The tumor suppressor p53 is a key mediator in cell cycle arrest, DNA repair, and apoptosis. PK11007 is a mild thiol alkylator that shows anticancer activity towards p53-compromised cell lines. Incubation of stabilized full-length p53 with 1mM PK11007 for 2 h did not affect the binding of p53-GADD45a and the Kd value was 33.7nM. Treatment with PK11007 at 15-30µM markedly reduced cell viability in mutant p53 cell lines MKN1 (V143A), HUH-7 (Y220C), NUGC-3 (Y220C), and SW480 (R273H/P309S). PK11007 reduced cell viability of p53 WT cancer cell lines (HUH-6 and NUGC-4) and fibroblast cell line WI-38 only at high concentrations (60 and 120µM). The downregulation of p53 protein expression by siRNA did not alter PK11007-mediated viability reduction in HUH-6 and HUH-7 cells. In MKN1 cells (p53-V143A), PK11007 at 15 and 20µM resulted in a significant viability difference between wild-type and p53-/- cells. The protein levels of p53 target genes, including p21, MDM2, and PUMA, were upregulated by PK11007 (15, 30, and 60µM) in NUGC-3 (p53-Y220C), HUH-7 (p53-Y220C), and MKN1 (p53-V143A) cells. PK11007 (15, 30, and 60µM) also dose-dependently upregulated the protein level of spliced XBP-1, a key marker for the activation of unfolded protein response, in HUH-7 cells[1]. PK11007 inhibited the proliferation of a panel of 17 breast cell lines with IC50 values varied from 2.3 to 42.2μM[2].
作用机制
The alkylation of the surface-exposed redox-sensitive cysteines (i.e. C182 and C277) by PK11007 stabilizes the DNA-binding domain of p53 in vitro without compromising its DNA-binding affinity[1].
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