Releasing the trap: How the segregase p97 extracts PARP1 from chromatin

Götz, Maximilian J.; Stingele, Julian

doi:10.1016/j.molcel.2022.02.012

Cited by 2 publications

(1 citation statement)

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“…This reinforcement could be realized by Disulfiram and PARPis individually or through their interaction. It was recently reported that small-molecule p97-complex inhibitors, including a metabolite of Disulfiram, prolonged PARP1 trapping (preventing DNA repair leading to cell death) and enhanced PARP inhibitor-induced cytotoxicity in homologous recombination-defective tumor cells and patient-derived tumor organoids ( 38 , 39 ). The work proposed that p97 ATPase plays a key role in the processing of trapped PARP1 and the response of tumor cells to PARP inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Combined treatment of disulfiram with PARP inhibitors suppresses ovarian cancer

Tang

Zhang

et al. 2023

Front. Oncol.

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IntroductionDue to the difficulty of early diagnosis, nearly 70% of ovarian cancer patients are first diagnosed at an advanced stage. Thus, improving current treatment strategies is of great significance for ovarian cancer patients. Fast-developing poly (ADP-ribose) polymerases inhibitors (PARPis) have been beneficial in the treatment of ovarian cancer at different stages of the disease, but PARPis have serious side effects and can result in drug resistance. Using PARPis in combination with other drug therapies could improve the efficacy of PRAPis.In this study, we identified Disulfiram as a potential therapeutic candidate through drug screening and tested its use in combination with PARPis.MethodsCytotoxicity tests and colony formation experiments showed that the combination of Disulfiram and PARPis decreased the viability of ovarian cancer cellsResultsThe combination of PARPis with Disulfiram also significantly increased the expression of DNA damage index gH2AX and induced more PARP cleavage. In addition, Disulfiram inhibited the expression of genes associated with the DNA damage repair pathway, indicating that Disulfiram functions through the DNA repair pathway.DiscussionBased on these findings, we propose that Disulfiram reinforces PARPis activity in ovarian cancer cells by improving drug sensitivity. The combined use of Disulfiram and PARPis provides a novel treatment strategy for patients with ovarian cancer.

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Section: Discussionmentioning

confidence: 99%