyuan 333, Taiwan, R.O.C., School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C., Division of Hematology‑Oncology, Department of Internal Medicine, New Taipei Municipal TuCheng Hospital, New Taipei City 236, Taiwan, R.O.C.
    Copyright: © Hsu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 170
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    Published online on: February 22, 2024
       https://doi.org/10.3892/ol.2024.14303
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Abstract

Lung cancer is the leading cause of cancer‑related death worldwide, and ~85% of lung cancers are non‑small cell lung cancer (NSCLC), which has a low 5‑year overall survival rate and high mortality. Several therapeutic strategies have been developed, such as targeted therapy, immuno-oncotherapy and combination therapy. However, the low survival rate indicates the urgent need for new NSCLC treatments. Vasculogenic mimicry (VM) is an endothelial cell‑free tumor blood supply system of aggressive and metastatic tumor cells present during tumor neovascularization. VM is clinically responsible for tumor metastasis and resistance, and is correlated with poor prognosis in NSCLC, making it a potential therapeutic target. In the present study, A549 cells formed glycoprotein‑rich lined tubular structures, and transcript levels of VM‑related genes were markedly upregulated in VM‑forming cells. Based on a drug repurposing strategy, it was demonstrated that doxazosin (an antihypertensive drug) displayed inhibitory activity on VM formation at non‑cytotoxic concentrations. Doxazosin significantly reduced the levels of vascular endothelial growth factor A (VEGF‑A) and matrix metalloproteinase‑2 (MMP‑2) in the cell media during VM formation. Further experiments revealed that the protein expression levels of VEGF‑A and vascular endothelial‑cadherin (VE‑cadherin), which contribute to tumor aggressiveness and VM formation, were downregulated following doxazosin treatment. Moreover, the downstream signaling Ephrin type‑A receptor 2 (EphA2)/AKT/mTOR/MMP/Laminin‑5γ2 network was inhibited in response to doxazosin treatment. In conclusion, the present study demonstrated that doxazosin displayed anti‑VM activity in an NSCLC cell model through the downregulation of VEGF‑A and VE‑cadherin levels, and the suppression of signaling pathways related to the receptor tyrosine kinase, EphA2, protein kinases, AKT and mTOR, and proteases, MMP‑2 and MMP‑9. These results support the add‑on anti‑VM effect of doxazosin as a potential agent against NSCLC.
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Copy and paste a formatted citation
Spandidos Publications style
Hsu J, Leu W, Hsu L, Hsieh C and Guh J: Doxazosin inhibits vasculogenic mimicry in human non‑small cell lung cancer through inhibition of the VEGF‑A/VE‑cadherin/mTOR/MMP pathway. Oncol Lett 27: 170, 2024.
APA
Hsu, J., Leu, W., Hsu, L., Hsieh, C., & Guh, J. (2024). Doxazosin inhibits vasculogenic mimicry in human non‑small cell lung cancer through inhibition of the VEGF‑A/VE‑cadherin/mTOR/MMP pathway. Oncology Letters, 27, 170. https://doi.org/10.3892/ol.2024.14303
MLA
Hsu, J., Leu, W., Hsu, L., Hsieh, C., Guh, J."Doxazosin inhibits vasculogenic mimicry in human non‑small cell lung cancer through inhibition of the VEGF‑A/VE‑cadherin/mTOR/MMP pathway". Oncology Letters 27.4 (2024): 170.
Chicago
Hsu, J., Leu, W., Hsu, L., Hsieh, C., Guh, J."Doxazosin inhibits vasculogenic mimicry in human non‑small cell lung cancer through inhibition of the VEGF‑A/VE‑cadherin/mTOR/MMP pathway". Oncology Letters 27, no. 4 (2024): 170. https://doi.org/10.3892/ol.2024.14303
Copy and paste a formatted citation
x
Spandidos Publications style
Hsu J, Leu W, Hsu L, Hsieh C and Guh J: Doxazosin inhibits vasculogenic mimicry in human non‑small cell lung cancer through inhibition of the VEGF‑A/VE‑cadherin/mTOR/MMP pathway. Oncol Lett 27: 170, 2024.
APA
Hsu, J., Leu, W., Hsu, L., Hsieh, C., & Guh, J. (2024). Doxazosin inhibits vasculogenic mimicry in human non‑small cell lung cancer through inhibition of the VEGF‑A/VE‑cadherin/mTOR/MMP pathway. Oncology Letters, 27, 170. https://doi.org/10.3892/ol.2024.14303
MLA
Hsu, J., Leu, W., Hsu, L., Hsieh, C., Guh, J."Doxazosin inhibits vasculogenic mimicry in human non‑small cell lung cancer through inhibition of the VEGF‑A/VE‑cadherin/mTOR/MMP pathway". Oncology Letters 27.4 (2024): 170.
Chicago
Hsu, J., Leu, W., Hsu, L., Hsieh, C., Guh, J."Doxazosin inhibits vasculogenic mimicry in human non‑small cell lung cancer through inhibition of the VEGF‑A/VE‑cadherin/mTOR/MMP pathway". Oncology Letters 27, no. 4 (2024): 170. https://doi.org/10.3892/ol.2024.14303
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