The comparative effects of diethyldithiocarbamate-copper complex with established proteasome inhibitors on expression levels of CYP1A2/3A4 and their master regulators, aryl hydrocarbon and pregnane X receptor in primary cultures of human hepatocytes
- 5 August 2016
- journal article
- Published by Wiley in Fundamental & Clinical Pharmacology
- Vol. 30 (6), 585-595
- https://doi.org/10.1111/fcp.12221
Abstract
In the recent years, a therapeutic potential of disulfiram (Antabuse) complex with copper, as an anticancer drug, was recognized towards several cancer cell lines. The proteasome was suggested as one of the cellular targets for this compound. As the therapeutic use of diethyldithiocarbamate-copper complex (CuET) is expected to increase, it is of great interest to know whether this compound may be the source of drug-drug interactions via the induction of biotransformation enzymes, especially cytochromes P450 (CYPs). To this purpose, we examined the effect of CuET and compared it with typical inducers (rifampicin and dioxin) of CYPs and with well-established proteasome inhibitors (MG132 and bortezomib). Diethyldithiocarbamate-copper complex revealed inconsistent and rather modulatory effect on the expression of CYP1A2 and CYP3A4 in several cultures of human hepatocytes. Moreover, it was able to cause neither ubiquitin accumulation nor significant and dose-dependent inhibition of proteasome activity. It had no effect on essential transcription factors involved in regulation of selected CYPs, aryl hydrocarbon (AhR) nor pregnane X receptor (PXR). However, the AhR protein was increased in majority of examined hepatocyte cultures. The main finding of this study is that: (i) disulfiram-copper complex is not the cause of drug-drug interactions via CYP1A2/3A4 induction; (ii) proteasome inhibitors may have different impact on studied parameters in given in vitro system.Keywords
Funding Information
- Grantová Agentura České Republiky (P303/12/0472, 13-07711S)
This publication has 48 references indexed in Scilit:
- Copper unlocks therapeutic potential of disulfiramNature Reviews Urology, 2014
- Copper Signaling Axis as a Target for Prostate Cancer TherapeuticsCancer Research, 2014
- Use of disulfiram and risk of cancerEuropean Journal of Cancer Prevention, 2014
- Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damageCarcinogenesis: Integrative Cancer Research, 2013
- High-Throughput Chemical Screens Identify Disulfiram as an Inhibitor of Human Glioblastoma Stem CellsOncotarget, 2012
- Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cellsBritish Journal of Cancer, 2012
- Use of the disulfiram/copper complex for breast cancer chemoprevention in MMTV-erbB2 transgenic miceMolecular Medicine Reports, 2012
- Disulfiram, a Clinically Used Anti-Alcoholism Drug and Copper-Binding Agent, Induces Apoptotic Cell Death in Breast Cancer Cultures and Xenografts via Inhibition of the Proteasome ActivityCancer Research, 2006
- The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applicationsBlood, 2003
- A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolitesActa Psychiatrica Scandinavica, 1992