Disulfiram, an old drug with new potential therapeutic uses for human cancers and fungal infections

Sauna, Zuben E.; Shukla, Suneet; Ambudkar, Suresh V.

doi:10.1039/b504392a

Cited by 90 publications

(67 citation statements)

References 87 publications

(115 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to acting as an aldehyde dehydrogenase inhibitor, DSF has been shown to inhibit, e.g., DNA topoisomerases, matrix metalloproteinases, and ABC drug transport proteins, and thereby to have antitumor and chemosensitizing activities (23,24). Monensin is a Na + /H + antiporter with antibiotic and antimalarial activities.…”

Section: Resultsmentioning

confidence: 99%

High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth

Iljin

Ketola

Vainio

et al. 2009

Clinical Cancer Research

200

165

View full text Add to dashboard Cite

Purpose: To identify novel therapeutic opportunities for patients with prostate cancer, we applied high-throughput screening to systematically explore most currently marketed drugs and drug-like molecules for their efficacy against a panel of prostate cancer cells. Experimental Design: We carried out a high-throughput cell-based screening with proliferation as a primary end-point using a library of 4,910 drug-like small molecule compounds in four prostate cancer (VCaP, LNCaP, DU 145, and PC-3) and two nonmalignant prostate epithelial cell lines (RWPE-1 and EP156T). The EC 50 values were determined for each cell type to identify cancer selective compounds. The in vivo effect of disulfiram (DSF) was studied in VCaP cell xenografts, and gene microarray and combinatorial studies with copper or zinc were done in vitro for mechanistic exploration. Results: Most of the effective compounds, including antineoplastic agents, were nonselective and found to inhibit both cancer and control cells in equal amounts. In contrast, histone deacetylase inhibitor trichostatin A, thiram, DSF, and monensin were identified as selective antineoplastic agents that inhibited VCaP and LNCaP cell proliferation at nanomolar concentrations. DSF reduced tumor growth in vivo, induced metallothionein expression, and reduced DNA replication by downregulating MCM mRNA expression. The effect of DSF was potentiated by copper in vitro. Conclusions: We identified three novel cancer-selective growth inhibitory compounds for human prostate cancer cells among marketed drugs. We then validated DSF as a potential prostate cancer therapeutic agent. These kinds of pharmacologically wellknown molecules can be readily translated to in vivo preclinical studies and clinical trials. (Clin Cancer Res 2009;15(19):6070-8)

show abstract

Section: Resultsmentioning

confidence: 99%

High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth

Iljin

Ketola

Vainio

et al. 2009

Clinical Cancer Research

200

165

View full text Add to dashboard Cite

show abstract

“…In this study, we report that tumor suppressive effects of DSF on leukemic cells depend on cell density, and we describe mechanism of this phenomenon. We show that DSF can significantly limit viability of human myeloid leukemia U937 and ML-1 cells by inducing caspase-dependent programmed cell death pathways in doses 100-200 ng/ml that are safe in human plasma (26). This effect is clearly cell density-dependent because it is most prominent in cells seeded at low density (50,000 cells/ml) and disappears as cell density increases.…”

Section: Discussionmentioning

confidence: 78%

Copper ions regulate cytotoxicity of disulfiram to myeloid leukemia cells

Navrátilová

Jungová²,

Vaňhara³

et al. 2009

Int J Mol Med

View full text Add to dashboard Cite

Abstract. White blood cell (WBC) count is considered a prognostic risk factor in acute myeloid leukemia. As density of leukemic cells increases, the cytotoxic activity of certain anticancer drugs, such as vincristine and doxorubicin, progressively decreases. In this study, we investigated the cell density-dependent induction of apoptosis of human acute myeloid leukemia U937 and ML-1 cells by disulfiram (DSF), the dithiocarbamate drug recently proposed for treatment of human cancers. This effect is dependent on uptake of extracellular copper and its intracellular accumulation. Highdensity cells cannot uptake and accumulate this metal to a sufficient level that would allow induction of apoptosis due to progressive decrease of its extracellular concentration. Simple addition of copper can resume sensitivity of highdensity leukemic cells to DSF and improve efficiency of antileukemic therapies using this drug, thus providing benefit to patients with high WBC count.

show abstract

“…Disulfiram, a member of dithiocarbamate family, has been widely used as an antialcoholism drug in the clinics for .60 years. 3 Recently, it has been demonstrated to possess strong antitumor ability for various tumors, including NSCLC. encapsulation of disulfiram with high drug loading, and meanwhile, they were not suitable for treating lung cancers owing to their low delivery ability to lungs in an oral or intravenous administration.…”

Section: Introductionmentioning

confidence: 99%

Disulfiram-loaded porous PLGA microparticle for inhibiting the proliferation and migration of non-small-cell lung cancer

Wang¹,

Yang²,

Han³

et al. 2017

IJN

View full text Add to dashboard Cite

In this study, poly(lactic- co -glycolic acid) (PLGA) was used as a carrier to construct disulfiram-loaded porous microparticle through the emulsion solvent evaporation method, using ammonium bicarbonate as a porogen. The microparticle possessed highly porous surface, suitable aerodynamic diameter for inhalation (8.31±1.33 µm), favorable drug loading (4.09%±0.11%), and sustained release profile. The antiproliferation effect of release supernatant was detected through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using non-small-cell lung cancer A549 as a model, with only 13.3% of cell viability observed for the release supernatant at 7 days. The antiproliferation mechanism was elucidated to be associated with the enhanced induction of cell apoptosis and cell cycle arrest at S phase through flow cytometry and Western blotting analysis. Finally, wound healing and transwell migration assay showed that they could efficiently inhibit the cell migration. These results demonstrated that disulfiram-loaded porous PLGA microparticle could achieve favorable antitumor efficiency, implying the potential of treating non-small-cell lung cancer in a pulmonary administration.

show abstract

Disulfiram, an old drug with new potential therapeutic uses for human cancers and fungal infections

Cited by 90 publications

References 87 publications

High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth

High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth

Copper ions regulate cytotoxicity of disulfiram to myeloid leukemia cells

Disulfiram-loaded porous PLGA microparticle for inhibiting the proliferation and migration of non-small-cell lung cancer

Contact Info

Product

Resources

About