Differential Induction of Cytoplasmic Vacuolization and Methuosis by Novel 2-Indolyl-Substituted Pyridinylpropenones
Christopher J Trabbic1, Heather M Dietsch2, Evan M Alexander1
1Center 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.
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.
Insights
Researchers explored new compounds to induce methuosis, a non-apoptotic cancer cell death. While larger substituents reduced toxicity, vacuolization persisted, suggesting complex cell death mechanisms.
Area of Science:
- Medicinal Chemistry
- Cell Biology
- Cancer Research
Background:
- Cancer cells often resist apoptosis, necessitating alternative cell death strategies.
- Methuosis, a novel non-apoptotic cell death, involves vacuole accumulation from macropinosomes and endosomes.
- Previous work identified MOMIPP, an indole-based chalcone, that triggers methuosis in human cancer cells.
Purpose of the Study:
- Synthesize and evaluate novel 2-indolyl substituted pyridinylpropenones.
- Investigate the effects of these compounds on U251 glioblastoma cells.
- Elucidate the relationship between structural modifications, methuosis induction, and cell death.
Main Methods:
- Chemical synthesis of novel indolyl substituted pyridinylpropenones.
- Cytotoxicity and growth inhibition assays on U251 glioblastoma cells.
- Microscopic analysis to observe vacuolization and computational modeling.
Main Results:
- Increasing the size of the 2-indolyl substituent decreased growth inhibition and cytotoxicity.
- Cell vacuolization was observed even when cytotoxicity was reduced.
- Computational models did not support steric-driven conformational effects as the cause.
Conclusions:
- The study synthesized and tested new compounds targeting methuosis.
- An uncoupling of vacuolization and cell death was observed, indicating complexity in methuosis mechanisms.
- These compounds offer a valuable tool for further research into methuosis.
