Antiproliferative mechanism of novel imidazoline compound in PC12 cells

Abstract

Common anti‐diabetic agents that cause release of insulin such as sulfonylurea drugs are linked to an increased risk of cancer. Clinically useful novel I1‐imidazoline receptor agonists such as moxonidine have pleiotropic effects, including antihypertensive and insulin sensitization effects. Recently, some of these compounds have been associated with cell death in vitro, however the mechanism of action is not fully elucidated. Our objective was to investigate the antiproliferative mechanism of the novel imidazoline compound, S43126 in PC12 pheochromocytoma cells. One group of cells were treated time dependently with vehicle or S43126 (1mM). A second group of cells were pretreated for 2 hours with z‐VAD‐fmk, NAC, SP600125, SB202190, followed by S43126 (1mM). Cells were then analyzed for apoptosis, ROS formation, mitochondrial membrane permeabilization, caspase activation and MAPK phosphorylation. Our results showed that in PC12 cells, stress activated MAPKs and caspases are involved in the antiproliferative activity of S43126. Our data also showed that in PC12 cells, S43126 increased oxidative stress and mitochondrial membrane permeabilization. These results indicate that S43126‐ induced PC12 cell death is partly mediated by oxidative stress, stress activated MAPKs, and caspases.These studies were supported in part by the Center for Dental Research at Loma Linda University