1 research outputs found
Liposome encapsulated Disulfiram inhibits NFκB pathway and targets breast cancer stem cells in vitro and in vivo
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 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