Affiliations 

  • 1 EMAN Cancer Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Pulau Pinang, Malaysia. Electronic address: jupitex@gmail.com
  • 2 EMAN Cancer Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Pulau Pinang, Malaysia. Electronic address: aminmalikshah@gmail.com
  • 3 The School of Chemical Sciences, Universiti Sains Malaysia (USM), 11800 Penang, Malaysia
  • 4 EMAN Cancer Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Pulau Pinang, Malaysia; QUEST International University, Ipoh, Perak, Malaysia
  • 5 EMAN Cancer Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Pulau Pinang, Malaysia
Eur J Pharm Sci, 2016 Oct 10;93:304-18.
PMID: 27552907 DOI: 10.1016/j.ejps.2016.08.032

Abstract

Glioblastoma multiforme is a highly malignant, heterogenic, and drug resistant tumor. The blood-brain barrier (BBB), systemic cytotoxicity, and limited specificity are the main obstacles in designing brain tumor drugs. In this study a computational approach was used to design brain tumor drugs that could downregulate VEGF and IL17A in glioblastoma multiforme type four. Computational screening tools were used to evaluate potential candidates for antiangiogenic activity, target binding, BBB permeability, and ADME physicochemical properties. Additionally, in vitro cytotoxicity, migration, invasion, tube formation, apoptosis, ROS and ELISA assays were conducted for molecule 6 that was deemed most likely to succeed. The efflux ratio of membrane permeability and calculated docking scores of permeability to glycoproteins (P-gps) were used to determine the BBB permeability of the molecules. The results showed BBB permeation for molecule 6, with the predicted efficiency of 0.55kcal/mol and binding affinity of -37kj/mol corresponding to an experimental efflux ratio of 0.625 and predicted -15kj/mol of binding affinity for P-gps. Molecule 6 significantly affected the angiogenesis pathways by 2-fold downregulation of IL17A and VEGF through inactivation of active sites of HSP90 (predicted binding: -37kj/mol, predicted efficiency: 0.55kcal/mol) and p23 (predicted binding: 12kj/mol, predicted efficiency: 0.17kcal/mol) chaperon proteins. Additionally, molecule 6 activated the 17.38% relative fold of ROS level at 18.3μg/mL and upregulated the caspase which lead the potential synergistic apoptosis through the antiangiogenic activity of molecule 6 and thereby the highly efficacious anticancer upshot. The results indicate that the binding of the molecules to the therapeutic target is not essential to produce a lethal effect on cancer cells of the brain and that antiangiogenic efficiency is much more important.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.