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

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 G2/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.