SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma.
Sara GomesBartolomeo BoscoJoana B LoureiroHelena RamosLiliana RaimundoJoana SoaresNair NazarethValentina BarcheriniLucília DominguesCarla OliveiraAlessandra BisioSilvano PiazzaMatthias R BauerJoão Paulo BrásMaria Inês AlmeidaCélia GomesFlávio ReisAlan R FershtAlberto IngaMaria M M SantosLucília SaraivaPublished in: Cancers (2019)
Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structural mutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC.
Keyphrases
- wild type
- cell cycle arrest
- heat shock protein
- cell death
- endothelial cells
- pi k akt
- heat shock
- induced apoptosis
- mouse model
- dna binding
- endoplasmic reticulum
- induced pluripotent stem cells
- high glucose
- pluripotent stem cells
- gene expression
- signaling pathway
- oxidative stress
- heat stress
- climate change
- anti inflammatory