PRIMA-1(MET) | Reactivates mutant p53

PRIMA-1^MET (5291-32-7) reactivates mutant p53, an important tumor suppressor gene, in cancer cells.¹ It induces p53-dependent mitochondrial apoptosis via activation of caspase-2.² PRIMA-1^MET showed significant antitumor activity in multiple myeloma via activation of p73³ and had previously been shown to target p53 family members p63 and p73⁴. Tumor cell death by PRIMA-1^MET has been also shown to be caused by glutathione depletion and induced ROS production in a p53 independent manner.^5-7 PRIMA-1^MET probably induces tumor cell death by both reactivating mutant p53 and inhibiting cellular thiol-dependent redox systems.⁸

References/Citations:

1) Bykov et al. (2005), PRIMA-1^MET synergizes with cisplatin to induce tumor cell apoptosis; Oncogene 24 3484
2) Shen et al. (2008), PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2; Oncogene 27 6571
3) Saha et al. (2013), PRIMA-1MET/APR-246 displays high antitumor in multiple myeloma by induction of p73 and Noxa; Mol. Cancer Ther. 12 2331
4) Rokaeus et al. (2010), PRIMA-1(MET)/APR-246 targets mutant forms of p53 family members p63 and p73; Oncogene 29 6442
5) Tessoulin et al. (2014), PRIMA-1Met induces myeloma cell death independent of p53 by impairing GSH/ROS balance; Blood 124 1626
6) Liu et al. (2017), Inhibiting the system xc-/glutathione axis selectively targets cancers with mutant-p53 accumulation; Nat. Commun. 28 14844
7) Synnott et al. (2018), The Mutant p53-Targeting Compound APR-246 Induces ROS-modulating Genes in Breast Cancer Cells; Transl. Oncol. 11 1343
8) Haffo et al. (2018), Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246; Oncogene 24 3484