Recent advances in the delivery of disulfiram: a critical analysis of promising approaches to improve its pharmacokinetic profile and anticancer efficacy

Farooq, Muhammad Asim; Aquib, Md; Khan, Daulat Haleem; Hussain, Zahid; Ahsan, Anam; Baig, Mirza Muhammad Faran Ashraf; Wande, Dickson Pius; Ahmad, Muhammad Masood; Ahsan, Hafiz Muhammad; Jiajie, Jiang; Wang, Bo

doi:10.1007/s40199-019-00308-w

Cited by 25 publications

(16 citation statements)

References 60 publications

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“…Also, it is known that there is an inhibitor of ALDH2, disulfiram, which was used as the first-line therapy to treat alcoholism [ 52 ]. Our result showed that the resistant cell line of CRC has low expression of ALDH2, and low expression of ALDH2 is also associated with poor overall survival of CRC.…”

Section: Discussionmentioning

confidence: 99%

Aldehyde Dehydrogenase 2 Family Member (ALDH2) Is a Therapeutic Index for Oxaliplatin Response on Colorectal Cancer Therapy with Dysfunction p53

Wang

Batzorig

Hung

et al. 2022

BioMed Research International

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Oxaliplatin resistance is a major issue in the treatment of p53 mutant colorectal cancer (CRC). Finding the specific biomarkers would improve therapeutic efficacy of patients with CRC. In order to figure out the biomarker for CRC patients with mutant p53 access oxaliplatin, a Gene Expression Omnibus dataset (GSE42387) was used to determine differentially expressed genes (DEGs). The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software were used to predict protein-protein interactions. The Database for Annotation, Visualization, and Integrated Discovery online tool was used to group the DEGs into their common pathways. 138 DEGs were identified with 46 upregulated and 92 downregulated. In the PPI networks, 7 of the upregulated genes and 13 of the downregulated genes were identified as hub genes (high degrees). Four hub genes, aldehyde dehydrogenase 2 family member (ALDH2), aldo-keto reductase family 1 member B1 (AKR1B1), aldo-keto reductase family 1 member B10 (AKR1B10), and monoglyceride lipase (MGLL) were enriched in the most significant pathway, glycerolipid metabolism. Further, we found that low expression of ALDH2 is correlated with poor overall survival and oxaliplatin resistance. Finally, we found that combined treatment with ALDH2 inhibitor and oxaliplatin will reduce the sensitivity to oxaliplatin in p53 mutant HT29 cells. In conclusion, we demonstrate that ALDH2 may be a biomarker for oxaliplatin resistance status in CRC patients and bring new insight into treatment strategy for p53 mutant CRC patients.

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Section: Discussionmentioning

confidence: 99%

Aldehyde Dehydrogenase 2 Family Member (ALDH2) Is a Therapeutic Index for Oxaliplatin Response on Colorectal Cancer Therapy with Dysfunction p53

Wang

Batzorig

Hung

et al. 2022

BioMed Research International

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“…This apparent discrepancy to the strong tumoricidal effect of disulfiram observed in preclinical studies might suggest that in the clinical setting, therapeutically effective disulfiram (Cu 2+ ) concentrations are not reached in the tumors. Encapsulation of disulfiram in polymeric nanoformulations, micelles, microparticles, nanocrystals or lipid-based drug delivery systems might be approaches in the future to improve the pharmacokinetic profile of disulfiram in patients [ 70 ]. Moreover, surface receptor-specific targeting of disulfiram-bearing nanoparticles might enhance tumor specificity and cellular drug uptake of disulfiram therapy [ 71 ].…”

Section: Discussionmentioning

confidence: 99%

Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study

et al. 2021

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Mesenchymal glioblastoma stem cells (GSCs), a subpopulation in glioblastoma that are responsible for therapy resistance and tumor spreading in the brain, reportedly upregulate aldehyde dehydrogenase isoform-1A3 (ALDH1A3) which can be inhibited by disulfiram (DSF), an FDA-approved drug formerly prescribed in alcohol use disorder. Reportedly, DSF in combination with Cu2+ ions exerts multiple tumoricidal, chemo- and radio-therapy-sensitizing effects in several tumor entities. The present study aimed to quantify these DSF effects in glioblastoma stem cells in vitro, regarding dependence on ALDH1A3 expression. To this end, two patient-derived GSC cultures with differing ALDH1A3 expression were pretreated (in the presence of CuSO4, 100 nM) with DSF (0 or 100 nM) and the DNA-alkylating agent temozolomide (0 or 30 µM) and then cells were irradiated with a single dose of 0–8 Gy. As read-outs, cell cycle distribution and clonogenic survival were determined by flow cytometry and limited dilution assay, respectively. As a result, DSF modulated cell cycle distribution in both GSC cultures and dramatically decreased clonogenic survival independently of ALDH1A3 expression. This effect was additive to the impairment of clonogenic survival by radiation, but not associated with radiosensitization. Of note, cotreatment with temozolomide blunted the DSF inhibition of clonogenic survival. In conclusion, DSF targets GSCs independent of ALDH1A3 expression, suggesting a therapeutic efficacy also in glioblastomas with low mesenchymal GSC populations. As temozolomide somehow antagonized the DSF effects, strategies for future combination of DSF with the adjuvant standard therapy (fractionated radiotherapy and concomitant temozolomide chemotherapy followed by temozolomide maintenance therapy) are not supported by the present study.

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“…DSF is a hydrophobic compound (with an aqueous solubility of 0.2 mg/mL) and is unstable under acidic conditions (eg, stomach) and fast clearance from the bloodstream in vivo. [ 50,51 ] Besides, DDC, the main metabolite of DSF with potent antitumor activity, is also unstable. [ 52 ] Moreover, DSF medication should be avoided in patients with certain diseases, including myocardial or coronary occlusion, psychosis, and allergy to DSF or its derivatives.…”

Section: Improving Disulfiram‐based Cancer Therapy Through Nanotechnologymentioning

confidence: 99%

Teaching new tricks to old dogs: A review of drug repositioning of disulfiram for cancer nanomedicine

Zhao

Tang

Huang

2021

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The increasing incidence and mortality of malignant tumors have required the development of diversified innovative therapies. Compared with the new therapeutic molecule invention, it is a more economical and efficient way to reposition old drugs that have been marketed or in clinical trials for tumor treatment. Studies have been carried out for repositioning the old approval drugs that are widely applied clinically with reliable biosafety and effectiveness evidence, including aspirin, artemisinin (and its derivatives, eg, dihydroartemisinin), metformin, and disulfiram (DSF). In addition to the approved pharmacological activity, these old drugs exhibited broad tumor‐suppressive effects. This review summarizes the drug repositioning strategy of DSF through nanotechnology and outlines the DSF nano‐formulations for cancer targeting delivery and therapy.

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Recent advances in the delivery of disulfiram: a critical analysis of promising approaches to improve its pharmacokinetic profile and anticancer efficacy

Cited by 25 publications

References 60 publications

Aldehyde Dehydrogenase 2 Family Member (ALDH2) Is a Therapeutic Index for Oxaliplatin Response on Colorectal Cancer Therapy with Dysfunction p53

Aldehyde Dehydrogenase 2 Family Member (ALDH2) Is a Therapeutic Index for Oxaliplatin Response on Colorectal Cancer Therapy with Dysfunction p53

Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study

Teaching new tricks to old dogs: A review of drug repositioning of disulfiram for cancer nanomedicine

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