The tumor suppressor p53 plays a key role in regulating cell cycle arrest, DNA repair, apoptosis, and cell senescence and is inactivated either by mutation or up-regulation of proteins such as MDM2 or MDMX in virtually all human cancers. Cancers with mutant p53 often show increased metastasis,
genomic instability, and higher chemoresistance. PK11007, a thiol-modifying compound, exerts antitumor function via reactivating p53. PK11007 increased protein levels of the p53 target genes p21, MDM2, and PUMA in a mostly concentration-dependent manner in NUGC-3 (p53-Y220C), HUH-7 (p53-Y220C) and MKN1 (p53-V143A) cells and also activated the unfolded protein response pathway in a concentration-dependent manner in HUH-7 cells. PK11007 slightly increased caspase 3/7 activity without inducing membrane permeabilization in SW480 (15% increase at 15 μM), SJSA-1 (40% increase at 30 μM), and HCT116 (10% increase at 60 μM) cells, and depleted GSH and increased concentration of ROS[1]. PK11007 was found to induce apoptosis in both a time and concentration-dependent manner in the two p53-mutated triple-negative breast cancer cell lines investigated, HCC1143 and MDA-MB-468, but not in the WT-p53 cell line, MCF-7[2].
作用机制
PK11007 stabilizes p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity.
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