Targeting integrin beta 1 using anti-tumorigenic quinazoline derivative in inhibition of glioblastoma cell invasion and survival: An in vitro preclinical study

Abstract

Objective: Glioblastoma (GBM) is the most common and malignant brain tumor, with a ~14.5 months median survival rate without disease-modifying curative treatment. After surgical resection, radiation, and adjuvant temozolomide (TMZ) chemotherapy is the first-line treatment of GBM with adverse effects, including bone marrow suppression, genotoxicity, and teratogenicity. Here, we report a synthetic quinazoline derivative that inhibits the growth of GBM cells as a new therapeutic approach.
Methods: A potent quinazoline derivative (6-Pyridin-2-yl-5,6-dihydro-benzo[4,5] imidazo[1,2-c] quinazoline) was synthesized by one chemical step with 90% yield, followed by in vitro testing in GBM and neuroblastoma cells.
Results: The in vitro studies showed that the quinazoline derivative is highly specific by decreasing GBM cell invasion while inducing cell death and inhibiting the cellular invasion in the three-dimensional Matrigel matrix. This compound is highly specific to GBM cell death compared with other cells. Synthetic quinazoline derivative is non-toxic to normal non-tumorigenic cells but toxic to cancerous cells. Under these experimental conditions, quinazoline derivatives caused inhibition of beta-1 integrin, which is an important cell adhesion molecule required for tumor cell invasion and metastasis, with extracellular matrix-mediated interactions. Furthermore, a synthetic quinazoline derivative decreases oncogenic PKC-epsilon activity in neuroblastoma cells.
Conclusions: These studies suggest that a synthetic quinazoline derivative may treat GBM effectively alone or combined with other chemotherapeutic/immunotherapeutic agents.