CGP74514A enhances TRAIL-induced apoptosis in breast cancer cells by reducing X-linked inhibitor of apoptosis protein.

Abstract

BACKGROUND:

Despite the selectivity of Tumor necrosis factor Related Apoptosis-Inducing Ligand (TRAIL) for cancer cell killing activity, breast cancer cells are resistant to TRAIL-induced apoptosis for various reasons.

MATERIALS AND METHODS:

From a functionally-characterized small-molecule dataset, CGP74514A was identified as a TRAIL sensitizer in MCF-7 breast cancer cells. Combination of sub-toxic dose of TRAIL with CGP74514A was evaluated in three TRAIL-resistant breast cancer cells, MCF-7, T47D and SK-BR-3.

RESULTS:

In all tested cells, CGP74514A enhanced TRAIL sensitivity. Combination treatment triggered apoptotic events faster than single treatment. Regarding its mechanism of action, CGP74514A reduced cytosolic X-linked inhibitor of apoptosis protein (XIAP). Small interfering RNA-mediated knockdown experiments showed that reduction of XIAP is the reason of sensitization.

CONCLUSION:

CGP74514A sensitized breast cancer cells to TRAIL via reduction of XIAP expression level.

• Authors: Sojung Park, Sang-Mi Shim, Sang-Hee Nam, Ladislav Andera, Nayoung Suh, Inki Kim
• Journal: Anticancer research (Anticancer Res) Vol. 34 Issue 7 Pg. 3557-62 (Jul 2014) ISSN: 1791-7530 [Electronic] Greece
• PMID: 24982369 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Chemical References

• N(2)-(2-aminocyclohexyl)-N(6)-(3-chlorophenyl)-9-ethyl-9H-purine-2,6-diamine
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• 2-Aminopurine

Topics

• 2-Aminopurine (administration & dosage, analogs & derivatives, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Drug Synergism
• Female
• Humans
• MCF-7 Cells
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage, pharmacology)
• X-Linked Inhibitor of Apoptosis Protein (metabolism)