“…The nano-encapsulation protects the thiol groups in DS and extends its half-life in the serum from less than 2 min to over 7 h and successfully delivers the intact DS to cancer tissues [ 14 ]. In combination with oral administration of copper gluconate, the nano-encapsulated DS demonstrated significantly stronger anticancer efficacy in mouse breast, liver, ovarian, lung and brain cancer models [ 11 , 14 , 28 – 31 ] (and our unpublished data). Fig.…”
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.
“…The nano-encapsulation protects the thiol groups in DS and extends its half-life in the serum from less than 2 min to over 7 h and successfully delivers the intact DS to cancer tissues [ 14 ]. In combination with oral administration of copper gluconate, the nano-encapsulated DS demonstrated significantly stronger anticancer efficacy in mouse breast, liver, ovarian, lung and brain cancer models [ 11 , 14 , 28 – 31 ] (and our unpublished data). Fig.…”
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.
“…However, special interest has been paid to the publication about the manifestation of the anticancer properties of disulfiram . Subsequent studies on cancer cells and animal models have confirmed this observation …”
Section: An Aldehyde Dehydrogenase Inhibitor Disulfiram As An Anticanmentioning
Malignant cells are characterized by an increased content of endogenous formaldehyde formed as a by‐product of biosynthetic processes. Accumulation of formaldehyde in cancer cells is combined with activation of the processes of cellular formaldehyde clearance. These mechanisms include increased ALDH and suppressed ADH5/FDH activity, which oncologists consider poor and favorable prognostic markers, respectively. Here, the sources and regulation of formaldehyde metabolism in cancer cells are reviewed. The authors also analyze the participation of oncoproteins such as fibulins, FGFR1, HER2/neu, FBI‐1, and MUC1‐C in the control of genes related to formaldehyde metabolism, suggesting the existence of two mutually exclusive processes in cancer cells: 1) production and 2) oxidation and elimination of formaldehyde from the cell. The authors hypothesize that the study of the anticancer properties of disulfiram and alpha lipoic acid – which affect the balance of formaldehyde in the body – may serve as the basis of future anticancer therapy.
“…[134,135] A combination of poly(pyridine-2-thiol) and copper could reverse the upregulation of oncogenes (CIRBP and STMN1) and the downregulation of tumor suppressor genes (CDKN1C and GADD45B) in tumor cells, which enhanced the specific cytotoxicity against cancer cells. Xu et al reported several GSH-responsive copper nanotoxins for specifically killing cancer cells.…”
Section: Copper Nanotoxinsmentioning
confidence: 99%
“…Xu et al reported several GSH-responsive copper nanotoxins for specifically killing cancer cells. [135] Adv. [134] They also synthesized poly(diethyldithiocarbamate) conjugated with β-D-galactose receptor targeting ligands.…”
Microelements such as copper are essential and involved in various biological processes and under strict homeostatic regulation. Compared to healthy individuals, cancer patients have aberrantly elevated intratumoral and systemic copper levels, which promote tumorigenesis, angiogenesis, tumor metastasis, and recurrence of diverse human cancers.
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