Anticancer effects of disulfiram in T-cell malignancies through NPL4-mediated ubiquitin–proteasome pathway

Abstract

T‐cell malignancies, including T‐cell acute lymphoblastic leukemia (T‐ALL) and T‐cell lymphoma (TCL), are characterized by inferior treatment effects, high heterogeneity, poor prognosis, and a lack of specific therapeutic targets and drugs to improve outcome. Disulfiram (DSF) is a drug used to clinically control alcoholism that has recently been shown to be cytotoxic for multiple cancers. However, the underlying effects and mechanisms of DFS treatment in patients with T‐cell malignancies are not well characterized. In this study, we report that DSF promotes apoptosis and inhibits the proliferation of malignant T‐cell cell lines and primary T‐ALL cells. We provide evidence that DSF exerts anticancer activity in T‐cell malignancies by targeting the NPL4‐mediated ubiquitin–proteasome pathway. Notably, high expression of NPL4 and 2 ubiquitin–proteasome pathway genes, anaphase‐promoting complex subunit 1 (ANAPC1) and proteasome 26S subunit ubiquitin receptor, non‐ATPase 2 (PSMD2), was significantly associated with unfavorable overall survival (OS) for patients with TCL and T‐ALL (p < 0.05). More importantly, the weighted combination of NPL4, ANAPC1, and PSMD2 could visually display the 1‐, 3‐, and 5‐year OS rates for patients with T‐cell malignancies in a nomogram model and facilitate risk stratification. Specifically, risk stratification was an independent predictor of OS for patients with T‐cell malignancies. In conclusion, DSF might induce apoptosis and inhibit the proliferation of malignant T‐cells via the NPL4‐mediated ubiquitin–proteasome pathway and offer a potential therapeutic option for T‐cell malignancies.

TNFAIP3 mutation is an independent poor overall survival factor for patients with T‐cell acute lymphoblastic leukemia

“…The endpoint of this study was OS, and the OS was defined as the time from the date of diagnosis to the date of death or last follow‐up time. 8 , 16 , 22 , 23 , 24 , 25 Whole‐exome sequencing data from 121 T‐ALL patients in the PRJCA002270 dataset, including 96 children, 22 adults, and 3 cases of unknown age, were downloaded from the BioProject database ( https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA002270 ). 26 …”

“… 1 , 2 , 3 , 4 , 5 Despite intensive chemotherapy or hematopoietic stem cell transplantation (HSCT) being used for T‐ALL, less than 50% of adults and 75% of children with T‐ALL have a 5‐year overall survival (OS), particularly for relapsed patients. 1 , 6 , 7 , 8 However, the pathogenesis of T‐ALL is relatively complex, mainly due to T‐cell receptor (TCR) rearrangement during the development and differentiation of T‐cells, which easily results in gene alterations by unstable factors. 9 , 10 These genetic alterations lead to malignant transformation of T‐cells, resulting in high heterogeneity of T‐ALL cells.…”

“…T‐cell acute lymphoblastic leukemia (T‐ALL) is a highly aggressive leukemia with poor clinical outcome, and there is currently no effective or targeted therapy for this disease 1–5 . Despite intensive chemotherapy or hematopoietic stem cell transplantation (HSCT) being used for T‐ALL, less than 50% of adults and 75% of children with T‐ALL have a 5‐year overall survival (OS), particularly for relapsed patients 1,6–8 . However, the pathogenesis of T‐ALL is relatively complex, mainly due to T‐cell receptor (TCR) rearrangement during the development and differentiation of T‐cells, which easily results in gene alterations by unstable factors 9,10 .…”

Low Expression of CD5 and CD6 Is Associated with Poor Overall Survival for Patients with T-Cell Malignancies

“…PB mononuclear cells (PBMCs) isolated from T-ALL patients and HI CD3+ T cells positively selected by human CD3 microbeads (Miltenyi Biotec, Bergisch. Gladbach, Germany) were extracted with TRIzol reagent (Invitrogen, Carlsbad, California, USA) according to the manufacturer's instructions [ 30 ]. Total RNA was reverse transcribed with a complementary DNA (cDNA) synthesis kit (Applied Biosystems, Foster, CA, USA).…”

Disulfiram, an aldehyde dehydrogenase inhibitor, works as a potent drug against sepsis and cancer via NETosis, pyroptosis, apoptosis, ferroptosis, and cuproptosis

“…Consistent with their results, our recent data revealed that DSF induces apoptosis and inhibits cell proliferation in cell lines of malignant T-cells and in primary T-cell acute lymphoblastic leukemia (T-ALL) cells by targeting the NPL4-mediated ubiquitin-proteasome pathway. 23 Of note, Skrott et al 18 demonstrated that CuET induces apoptosis in sensitive cell lines, whereas in most cell lines, CuET induces apoptosis-independent cell death. The detailed molecular mechanism and significance of the apoptosis-independent cell death induced by DSF remain obscure.…”