A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death
- Author(s)
- Ceder, S; Eriksson, SE; Cheteh, EH; Dawar, S; Corrales Benitez, M; Bykov, VJN; Fujihara, KM; Grandin, M; Li, X; Ramm, S; Behrenbruch, C; Simpson, KJ; Hollande, F; Abrahmsen, L; Clemons, NJ; Wiman, KG;
- Details
- Publication Year 2021-02,Volume 13,Issue #2,Page e10852
- Journal Title
- EMBO Molecular Medicine
- Publication Type
- Research article
- Abstract
- The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR-246 (PRIMA-1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR-246 is currently tested in a phase III clinical trial in myelodysplastic syndrome (MDS). By in vitro, ex vivo, and in vivo models, we show that combined treatment with APR-246 and inhibitors of efflux pump MRP1/ABCC1 results in synergistic tumor cell death, which is more pronounced in TP53 mutant cells. This is associated with altered cellular thiol status and increased intracellular glutathione-conjugated MQ (GS-MQ). Due to the reversibility of MQ conjugation, GS-MQ forms an intracellular drug reservoir that increases availability of MQ for targeting mutant p53. Our study shows that redox homeostasis is a critical determinant of the response to mutant p53-targeted cancer therapy.
- Keywords
- Cell Death; Cell Line, Tumor; Humans; Mutation; *Neoplasms/drug therapy; *Pharmaceutical Preparations; Quinuclidines; Sulfhydryl Compounds; Tumor Suppressor Protein p53/genetics
- Department(s)
- Laboratory Research; Surgical Oncology
- PubMed ID
- 33314700
- Publisher's Version
- https://doi.org/10.15252/emmm.201910852
- Open Access at Publisher's Site
https://doi.org/10.15252/emmm.201910852- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-06-20 03:32:01
Last Modified: 2025-06-20 03:33:48