Diethyl maleate inhibits MCA+TPA transformed cell growth via modulation of GSH, MAPK, and cancer pathways.

Abstract

Murine or human cancer cells have high glutathione levels. Depletion of the elevated GSH inhibits proliferation of cancer cells. Molecular basis for this observation is little understood. In an attempt to find out the underlying mechanism, we reproduced these effects in transformed C3H10T1/2 and BALB/c 3T3 cells using diethyl maleate and studied cytogenomic changes in the whole mouse genome using spotted 8 × 60 K arrays. Transformed cells revealed an increase in GSH levels. GSH depletion by DEM inhibited the growth of transformed cells. The non-cytotoxic dose of DEM (0.25 mM) resulted in GSH depletion, ROS generation, cell cycle arrest, apoptosis, decrease in anchorage independent growth, gene expression changes and activation of all three members of the MAPK family. Increase in intracellular GSH levels by GSHe countered the effect of DEM. These results support the physiological importance of GSH in regulation of gene expression for transformed cell growth restraint. This study is of interest in not only understanding the molecular biology of the transformed cells, but also in identifying new targets for development of gene therapy together with the chemotherapy.

• Authors: Shivam Priya, Akanksha Nigam, Preeti Bajpai, Sushil Kumar
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 219 Pg. 37-47 (Aug 05 2014) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 24814887 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Malates
• RNA, Messenger
• Reactive Oxygen Species
• diethyl malate
• Mitogen-Activated Protein Kinases
• Glutathione

Topics

• 3T3 Cells
• Animals
• Apoptosis (physiology)
• Cell Cycle Checkpoints (physiology)
• Cell Proliferation (physiology)
• Cell Transformation, Neoplastic (genetics, metabolism)
• Enzyme Activation (physiology)
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (physiology)
• Glutathione (metabolism)
• In Situ Nick-End Labeling
• Malates (pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C3H
• Mitogen-Activated Protein Kinases (metabolism)
• RNA, Messenger (chemistry, genetics)
• Reactive Oxygen Species (metabolism)
• Real-Time Polymerase Chain Reaction