A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death
| Autor: | Kenji M Fujihara, Kaylene J. Simpson, Nicholas J Clemons, Sofi E. Eriksson, Swati Dawar, Corina Behrenbruch, Klas G. Wiman, Sophia Ceder, Frédéric Hollande, Mariana Corrales Benitez, Mélodie Grandin, Xiaodun Li, Lars Abrahmsén, Susanne Ramm, Emarndeena H Cheteh, Vladimir J.N. Bykov |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
p53 Medicine (General) Programmed cell death Quinuclidines Tumor suppressor gene Mutant QH426-470 Article 03 medical and health sciences R5-920 0302 clinical medicine In vivo Cell Line Tumor Neoplasms Chemical Biology Genetics Humans Sulfhydryl Compounds glutathione APR‐246 Cancer biology Cell Death Chemistry Eprenetapopt Articles Molecular biology 030104 developmental biology Pharmaceutical Preparations Cell culture Mutation ABCC1 biology.protein Molecular Medicine MRP1 Tumor Suppressor Protein p53 030217 neurology & neurosurgery Ex vivo Intracellular |
| Zdroj: | EMBO Molecular Medicine EMBO Molecular Medicine, Vol 13, Iss 2, Pp n/a-n/a (2021) |
| ISSN: | 1757-4684 |
| Popis: | 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. Tumor suppressor TP53 is mutated in a large fraction of tumors. APR‐246/Eprenetapopt is the most clinically advanced mutant p53‐targeting drug candidate (Phase III). Besides restoring wild type p53 activity, the active product MQ also disrupts the redox balance, resulting in cancer cell death. |
| Databáze: | OpenAIRE |
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