Open AccessDifferential Induction of Cytoplasmic Vacuolization and Methuosis by Novel 2-Indolyl-Substituted Pyridinylpropenones
Author(s) -
Christopher Trabbic,
Heather M. Dietsch,
Evan Alexander,
Péter Nagy,
Marion F. Robinson,
Jean H. Overmeyer,
William A. Maltese,
Paul Erhardt
Publication year - 2013
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml4003925
Subject(s) - vacuolization , programmed cell death , chalcone , endosome , apoptosis , microbiology and biotechnology , cytoplasm , cytotoxicity , vacuole , chemistry , indole test , cancer cell , cell , cell growth , cancer research , biochemistry , stereochemistry , biology , cancer , in vitro , genetics , endocrinology
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.