Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2

Abstract

Acute myeloid leukemia (AML) is a heterogeneous malignancy. Despite the advances in past decades, the clinical outcomes of AML patients remain poor. Leukemia stem cells (LSCs) is the major cause of the recurrence of AML even after aggressive treatment making, promoting development of LSC-targeted agents is an urgent clinical need. Although the antitumor activity of disulfiram (DS), an approved anti-alcoholism drug, has been demonstrated in multiple types of tumors including hematological malignancies such as AML, it remains unknown whether this agent would also be able to target cancer stem cells like LSCs. Here, we report the in vitro and in vivo activity of DS in combination with copper (Cu) against CD34+/CD38+ leukemia stem-like cells sorted from KG1α and Kasumi-1 AML cell lines, as well as primary CD34+ AML samples. DS plus Cu (DS/Cu) displayed marked inhibition of proliferation, induction of apoptosis, and suppression of colony formation in cultured AML cells while sparing the normal counterparts. DS/Cu also significantly inhibited the growth of human CD34+/CD38+ leukemic cell-derived xenografts in NOD/SCID mice. Mechanistically, DS/Cu-induced cytotoxicity was closely associated with activation of the stress-related ROS-JNK pathway as well as simultaneous inactivation of the pro-survival Nrf2 and nuclear factor-κB pathways. In summary, our findings indicate that DS/Cu selectively targets leukemia stem-like cells both in vitro and in vivo, thus suggesting a promising LSC-targeted activity of this repurposed agent for treatment of relapsed and refractory AML.

Loss of Tet2 affects proliferation and drug sensitivity through altered dynamics of cell-state transitions

“…6C) were used, namely the inflammatory stimulus interferon gamma (IFNg) and the aldehyde dehydrogenase inhibitor disulfiram (DS)(Amici et al, 2018;Xu et al, 2017). We confirmed that treatment with IFNg or DS enriched both Tet2 KO and WT populations for the differentiated cell state after 72 hours of exposure (Methods,Figure 4E, SupplementalFigure 6A-B).…”

HO-1 alleviates cholesterol-induced oxidative stress through activation of Nrf2/ERK and inhibition of PI3K/AKT pathways in endothelial cells

“…NF-κB consists of a family of transcription factors, including p52, p50, c-rel, RelA (p65) and RelB, and is a key transcription factor, which mediates immune responses to inflammation and cell proliferation, and protects against UV radiation (25). Several studies have shown that the generation of ROS can subsequently activate NF-κB (26,27). The results of the present study showed that expression levels of the NF-κB p65 subunit were increased following exposure to cholesterol, indicating that cholesterol induced the accumulation of ROS in EA.hy926 cells (28) and then caused the upregulation of NF-κB.…”

Disulfiram/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS/MAPK and Ferroptosis Pathways

“…Recent studies showed that DSF/Cu induced NPL4 (an adapter of p97/VCP segregase) aggregation and induced a complex cellular phenotype, finally leading to cell death [11]. Moreover, DSF/Cu was reported to induce significant cell cycle arrest and apoptosis, cause the disturbance of the ROS balance, and activate the stress-related ROS-JNK pathway as well as downregulate the NF-E2-related factor-2 (Nrf2) and Nuclear factor-кB (NF-кB) pathways in some tumor cells [12][13][14]. In addition, the anticancer effect of DSF is also related to epigenetics [15].…”