A major physiological negative regulator of p53 can bind to

A major physiological negative Salvianolic acid B regulator of p53 can bind to the p53 transactivation domain and interfere with the transcriptional regulatory mechanisms of p53. MDM2 is also an E3 ubiquitin ligase that promotes p53 proteasomal degradation. For this reason, inhibition of the interaction between MDM2 and p53 to reactivate endogenous p53 activity offers the opportunity for therapeutic intervention, particularly in GBMs. In GBMs, the p53 gene is relatively infrequently mutated; however, wild-type p53 remains dysfunctional due to overexpressed MDM2. Intensive work on different classes of MDM2 inhibitors has proven their therapeutic utility as activators of p53 in multiple tumor models. Indeed, it has been demonstrated that a number of small-molecule MDM2 inhibitors can disrupt the MDM2-p53 interaction, release p53 from negative control and activate the p53 pathway, leading to cell cycle arrest and apoptosis in a number of solid cancers and haematological malignancies. Moreover, many laboratories have shown that MDM2 inhibitors can synergise with conventional chemotherapeutic agents, resulting in enhanced efficacy. Interestingly, MDM2 inhibitors have been reported to induce cancer cell apoptosis even without the concomitant application of genotoxic CBR-5884 stimuli. Little is known about the effects of MDM2 inhibitors on the in vitro growth of GBM cells. Recently, Nutlin-3, the first potent MDM2 small-molecule inhibitor identified, and new D-peptide derivatives were reported to be effective at inhibiting GBM cell growth in vitro, suggesting the validity of this experimental approach for the treatment of GBM. In the present study, we investigated the responsiveness of human GBM cell lines to a novel small-molecule MDM2 inhibitor with a spirooxoindolepyrrolidine core structure, named ISA27, which has been recently shown by nuclear magnetic resonance analysis to efficiently dissociate the reconstituted human MDM2-p53 complex. Consistently, ISA27 activated the p53 pathway in GBM cells and elicited the dose- and time-dependent inhibition of cell growth. ISA27 induced apoptosis and evoked cellular senescence, indicating that ISA27 promotes a pleiotropic anticancer effect in the GBM cells. The administration of ISA27 in vivo efficiently inhibited tumor growth in nude mice bea