Seleno-cyclodextrin sensitises human breast cancer cells to TRAIL-induced apoptosis through DR5 induction and NF-κB suppression.

Abstract

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits potent antitumour activity via membrane receptors on cancer cells without deleterious side-effects for normal tissue. Unfortunately, like many other cancer types, breast cancer cells develop resistance to TRAIL; therefore, TRAIL-sensitising agents are currently being explored. In this study, we report that seleno-cyclodextrin (2-selenium-bridged β-cyclodextrin, 2-SeCD), a seleno-organic compound with glutathione peroxidase (GPx)-mimetic activity, sensitises TRAIL-resistant human breast cancer cells and xenograft tumours to undergo apoptosis. In vitro, 2-SeCD reduces the viability of cancer cells by inducing cell cycle arrest in G(2)/M phase. Furthermore, 2-SeCD efficiently sensitises MDA-MB-468 and T47D cells but not untransformed human mammary epithelial cells to TRAIL-mediated apoptosis, as evidenced by enhanced caspase activity and poly-ADP-ribose-polymerase (PARP) cleavage. From a mechanistic standpoint, we show that 2-SeCD induces the expression of TRAIL receptors DR5 but not DR4 on both mRNA and protein levels in a dose-dependent manner. Moreover, 2-SeCD treatment also suppresses TRAIL-induced nuclear factor-κB (NF-κB) pro-survival pathways by preventing cytosolic IκBα degradation and p65 nuclear translocation. Consequently, the combined administration suppresses anti-apoptotic proteins transcriptionally regulated by NF-κB. In vivo, 2-SeCD and TRAIL are well tolerated in mice, and their combination significantly inhibits the growth of MDA-MB-468 xenografts and promotes apoptosis. Up-regulation of DR5 and down-regulation of NF-κB by dual treatment were also observed in tumour tissues. Overall, 2-SeCD sensitises resistant breast cancer cells to TRAIL-based apoptosis in vitro and in vivo. These findings provide strong evidence for the therapeutic potential of this combination against breast cancers.

• Authors: Tingting Lin, Zhiying Ding, Nan Li, Jiayun Xu, Guimin Luo, Junqiu Liu, Jiacong Shen
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 47 Issue 12 Pg. 1890-907 (Aug 2011) ISSN: 1879-0852 [Electronic] England
• PMID: 21565489 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• 2-selenium-bridged beta-cyclodextrin
• Antineoplastic Agents
• NF-kappa B
• Organoselenium Compounds
• RNA, Small Interfering
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Recombinant Proteins
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• beta-Cyclodextrins
• Luciferases
• Poly(ADP-ribose) Polymerases
• beta-Galactosidase
• Caspases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Female
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Luciferases (metabolism)
• Mice
• NF-kappa B (antagonists & inhibitors)
• Organoselenium Compounds (pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• RNA, Small Interfering (metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Recombinant Proteins (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Transplantation, Heterologous
• beta-Cyclodextrins (pharmacology)
• beta-Galactosidase (metabolism)