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

Resumen:
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 liposomeencapsulated 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 NF¿B activation in bridging hypoxia and CSC-related pan-resistance, the CSC characters and drug sensitivity in BC cell lines were observed in NF¿B p65 transfected cell lines. The effect of Lipo-DS on the NF¿B 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 NF¿B and chemoresistance. Transfection of BC cells with NF¿B p65 also induced CSC characters and pan-resistance. Lipo-DS blocked NF¿B 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 NF¿B activation is responsible for stemness and chemoresistance in BCSCs. Lipo-DS targets NF¿B pathway and CSCs. Further study may translate DS into cancer therapeutics.