Our website uses cookies to improve your on-site experience. By using the website, cookies are being used as described in our Policy Document
Warning: To log in you will need to enable cookies and reload the page (Policy Document)
My ePortfolio Register   
 

Abstract | Full HTML Article | PDF ecancer 13 890 / https://doi.org/10.3332/ecancer.2019.890

Research

Anticancer response to disulfiram may be enhanced by co-treatment with MEK inhibitor or oxaliplatin: modulation by tetrathiomolybdate, KRAS/BRAF mutations and c-MYC/p53 status

Ammonium tetrathiomolybdate (TTM) and disulfiram (DSF) are copper (Cu) chelators in cancer clinical trials partly because Cu chelation: a) restricts the activity of Cu-binding MEK1/2 enzymes which drive tumourigenesis by KRAS or BRAF oncogenic mutations and b) enhances uptake of oxaliplatin (OxPt), clinically used in advanced KRAS-mutant colorectal carcinomas (CRC). Whereas TTM decreases intracellular Cu trafficking, DSF can reach other Cu-dependent intracellular proteins. Since the use of individual or combined Cu chelation may help or interfere with anti-cancer therapy, this study investigated whether TTM modifies the response to DSF supplemented with: 1) UO126, a known MEK1/2 inhibitor; 2) other Cu chelators like neocuproine (NC) or 1, 10-o-phenanthroline (OPT) in wt p53 melanoma cells differing in BRAF or KRAS mutations; 3) OxPt in mutant p53 CRC cells devoid of KRAS and BRAF mutations or harbouring either KRAS or BRAF mutations. TTM was not toxic against V600E-mut-BRAF A375 and G12D-mut-KRAS/high c-myc C8161 melanoma cells. Moreover, TTM protected both melanoma types from toxicity induced by DSF, NC and co-treatment with sub-lethal levels of DSF and the MEK inhibitor, UO126. Toxicity by co-treatment with DSF OPT was poorly reversed by TTM in C8161 melanoma cells. In contrast to the greater toxicity of 0.1 μM DSF against mutant p53 CRC cells irrespective of their KRAS mutation, TTM did not protect G12V-mut-KRAS/high c-myc SW620 CRC from DSF OxPt compared to KRAS-WT/BRAF-WT Caco-2 CRC. Our results show that DSF co-treatment with: a) MEK inhibitors may enhance tumour suppression; b) OxPt in CRC may counteract impaired response to cetuximab by KRAS/BRAF mutations and c) as a single treatment, TTM may be less effective than DSF and decreases the efficacy of the latter.

Highlights

(a) Potentiation of melanoma antitumour toxicity of DSF by MEK inhibitor is reversed by TTM.

(b) KRAS/c-MYC dysregulation attenuates TTM reversion of melanoma toxicity by DSF OPT.

(c) KRAS/c-MYC dysregulation increases melanoma NC toxicity reversed by TTM.

(d) BRAF mutation and lower c-MYC may attenuate toxicity by DSF ± OxPt in colorectal cancer cells.

Keywords: cu chelation, Cu-MEK activation, KRAS/c-MYC, p53 status, oxaliplatin, tetrathiomolybdate, disulfiram

Loading Article Metrics ... Please wait

Related articles

Review: Conservative treatment for well-differentiated endometrial cancer: when and why it should be considered in young women

Abstract | Full Article | PDF Published: 17 Jan 2019 / https://doi.org/10.3332/ecancer.2019.892

Research: Proteomics characterisation of central nervous system metastasis biomarkers in triple negative breast cancer

Abstract | Full Article | PDF Published: 15 Jan 2019 / https://doi.org/10.3332/ecancer.2019.891

Research: The cardioprotective effect of dexrazoxane (Cardioxane) is consistent with sequestration of poly(ADP-ribose) by self-assembly and not depletion of topoisomerase 2B

Abstract | Full Article | PDF Published: 21 Dec 2018 / https://doi.org/10.3332/ecancer.2018.889

Review: Spontaneous testicular tumor regression: case report and historical review

Abstract | Full Article | PDF | Spanish Published: 18 Dec 2018 / https://doi.org/10.3332/ecancer.2018.888

Case Report: Palliative splenic irradiation for symptomatic splenomegaly in non-Hodgkin lymphoma

Abstract | Full Article | PDF Published: 13 Dec 2018 / https://doi.org/10.3332/ecancer.2018.887



Founding partners

European Cancer Organisation European Institute of Oncology

Founding Charities

Foundazione Umberto Veronesi Fondazione IEO Swiss Bridge

Published by

ecancer Global Foundation