Liposome encapsulated Disulfiram inhibits NFκB pathway and targets breast cancer stem cells in vitro and in vivo
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Peng Liu1, Zhipeng Wang1, Sarah Brown1, Vinodh Kannappan1, Patricia Erebi Tawari1, Wenguo Jiang2, Juan M. Irache3, James Z. Tang1, Stephen Britland1, Angel L. Armesilla1, John L. Darling1, Xing Tang4 and Weiguang Wang1
1 Research Institute in Healthcare Science, Faculty of Science & Engineering, University of Wolverhampton, Wolverhampton, UK
2 Cardiff University-Peking University Cancer Institute, Cardiff University School of Medicine, Henry Wellcome Building, Heath Park, Cardiff, UK
3 School of Pharmacy, University of Navarra, Pamplona, Spain
4 School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
Weiguang Wang, email:
Keywords: Breast cancer, cancer stem cells, Disulfiram, NFkappaB, chemoresistance
Received: May 11, 2014 Accepted: July 3, 2014 Published: July 4, 2014
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.
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