The p21-Dependent Radiosensitization of Human Breast Cancer Cells by MLN4924, an Investigational Inhibitor of NEDD8 Activating Enzyme

Radiotherapy is a treatment choice for local control of breast cancer. However, intrinsic radioresistance of cancer cells limits therapeutic efficacy. We have recently validated that SCF (SKP1, Cullins, and F-box protein) E3 ubiquitin ligase is an attractive radiosensitizing target. Here we tested our hypothesis that MLN4924, a newly discovered investigational small molecule inhibitor of NAE (NEDD8 Activating Enzyme) that inactivates SCF E3 ligase, could act as a novel radiosensitizing agent in breast cancer cells. Indeed, we found that MLN4924 effectively inhibited cullin neddylation, and sensitized breast cancer cells to radiation with a sensitivity enhancement ratio (SER) of 1.75 for SK-BR-3 cells and 1.32 for MCF7 cells, respectively. Mechanistically, MLN4924 significantly enhanced radiation-induced G2/M arrest in SK-BR-3 cells, but not in MCF7 cells at early time point, and enhanced radiation-induced apoptosis in both lines at later time point. However, blockage of apoptosis by Z-VAD failed to abrogate MLN4924 radiosensitization, suggesting that apoptosis was not causally related. We further showed that MLN4924 failed to enhance radiation-induced DNA damage response, but did cause minor delay in DNA damage repair. Among a number of tested SCF E3 substrates known to regulate growth arrest, apoptosis and DNA damage response, p21 was the only one showing an enhanced accumulation in MLN4924-radiation combination group, as compared to the single treatment groups. Importantly, p21 knockdown via siRNA partialy inhibited MLN4924-induced G2/M arrest and radiosensitization, indicating a causal role played by p21. Our study suggested that MLN4924 could be further developed as a novel class of radiosensitizer for the treatment of breast cancer

Colonoscopia com polipectomia: análise crítica de fatores de risco e complicações Colonic snare polipectomy: critical analysis of risk factors and complications

Objetivo: Analisar complicações de polipectomia com alça ditérmica em cólon. Pacientes e Métodos: Estudo retrospectivo de polipectomias em colonoscopias realizadas em dois hospitais de 2001 a 2007. Teste t de Student foi usado para média, desvio padrão e qui-quadrado para números absolutos. P< que 0,05 foi considerado significativo. Resultados: Foram 1687 polipectomias em 8447 colonoscopias. Sangramento imediato em 24 (11,8%) em pólipos maiores do que 2 cm contra 1 (0,07%) em menores p<0,01. Somente 1, maior que 2 cm, (0,49%) necessitou de cirurgia para controle do sangramento p<0,01. Sangramento tardio em 7 (3,4%), todos maiores que 2 cm p<0,01. Perfuração em 6 (2.9%), todas em cólon direito. Não houve necessidade de cirurgia. A idade foi 59,8±6,7 para sangramento imediato, 60±9,8 para tardio e 63,8±16,3 para os que não sangraram p>0,05. Síndrome pós-polipectomia em 6 (0,35%). Ressecção fatiada somente em maiores que 2 cm, 89/116 (77%) sésseis e 11/87 (13%) pediculados p<0,01. Carcinoma invasivo em 40 adenomas maiores que 2 cm (19,7%). Conclusão: Polipectomia com alça é segura, sangramento a complicação mais comum, relacionada ao tamanho da base. Perfuração vem a seguir. Ambas tem tratamento endoscópico prioritário.<br>Purpose: The aim of this study was to evaluate adverse events from snare polypectomy. Methods: We retrospectively analysed the rate of complications of 1687 snare polypectomies carried out in 8447 colonoscopies between 2001 and 2007 at two Medical Institutions. Student t test was used for statistical analysis of mean and chi-square to compare absolute numbers. A significant p-value was defined as < 0,05. Results: Of the 1687 colonoscopic polypectomies 203 were performed in polyps larger than 2 cm in diameter ( range 2-10 cm ). In this group 24 (11,8%) had immediate bleeding, against 1 ( 0,07%) smaller than 2 cm p<0,01. Only one, larger than 2 cm, needed surgery to control bleeding episod p<0,01. Delayed bleeding occurred in 6 (0,35%).None required surgery. The age group for bleeding post-polypectomy did not differ, being 59,8±6,7 for immediate bleeding, 60±9,8 for delayed and 63,8±16,3 for no bleeding p>0,05.Post-polypectomy syndrome occurred in 6 patients (0,35%). In polyps larger than 2 cm, piecemeal resection was performed more often in sessile than in pedunculated ones 89/116 ( 77%) versus 11/87 (13%) p<0,01. Invasive carcinoma was present in 40 adenoma larger than 2 cm (19,7%). Conclusion: Snare polypectomy is safe procedure, being bleeding the most common complication, related with polyp size mainly its base, treated most of the time endoscopically. Perforation being the next, treated too without surgery