Identifying chronic alcoholism drug disulfiram as a potent DJ-1 inhibitor for cancer therapeutics

As a key regulator involved in tumor development and progression, DJ-1 has been proposed as a potential therapeutic target against cancer. Also, the development of DJ-1 inhibitors holds great interests in cancer treatment. In the current study, by utilizing a small molecule covalent compounds librar...

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Veröffentlicht in:European journal of pharmacology 2022-07, Vol.926, p.175035, Article 175035
Hauptverfasser: Wu, Qian, Zhang, Mingyang, Wen, Yuanmei, He, Peihao, He, Qiaojun, Yang, Bo, Jiang, Li, Yuan, Meng, Cao, Ji
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Sprache:eng
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Zusammenfassung:As a key regulator involved in tumor development and progression, DJ-1 has been proposed as a potential therapeutic target against cancer. Also, the development of DJ-1 inhibitors holds great interests in cancer treatment. In the current study, by utilizing a small molecule covalent compounds library screening, we found that disulfiram (DSF), an FDA-approved chronic alcoholism drug, is a potent DJ-1 inhibitor. Glyoxalase assay and microscale thermophoresis analysis suggested that DSF exhibits strong inhibitory activity and high affinity to DJ-1 protein. Additionally, DSF similarly inhibited the methylglyoxal detoxification function of DJ-1 protein at the intracellular level. Notably, we discovered that DSF could significantly enhance N-(4-hydroxyphenyl) retinamide-based proliferation inhibition and apoptosis induction in different types of cancer cell lines, but not in normal tissue lines. Thus, our data suggest DSF functions as a potential inhibitor targeting DJ-1, which may provide a potential synergistic treatment option for cancer therapy.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2022.175035