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

Autor: Tereza Buchtova, Zdenek Skrott, Katarina Chroma, Jiri Rehulka, Petr Dzubak, Marian Hajduch, David Lukac, Stefanos Arampatzis, Jiri Bartek, Martin Mistrik
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Molecular Oncology, Vol 16, Iss 7, Pp 1541-1554 (2022)
Druh dokumentu: article
ISSN: 1878-0261
1574-7891
97405485
DOI: 10.1002/1878-0261.13114
Popis: 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.
Databáze: Directory of Open Access Journals
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