Liposome encapsulated Disulfiram inhibits NFκB pathway and targets breast cancer stem cellsin vitroandin 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.

In Vitro Cytotoxicity Effect on McF-7 Cell Line of Co-Encapsulated Artesunate and Curcumin Liposome

“…In order to overcome the undesirable side effects of drugs, synergistic combination of two or more drugs is a flexible strategy (16). In comparison with single drug delivery system, co-delivery of drugs through nanocarriers and convey them to the same cancer cell simultaneously (17,18).…”

Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds

“…It inhibits aldehyde dehydrogenase, which is an enzyme highly expressed in TMZ-refractory and GBM CSCs [37][38][39]. Several targets of disulfiram, leading to in vitro and in vivo anticancer activities, have been suggested, such as the inhibition of the ubiquitin proteasome system [40] and nuclear factor (NF)-κB pathways [41], and epigenetic mechanisms in prostate cancer cells [42] and acute myeloid leukemia (AML) [43]. Disulfiram elicits copperdependent pro-apoptotic and antiangiogenic effects in GBM, via the epidermal growth factor receptor (EGFR)/Src/VEGF pathway [44].…”

Development and characterisation of disulfiram-loaded PLGA nanoparticles for the treatment of non-small cell lung cancer

“…The antialcoholism drug disulfiram (DSF) has been shown to have an anticancer effect against prostate cancer, breast cancer, brain tumours, leukaemia, cervical adenocarcinoma and NSCLC [21][22][23][24][25][26][27][28][29][30][31][32][33][34]. Furthermore, DSF has been shown to be an irreversible aldehyde dehydrogenase (ALDH) inhibitor targeting CSCs [22,[35][36].…”

“…Therefore, a drug delivery system which protects DSF from metabolism in the blood stream and targets it to NSCLC cells would expedite translation of DSF into the clinic as a treatment for NSCLC. To this end, we recently formulated DSF into liposomes, PLGA and gold nanoparticles, which at very low dose in combination with an oral Cu supplement demonstrated a significant tumour inhibiting effect in xenograft mouse models of breast and lung cancer [36,45].…”