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Cited by 11Trace Elements in HealthMetal complexes synthesis and propertiesHeavy Metal Exposure and Toxicity

Cannabidiol‐induced activation of the metallothionein pathway impedes anticancer effects of disulfiram and its metabolite CuET

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Buchtova, Tereza, Skrott, Zdenek, Chroma, Katarina, Rehulka, Jiri, Dzubak, Petr, Hajduch, Marian, Lukac, David, Arampatzis, Stefanos +2 more·2022·Molecular Oncology
DOI 10.1002/1878-0261.13114PMC PMC8978514
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Abstract

Disulfiram (DSF), an established alcohol-aversion drug, is a candidate for repurposing in cancer treatment. DSF's antitumor activity is supported by preclinical studies, case reports, and small clinical trials; however, ongoing clinical trials of advanced-stage cancer patients encounter variable results. Here, we show that one reason for the inconsistent clinical effects of DSF may reflect interference by other drugs. Using a high-throughput screening and automated microscopy, we identify cannabidiol, an abundant component of the marijuana plant used by cancer patients to mitigate side effects of chemotherapy, as a likely cause of resistance to DSF. Mechanistically, in cancer cells, cannabidiol triggers the expression of metallothioneins providing protective effects by binding heavy metal-based substances including the bis-diethyldithiocarbamate-copper complex (CuET). CuET is the documented anticancer metabolite of DSF, and we show here that the CuET's anticancer toxicity is effectively neutralized by metallothioneins. Overall, this work highlights an example of undesirable interference between cancer therapy and the concomitant usage of marijuana products. In contrast, we report that insufficiency of metallothioneins sensitizes cancer cells toward CuET, suggesting a potential predictive biomarker for DSF repurposing in oncology.

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Authors
Buchtova, T., Skrott, Z., Chroma, K., Rehulka, J., Dzubak, P., Hajduch, M., Lukac, D., Arampatzis, S., Bartek, J., & Mistrik, M.
Affiliations
  • Faculty of Medicine and Dentistry Institute of Molecular and Translational Medicine Palacky University Olomouc Czech Republic
  • Institute of Molecular and Translational Medicine (CZ)
  • Danish Cancer Society (DK)
ORCID
Venue
Molecular Oncology
Publisher
Wiley
Published
2021-10-26
Volume
16
Issue
7
Pages
1541-1554
ISSN
  • 1574-7891 (ISSN-L)
  • 1878-0261
DOI
10.1002/1878-0261.13114
PMC
PMC8978514
OpenAlex
W3205987012
Cited by
11
References
43
Citations by year
2026: 1 · 2025: 1 · 2023: 7 · 2022: 2
FWCI
1.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Ministry of Education, Youth and Science (LM2018129)
  • European Regional Development Fund (CZ.02.1.01./0.0/0.0./16_013/0001775)
  • Grantová Agentura České Republiky (20‐28685S)
  • Technology Agency of the Czech Republic (TN01000013)
  • Novo Nordisk Fonden (16854, 0060590)
  • Vetenskapsrådet (VR‐MH 2014‐46602‐117891‐30)
  • Cancerfonden (#170176)
  • Danmarks Grundforskningsfond (DNRF 125)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
  • Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
Keywords
cannabidiol, disulfiram, metallothionein, drug repurposing, chemoresistance, drug-drug interactions, cannabis, chemotherapy side effects, predictive biomarkers
MeSH terms
Cannabidiol, Copper, Disulfiram, Humans, Metallothionein, Cell Line, Tumor

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