title: Differential Induction of Cytoplasmic Vacuolization and Methuosis by Novel 2-Indolyl-Substituted Pyridinylpropenones.
abstract: Because many cancers harbor mutations that confer resistance to apoptosis, there is a need for therapeutic agents that can trigger alternative forms of cell death. Methuosis is a novel form of non-apoptotic cell death characterized by accumulation of vacuoles derived from macropinosomes and endosomes. Previous studies identified an indole-based chalcone, 3-(5-methoxy-2-methylindol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (MOMIPP), that induces methuosis in human cancer cells. Herein, we describe the synthesis of related 2-indolyl substituted pyridinylpropenones and their effects on U251 glioblastoma cells. Increasing the size of the 2-indolyl substituent substantially reduces growth inhibitory activity and cytotoxicity, but does not prevent cell vacuolization. Computational models suggest that the results are not due to steric-driven conformational effects. The unexpected uncoupling of vacuolization and cell death implies that the relationship between endosomal perturbations and methuotic cell death is more complex than previously realized. The new series of compounds will be useful in further defining the molecular and cellular mechanisms underlying methuosis.
authors: Center for Drug Design and Development, Department of Medicinal & Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, 2801 W. Bancroft St., Toledo, Ohio 43606, United States.
authors: Christopher J
authors: CJ
authors: Trabbic
authors: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, 3000 Arlington Ave, Toledo, Ohio 43614, United States.
authors: Heather M
authors: HM
authors: Dietsch
authors: Center for Drug Design and Development, Department of Medicinal & Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, 2801 W. Bancroft St., Toledo, Ohio 43606, United States.
authors: Evan M
authors: EM
authors: Alexander
authors: Center for Drug Design and Development, Department of Medicinal & Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, 2801 W. Bancroft St., Toledo, Ohio 43606, United States.
authors: Peter I
authors: PI
authors: Nagy
authors: Center for Drug Design and Development, Department of Medicinal & Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, 2801 W. Bancroft St., Toledo, Ohio 43606, United States ; Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, 3000 Arlington Ave, Toledo, Ohio 43614, United States.
authors: Michael W
authors: MW
authors: Robinson
authors: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, 3000 Arlington Ave, Toledo, Ohio 43614, United States.
authors: Jean H
authors: JH
authors: Overmeyer
authors: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, 3000 Arlington Ave, Toledo, Ohio 43614, United States.
authors: William A
authors: WA
authors: Maltese
authors: Center for Drug Design and Development, Department of Medicinal & Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, 2801 W. Bancroft St., Toledo, Ohio 43606, United States.
authors: Paul W
authors: PW
authors: Erhardt
keywords: Methuosis; chalcones; glioblastoma multiforme; indole-based pyridinylpropenones; vacuolization