Abstract
A variety of drugs targeting monoamine receptors are routinely used in human pharmacology. We assessed the effect of these drugs on the viability of tumor-initiating cells isolated from patients with glioblastoma. Among the drugs targeting monoamine receptors, we identified prazosin, an α1- and α2B-adrenergic receptor antagonist, as the most potent inducer of patient-derived glioblastoma-initiating cell death. Prazosin triggered apoptosis of glioblastoma-initiating cells and of their differentiated progeny, inhibited glioblastoma growth in orthotopic xenografts of patient-derived glioblastoma-initiating cells, and increased survival of glioblastoma-bearing mice. We found that prazosin acted in glioblastoma-initiating cells independently from adrenergic receptors. Its off-target activity occurred via a PKCδ-dependent inhibition of the AKT pathway, which resulted in caspase-3 activation. Blockade of PKCδ activation prevented all molecular changes observed in prazosin-treated glioblastoma-initiating cells, as well as prazosin-induced apoptosis. Based on these data, we conclude that prazosin, an FDA-approved drug for the control of hypertension, inhibits glioblastoma growth through a PKCδ-dependent mechanism. These findings open up promising prospects for the use of prazosin as an adjuvant therapy for glioblastoma patients.
Overview
- The study assessed the effect of drugs targeting monoamine receptors on the viability of tumor-initiating cells isolated from patients with glioblastoma. The hypothesis being tested was whether prazosin, an α1- and α2B-adrenergic receptor antagonist, would be the most potent inducer of patient-derived glioblastoma-initiating cell death. The methodology used for the experiment included the use of patient-derived glioblastoma-initiating cells, which were treated with prazosin and other drugs targeting monoamine receptors. The primary objective of the study was to identify the most potent inducer of patient-derived glioblastoma-initiating cell death and to determine the mechanism by which prazosin inhibits glioblastoma growth.
Comparative Analysis & Findings
- The study found that prazosin was the most potent inducer of patient-derived glioblastoma-initiating cell death among the drugs targeting monoamine receptors. Prazosin triggered apoptosis of glioblastoma-initiating cells and of their differentiated progeny, inhibited glioblastoma growth in orthotopic xenografts of patient-derived glioblastoma-initiating cells, and increased survival of glioblastoma-bearing mice. The study also found that prazosin acted in glioblastoma-initiating cells independently from adrenergic receptors. Its off-target activity occurred via a PKCδ-dependent inhibition of the AKT pathway, which resulted in caspase-3 activation. Blockade of PKCδ activation prevented all molecular changes observed in prazosin-treated glioblastoma-initiating cells, as well as prazosin-induced apoptosis.
Implications and Future Directions
- The study's findings suggest that prazosin, an FDA-approved drug for the control of hypertension, could be used as an adjuvant therapy for glioblastoma patients. The study's findings also open up promising prospects for the use of prazosin as a target for the development of new therapies for glioblastoma. Future research could focus on further exploring the mechanism by which prazosin inhibits glioblastoma growth and on identifying other drugs that target the same pathway.