Recent Advances in Antabuse (Disulfiram): The Importance of its Metal-binding Ability to its Anticancer Activity

Viola-Rhenals, Maricela; Patel, Kush; Jaimes-Santamaria, Laura; Wu, Guojun; Liu, Jinbao; Dou, Q. Ping

doi:10.2174/0929867324666171023161121

Cited by 68 publications

(50 citation statements)

References 108 publications

(153 reference statements)

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“…DS shows very strong anticancer activity in laboratory but not in clinic. Elucidation of the key anticancer chemical structure of DS will speed up its translation into clinic as a cancer treatment [ 34 ]. The anticancer activity of DS is Cu(II) and other transition metal ions dependent.…”

Section: Discussionmentioning

confidence: 99%

“…Cu-DDC is also toxic to lung cancer cells and targets CSC-like cells. Copper, a redox metal ion, can produce ROS using Fenton and Haber Weiss reactions and induce apoptosis [ 34 ]. Development of copper-based drugs has been very attractive for anticancer drug development [ 41 , 42 ] but transport of copper into cells is strictly regulated by a trans-membrane copper transporter Ctr1 [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

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Investigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell line

et al. 2018

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BackgroundDisulfiram (DS), an antialcoholism medicine, demonstrated strong anticancer activity in the laboratory but did not show promising results in clinical trials. The anticancer activity of DS is copper dependent. The reaction of DS and copper generates reactive oxygen species (ROS). After oral administration in the clinic, DS is enriched and quickly metabolised in the liver. The associated change of chemical structure may make the metabolites of DS lose its copper-chelating ability and disable their anticancer activity. The anticancer chemical structure of DS is still largely unknown. Elucidation of the relationship between the key chemical structure of DS and its anticancer activity will enable us to modify DS and speed its translation into cancer therapeutics.MethodsThe cytotoxicity, extracellular ROS activity, apoptotic effect of DS, DDC and their analogues on cancer cells and cancer stem cells were examined in vitro by MTT assay, western blot, extracellular ROS assay and sphere-reforming assay.ResultsIntact thiol groups are essential for the in vitro cytotoxicity of DS. S-methylated diethyldithiocarbamate (S-Me-DDC), one of the major metabolites of DS in liver, completely lost its in vitro anticancer activity. In vitro cytotoxicity of DS was also abolished when its thiuram structure was destroyed. In contrast, modification of the ethyl groups in DS had no significant influence on its anticancer activity.ConclusionsThe thiol groups and thiuram structure are indispensable for the anticancer activity of DS. The liver enrichment and metabolism may be the major obstruction for application of DS in cancer treatment. A delivery system to protect the thiol groups and development of novel soluble copper-DDC compound may pave the path for translation of DS into cancer therapeutics.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4617-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Investigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell line

et al. 2018

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“…Furthermore, this drug specifically and effectively terminates drug-resistant cancer stem cells (CSCs) and reverse chemoresistance [3,4]. DS also has a significant synergic cytotoxicity with a wide range of first-line anticancer drugs such as cisplatin, 5-flurouracil, paclitaxel, gemcitabine, doxorubicin and temozolomide in vitro and saves normal cells in kidney, gut and bone marrow in vivo by increasing the therapeutic index [5,6,7]. The anticancer activity of DS is copper (II)-dependent as DS strongly chelates Cu to form a DS/Cu complex [8] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment

et al. 2019

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Disulfiram (DS), an anti-alcoholism medicine, shows strong anti-cancer activity in the laboratory, but the application in clinics for anti-cancer therapy has been limited by its prompt metabolism. Conventional liposomes have shown limited ability to protect DS. Therefore, the aim of this study is to develop PEGylated liposomes of DS for enhanced bio-stability and prolonged circulation. PEGylated liposomes were prepared using ethanol-based proliposome methods. Various ratios of phospholipids, namely: hydrogenated soya phosphatidylcholine (HSPC) or dipalmitoyl phosphatidylcholine (DPPC) and N-(Carbonyl-methoxypolyethylenglycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG2000) with cholesterol were used. DS was dissolved in the alcoholic solution in different lipid mol% ratios. The size of the resulting multilamellar liposomes was reduced by high-pressure homogenization. Liposomal formulations were characterized by size analysis, zeta potential, drug loading efficiency and stability in horse serum. Small unilamellar vesicles (SUVs; nanoliposomes) were generated with a size of approximately 80 to 120 nm with a polydispersity index (PDI) in the range of 0.1 to 0.3. Zeta potential values of all vesicles were negative, and the negative surface charge intensity tended to increase by PEGylation. PEGylated liposomes had a smaller size (80–90 nm) and a significantly lower PDI. All liposomes showed similar loading efficiencies regardless of lipid type (HSPC or DPPC) or PEGylations. PEGylated liposomes provided the highest drug biostability amongst all formulations in horse serum. PEGylated DPPC liposomes had t1/2 =77.3 ± 9.6 min compared to 9.7 ± 2.3 min for free DS. In vitro cytotoxicity on wild type and resistant colorectal cancer cell lines was evaluated by MTT assay. All liposomal formulations of DS were cytotoxic to both the wild type and resistant colorectal cancer cell lines and were able to reverse chemoresistance at low nanomolar concentrations. In conclusion, PEGylated liposomes have a greater potential to be used as an anticancer carrier for disulfiram.

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“…Moreover, 5-aza-2’-deoxycytidine was demonstrated to suppress hormone-independent growth of PCa in castrated mice 107. Furthermore, RG108 and disulfiram, two nonnucleoside compounds that supposedly inhibit enzymatic activity of human DNMTs, exerted antitumor effects in PCa cell lines and animal models 108109. Both types of DNMT inhibitors are thought to reactivate tumor suppressor genes, such as GSTP1, APC, RASSF1A , and RAR2 , by specific demethylation of their promoters 110.…”

Section: Epigenetic Therapymentioning

confidence: 99%

Epigenetic regulation of prostate cancer: the theories and the clinical implications

Liao

2019

Asian J Androl

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Epigenetics is the main mechanism that controls transcription of specific genes with no changes in the underlying DNA sequences. Epigenetic alterations lead to abnormal gene expression patterns that contribute to carcinogenesis and persist throughout disease progression. Because of the reversible nature, epigenetic modifications emerge as promising anticancer drug targets. Several compounds have been developed to reverse the aberrant activities of enzymes involved in epigenetic regulation, and some of them show encouraging results in both preclinical and clinical studies. In this article, we comprehensively review the up-to-date roles of epigenetics in the development and progression of prostate cancer. We especially focus on three epigenetic mechanisms: DNA methylation, histone modifications, and noncoding RNAs. We elaborate on current models/theories that explain the necessity of these epigenetic programs in driving the malignant phenotypes of prostate cancer cells. In particular, we elucidate how certain epigenetic regulators crosstalk with critical biological pathways, such as androgen receptor (AR) signaling, and how the cooperation dynamically controls cancer-oriented transcriptional profiles. Restoration of a "normal" epigenetic landscape holds promise as a cure for prostate cancer, so we concluded by highlighting particular epigenetic modifications as diagnostic and prognostic biomarkers or new therapeutic targets for treatment of the disease.

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Recent Advances in Antabuse (Disulfiram): The Importance of its Metal-binding Ability to its Anticancer Activity

Abstract: This review confirms the importance of chemical features of compounds such as Disulfiram to their biological activities, and supports repurposing DSF as a potential anticancer agent.

Cited by 68 publications

References 108 publications

Investigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell line

Investigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell line

Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment

Epigenetic regulation of prostate cancer: the theories and the clinical implications

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