Liposome encapsulated Disulfiram inhibits NFκB pathway and targets breast cancer stem cells in vitro and in vivo.

Abstract

Breast cancer stem cells (BCSCs) are pan-resistant to different anticancer agents and responsible for cancer relapse. Disulfiram (DS), an antialcoholism drug, targets CSCs and reverses pan-chemoresistance. The anticancer application of DS is limited by its very short half-life in the bloodstream. This prompted us to develop a liposome-encapsulated DS (Lipo-DS) and examine its anticancer effect and mechanisms in vitro and in vivo. The relationship between hypoxia and CSCs was examined by in vitro comparison of BC cells cultured in spheroid and hypoxic conditions. To determine the importance of NFκB activation in bridging hypoxia and CSC-related pan-resistance, the CSC characters and drug sensitivity in BC cell lines were observed in NFκB p65 transfected cell lines. The effect of Lipo-DS on the NFκB pathway, CSCs and chemosensitivity was investigated in vitro and in vivo. The spheroid cultured BC cells manifested CSC characteristics and pan-resistance to anticancer drugs. This was related to the hypoxic condition in the spheres. Hypoxia induced activation of NFκB and chemoresistance. Transfection of BC cells with NFκB p65 also induced CSC characters and pan-resistance. Lipo-DS blocked NFκB activation and specifically targeted CSCs in vitro. Lipo-DS also targeted the CSC population in vivo and showed very strong anticancer efficacy. Mice tolerated the treatment very well and no significant in vivo nonspecific toxicity was observed. Hypoxia induced NFκB activation is responsible for stemness and chemoresistance in BCSCs. Lipo-DS targets NFκB pathway and CSCs. Further study may translate DS into cancer therapeutics.

• Authors: Peng Liu, Zhipeng Wang, Sarah Brown, Vinodh Kannappan, Patricia Erebi Tawari, Wenguo Jiang, Juan M Irache, James Z Tang, Angel L Armesilla, John L Darling, Xing Tang, Weiguang Wang
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 17 Pg. 7471-85 (Sep 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25277186 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Liposomes
• NF-kappa B
• Disulfiram

Topics

• Animals
• Antineoplastic Agents (administration & dosage)
• Blotting, Western
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Disulfiram (administration & dosage)
• Electrophoretic Mobility Shift Assay
• Female
• Flow Cytometry
• Fluorescent Antibody Technique
• Heterografts
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Liposomes
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• NF-kappa B (drug effects, metabolism)
• Neoplastic Stem Cells (drug effects, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction