Anti-angiogenic Potential of Trans-chalcone in an In Vivo Chick Chorioallantoic Membrane Model: An ATP Antagonist to VEGFR with Predicted Blood-brain Barrier Permeability

Anna Senrung; Tanya Tripathi; Nikita Aggarwal; Divya Janjua; Arun Chhokar; Joni Yadav; Apoorva Chaudhary; Kulbhushan Thakur; Tejveer Singh; Alok Chandra Bharti

doi:10.2174/0118715257250417231019102501

Anti-angiogenic Potential of Trans-chalcone in an In Vivo Chick Chorioallantoic Membrane Model: An ATP Antagonist to VEGFR with Predicted Blood-brain Barrier Permeability

Cardiovasc Hematol Agents Med Chem. 2023 Nov 3. doi: 10.2174/0118715257250417231019102501. Online ahead of print.

Authors

Affiliations

¹ Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India.
² Neuropharmacology & Drug Delivery Laboratory, Zoology Department, Daulat Ram College, University of Delhi, Delhi, 110007, India.
³ Department of Zoology, Deshbandhu College, University of Delhi, Delhi, 110019, India.
⁴ Translational Oncology Laboratory, Department of Zoology, Hansraj College, University of Delhi, Delhi, 110007, India.

PMID: 37936455
DOI: 10.2174/0118715257250417231019102501

Abstract

Background: Glioblastoma multiforme (GBM) is characterized by massive tumorinduced angiogenesis aiding tumorigenesis. Vascular endothelial growth factor A (VEGF-A) via VEGF receptor 2 (VEGFR-2) constitutes majorly to drive this process. Putting a halt to tumordriven angiogenesis is a major clinical challenge, and the blood-brain barrier (BBB) is the prime bottleneck in GBM treatment. Several phytochemicals show promising antiangiogenic activity across different models, but their ability to cross BBB remains unexplored.

Methods: We screened over 99 phytochemicals having anti-angiogenic properties reported in the literature and evaluated them for their BBB permeability, molecular interaction with VEGFR-2 domains, ECD2-3 (extracellular domains 2-3) and TKD (tyrosine kinase domain) at VEGF-A and ATP binding site, cell membrane permeability, and hepatotoxicity using in silico tools. Furthermore, the anti-angiogenic activity of predicted lead Trans-Chalcone (TC) was evaluated in the chick chorioallantoic membrane.

Results: Out of 99 phytochemicals, 35 showed an efficient ability to cross BBB with a probability score of >0.8. Docking studies revealed 30 phytochemicals crossing benchmark binding affinity <-6.4 kcal/mol of TKD with the native ligand ATP alone. Out of 30 phytochemicals, 12 showed moderate to low hepatotoxicity, and 5 showed a violation of Lipinski's rule of five. Our in silico analysis predicted TC as a BBB permeable anti-angiogenic compound for use in GBM therapy. TC reduced vascularization in the CAM model, which was associated with the downregulation of VEGFR-2 transcript expression.

Conclusion: The present study showed TC to possess anti-angiogenic potential via the inhibition of VEGFR-2. In addition, the study predicted TC to cross BBB as well as a safe alternative for GBM therapy, which needs further investigation.

Keywords: Anti-angiogenesis; Blood Brain Barrier; Glioblastoma multiforme; Tumor induced-angiogenesis; VEGF.