Effect of Alpha-1-Adrenoceptor Blocker on Cytosolic Enzyme Targets for Potential use in Cancer Chemotherapy

Abstract

Doxazosin is one of the quinazoline-based alpha 1-adrenergic receptor antagonists in clinical use for the treatment of hypertension and benign prostate hyperplasia. Doxazosin-induced cytotoxicity studies, resulted in growth inhibition and apoptosis, show its potential therapeutic benefits for several forms of cancers. These effects on cells occur as adrenoceptor-independent mechanisms, as observed with other quinazoline family of alpha-1 blockers. Moreover, Doxazosin induced apoptosis is associated with pathways, including EGFR, NF-kappa beta and TGF-beta signaling which typically engage Src as a central signaling component. Recent evidences show that glutathione transferases, may also contribute to these signaling events, through the kinases that share signaling pathways with Src, responsible for the regulation of transferase activity. In addition, the overactive glutathione transferases are related with anticancer drug resistance, as well as cancer development. Therefore, in the present study, the anticancer potential of Doxazosin was investigated by in vitro enzyme assays that were used to develop full dose-response profiles of drug at varying doses. The drug dose that exerts 50% inhibition of enzyme activity is defined as IC50 value and determined through the nonlinear regression analysis of dose-response data. The IC50 values determined for Src kinase, total protein tyrosine kinase, cytosolic total Src family kinase and total glutathione transferase enzymes were within nanomolar to low micromolar range. These results suggest that Doxazosin may be used to improve multifunctional therapeutic formulations to provide reduced drug resistance and enhanced cytotoxicity at target tissues.