title: Antiproliferative effect induced by novel imidazoline S43126 in PC12 cells is mediated by ROS, stress activated MAPKs and caspases.
abstract: BACKGROUND
  Some imidazoline compounds have pleiotropic effects including cell death in vitro. We examined the antiproliferative action of a novel imidazoline compound S43126, and the role of the I1-imidazoline receptor, ROS, MAPKs and caspases in S43126-induced cell death.
  
  
  METHODS
  PC 12 cells were treated with various concentrations of S43126 in the presence or absence of several ligands, and the effects on cell proliferation, ROS levels, and apoptosis were evaluated using Trypan Blue, Alamar Blue, Western blot and microscopy.
  
  
  RESULTS
  We showed that S43126 reduced PC12 cell proliferation by greater than 50%, increased cell death by greater than 40% and increased apoptotic body formation. These effects were reversed by I1R-antagonist, efaroxan. S43126 also increased intracellular ROS levels by greater than 2.5-fold relative to vehicle-treated control. These effects were significantly inhibited by N-acetyl-cysteine. In addition, pharmacologic inhibitors of ERK, JNK and p38 MAPK, significantly reduced S43126-induced antiproliferative activity. Caspases 3, 8 and 9 were all activated in a time-dependent manner by S43126. Pan caspase inhibitor z-VAD-fmk, ameliorated the effects of S43126 on cell death and cell proliferation.
  
  
  CONCLUSIONS
  Our data showed that the effects of S43126 on PC12 cell death were partly mediated by ROS production, MAPK and caspase activation. These results further indicate an emerging role for I1R in apoptotic processes.
authors.affiliation: Center for Dental Research, Loma Linda University School of Dentistry, Loma Linda, United States.
authors.forename: Lancelot S
authors.initials: LS
authors.lastname: McLean
authors.affiliation: Faculté des Sciences Pharmaceutiques, Laboratoire de Chimie Pharmaceutique, Toulouse, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Crane
authors.affiliation: Faculté des Sciences Pharmaceutiques, Laboratoire de Chimie Pharmaceutique, Toulouse, France.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Baziard-Mouysset
authors.affiliation: Center for Dental Research, Loma Linda University School of Dentistry, Loma Linda, United States; Department of Diagnostic and Biomedical Sciences, University of Texas School of Dentistry, Houston, United States. Electronic address: lpedwards@llu.edu.
authors.forename: Lincoln P
authors.initials: LP
authors.lastname: Edwards
mesh_terms: D000818:Animals; D000840:Anisoles / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D054755:Imidazoline Receptors / Q000378:metabolism; D048288:Imidazolines / Q000008:administration & dosage / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000840:Anisoles; D054755:Imidazoline Receptors; D048288:Imidazolines; D017382:Reactive Oxygen Species; C000602789:S43126; C410887:imidazoline I1 receptors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases
keywords: Caspase; Cell death; Imidazoline; Mitogen activated protein kinase; Reactive oxygen species