Anticancer effects of the p53 activator nutlin-3 in Ewing’s sarcoma cells
University Children's Hospital Jena, Department of Paediatric Haematology and Oncology, Jena, Germany.European journal of cancer (Oxford, England: 1990) (Impact Factor: 5.42). 02/2011; 47(9):1432-41. DOI: 10.1016/j.ejca.2011.01.015
Mutation of p53 is rare in Ewing's sarcoma (ES), suggesting that targeting and activation of wild-type p53 may be an effective therapeutic strategy for ES. The recently developed small-molecule MDM2 inhibitor nutlin-3 restores wild-type p53 function, resulting in the inhibition of cancer cell growth and the induction of apoptosis. In the present study, we explored the responsiveness of ES cell lines with wild-type or mutated p53 to nutlin-3. We found that treatment with nutlin-3 increased p53 level and induced p53 target gene expression (MDM2, p21, PUMA) in ES cells with wild-type p53, but not in ES cells with mutated p53. Consistently, nutlin-3 elicited apoptosis only in wild-type p53 cells, as assessed by caspase-3 activity assay and flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation. In addition, we found nutlin-3 to evoke cellular senescence, indicating that nutlin-3 induces pleiotropic anticancer effects in ES. Furthermore, combined treatment with nutlin-3 and an inhibitor of NF-κB produced synergistic antineoplastic activity in ES cells. Our findings suggest that the direct activation of p53 by nutlin-3 treatment may be a useful new therapeutic approach for patients with ES.
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- "The p53 pathway is also an appealing target for the treatment of ES . We and others have recently shown that the small-molecule MDM2 antagonist nutlin-3 exerted potent antineoplastic effects in ES cells with wt-p53, but not in ES cells with mt-p53  . About 90% of ES express wt-p53      and thus are potentially amenable to nutlin-3 treatment. "
ABSTRACT: Mutant p53 can exert oncogenic activity by inhibitory interaction with p73. The small-molecule RETRA has been described to disrupt this interaction and to suppress carcinoma cells (Kravchenko et al., 2008). RETRA's anticancer activity was restricted to tumour cells bearing mutant p53; it was not active in p53 negative and in p53 wild-type cells. Here, we explored the responsiveness of Ewing's sarcoma (ES) cells with mutant p53 to RETRA. For comparison, we also tested RETRA in p53 null and in p53 wild-type ES cells. We found RETRA to be effective in the three mutant p53 ES cell lines investigated. Strikingly, however, RETRA was similarly effective in the p53-deficient and in the two p53 wild-type ES cell lines examined. RETRA elicited apoptosis, as assessed by flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation, caspase 3/7 activity assay and PARP-1 cleavage immunodetection, and G2/M cell cycle arrest completely independent of the cellular TP53 status. In contrast, various p53-deficient and -proficient carcinoma, osteosarcoma and leukaemia cells were unresponsive to RETRA. RETRA also induced gene expression of p53 target genes PUMA and p21 in ES cells irrespective of their TP53 status. These in vitro findings provide a rationale for an in vivo exploration of RETRA's potential as an effective therapeutic approach for patients with ES. Copyright © 2015 Elsevier Ltd. All rights reserved.European journal of cancer (Oxford, England: 1990) 03/2015; 51(7). DOI:10.1016/j.ejca.2015.02.016 · 5.42 Impact Factor
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ABSTRACT: Ultra shallow p-type junctions were formed by low energy BF<sub>2 </sub><sup>+</sup> implantation and optimized rapid thermal annealing (RTA) at various soak time and temperatures in pure N<sub>2</sub> atmosphere. Especially, the spike annealing was defined as a fraction of a second soak time at the peak temperature. The dependence of junction depth and sheet resistance on ramp-up rate were investigated for rates of 23°C/s and 38°C/s. The samples implanted BF<sub>2</sub><sup>+ </sup> at energy of 2 keV with doses of 6×10<sup>14</sup> cm<sup>-2</sup> and 1×10<sup>15</sup> cm<sup>-2</sup> were annealed. The peak carrier concentration was calculated from sheet resistance and SIMS profile. The carrier concentration depends on the implant dose strongly; the carrier concentration of 1×10<sup>15 </sup> cm<sup>-2</sup> is higher than one of 6×10<sup>14</sup> cm <sup>-2</sup>. In the case of 6×10<sup>14</sup> cm<sup>-2</sup> lower thermal budget by decreasing the soak time or increasing the ramp-up rate results in shallower junction depth monotonously. It is observed that junction depth is deeper and peak carrier concentration decreases by decreasing thermal budget with extremely high ramp-up rate of spike annealing at dose of 1×10<sup>15</sup> cm<sup>-2</sup>. It is concluded that moderate ramp up rates of spike annealing for low energy and high dose BF<sub>2</sub><sup>+</sup> implant, e.g. 2 keV, 1×10<sup>15</sup> cm<sup>-2</sup>, can achieve the shallowest junction and lowest sheet resistanceIon Implantation Technology, 2000. Conference on; 02/2000
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ABSTRACT: Worldwide research efforts have driven recent pharmaceutical successes, and consequently, the emerging role of Protein-Protein Interactions (PPIs) as drug targets has finally been widely embraced by the scientific community. Inhibitors of these Protein-Protein Interactions (2P2Is or i-PPIs) are likely to represent the next generation of highly innovative drugs that will reach the market over the next decade. This review describes up-to-date knowledge on this particular chemical space, with a specific emphasis on a subset of this ensemble. We also address current structural knowledge regarding both protein-protein and protein-inhibitor complexes, that is, the 2P2I database. Finally, ligand efficiency analyses permit us to relate potency to size and polarity and to discuss the need to co-develop nanoparticle drug delivery systems.Current opinion in chemical biology 06/2011; 15(4):475-81. DOI:10.1016/j.cbpa.2011.05.024 · 6.81 Impact Factor
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