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A thiol‐bound drug reservoir enhances APR‐246‐induced mutant p53 tumor cell death

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 tr...

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Detalles Bibliográficos
Autores principales: Ceder, Sophia, Eriksson, Sofi E, Cheteh, Emarndeena H, Dawar, Swati, Corrales Benitez, Mariana, Bykov, Vladimir J N, Fujihara, Kenji M, Grandin, Mélodie, Li, Xiaodun, Ramm, Susanne, Behrenbruch, Corina, Simpson, Kaylene J, Hollande, Frédéric, Abrahmsen, Lars, Clemons, Nicholas J, Wiman, Klas G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863383/
https://www.ncbi.nlm.nih.gov/pubmed/33314700
http://dx.doi.org/10.15252/emmm.201910852
Descripción
Sumario: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.