The p53 pathway and its inactivation in neuroblastoma

Tweddle, Deborah A.; Pearson, Andrew D.J.; Haber, Michelle; Norris, Murray D.; Xue, Chunyu; Flemming, Claudia L.; Lunec, John

doi:10.1016/s0304-3835(03)00088-0

Cited by 153 publications

(156 citation statements)

References 9 publications

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“…22 The p53/ MDM2/p14 ARF genomic status of most cell lines has been described previously, 7,18,23 except for one line established at Memorial Sloan-Kettering Cancer Center (MSKCC): SKNJC2 has a p53 nonsense mutation at codon 204. All cell lines have been tested and authenticated by short tandem repeat profiling using PowerPlex 1.2 System (Promega), by comparison with either ATCC database, our original tumor samples, or the original batch of cells from outside resources.…”

Section: Cell Lines and Human Tissuesmentioning

confidence: 99%

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma

Xu¹,

Cheung²,

Wei³

et al. 2011

Intl Journal of Cancer

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Checkpoint kinase inhibitors can enhance the cancer killing action of DNA-damaging chemotherapeutic agents by disrupting the S/G 2 cell cycle checkpoints. The in vitro and in vivo effects of the Chk1/2 inhibitor AZD7762 when combined with these agents were examined using neuroblastoma cell lines with known p53/MDM2/p14 ARF genomic status. Four of four p53 mutant lines and three of five MDM2/p14 ARF abnormal lines were defective in G 1 checkpoint, correlating with failure to induce endogenous p21 after treatment with DNA-damaging agents. In cytotoxicity assays, these G 1 checkpoint-defective lines were more resistant to DNA-damaging agents when compared to G 1 checkpoint intact lines, yet becoming more sensitive when AZD7762 was added. Moreover, AZD7762 abrogated DNA damage-induced S/G 2 checkpoint arrest both in vitro and in vivo. In xenograft models, a significant delay in tumor growth accompanied by histological evidence of increased apoptosis was observed, when AZD7762 was added to the DNA-damaging drug gemcitabine. These results suggest a therapeutic potential of combination therapy using checkpoint kinase inhibitor and chemotherapy to reverse or prevent drug resistance in treating neuroblastomas with defective G 1 checkpoints.

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Section: Cell Lines and Human Tissuesmentioning

confidence: 99%

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma

Xu¹,

Cheung²,

Wei³

et al. 2011

Intl Journal of Cancer

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“…Phosphorylation at several serine and threonine residues in p53 has been shown to occur after cells are exposed to DNAdamaging agents and is critical for p53 to function as an effective tumor suppressor (Kruse and Gu, 2009). Aberrant regulation of the p53 tumor suppressor pathway has been suggested as an important mechanism of chemoresistance in neuroblastoma (Tweddle et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…The p53 protein is mostly wild type (WT) in neuroblastoma, suggesting that inhibition of p53 tumor suppressor function contributes to chemoresistance, tumor metastasis and poor patient survival (Moll et al, 1995;Tweddle et al, 2001). Thus, the strategy of restoring p53 function represents an attractive therapeutic approach to this cancer (Tweddle et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma

Shang

Vasudevan

et al. 2010

Oncogene

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“…In NB, p53 although rarely mutated (Vogan et al, 1993), can still be functionally inactivated through cytoplasmic sequestration secondary to multiple mechanisms (Moll et al, 1995;Tweddle et al, 2003) and, among them, even to a possible binding to parkin protein (Nikolaev et al, 2003). In order to determine the relevance of this phenomenon, we investigated the expression of p53 and parkin in paraffin sections from 60 out of 110 NTs, 30 with low and 30 with high MKI.…”

Section: Resultsmentioning

confidence: 99%

“…Cells harbouring an impaired p53 can survive and proliferate inappropriately and this event can result in cancer development (Prives and Hall, 1999). In NB, a tumour that usually shows an initial response to chemotherapy but tends to relapse as drug-resistant disease, the inactivation of p53 via mutational or nonmutational mechanisms could eventually represent one of the most critical factors of therapeutic failure (Tweddle et al, 2003).…”

mentioning

confidence: 99%

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours

et al. 2006

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Multiple defects in apoptotic pathways have been described in peripheral neuroblastic tumours (NTs). Mitosis -karyorrhexis index (MKI) is a reliable morphological marker identifying favourable and unfavourable NTs. The extent to which apoptotic processes contribute to determine the clinical significance of MKI is still undefined. Apoptosis was investigated in a series of 110 peripheral NTs by comparing MKI to immunohistochemical and molecular apoptotic features. High MKI was found in 55 out of 110 NTs (50%) and was associated with advanced stage (P ¼ 0.007), neuroblastoma (NB) histological category (P ¼ 0.024), MYCN amplification (Po0.001), and poor outcome (P ¼ 0.011). Overall survival probability was 45% in patients with high MKI compared to 73% in patients with low MKI. In the same 110 NTs, the expression of Bcl-2, Bcl-X L , Bax and Mcl-1 was studied by immunohistochemistry, but no significant associations were found with clinicohistological features. Microarray analysis of apoptotic genes was performed in 40 out of 110 representative tumours. No significant association was found between the expression of apoptotic genes and MKI or clinicohistological features. Proliferative activity was assessed in 60 out of 110 representative tumours using Ki67 immunostaining, but no significant correlations with MKI or clinicobiological features were found. In NTs, the combination of apoptosis and proliferation as expressed by MKI is a significant prognostic parameter, although neither of them is per se indicative of the clinicobiological behaviour and outcome.

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The p53 pathway and its inactivation in neuroblastoma

Cited by 153 publications

References 9 publications

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma

Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours

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The p53 pathway and its inactivation in neuroblastoma

Cited by 153 publications

References 9 publications

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G1 checkpoint‐defective neuroblastoma

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G1 checkpoint‐defective neuroblastoma

Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours

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Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma