PRIMA-1MET-induced neuroblastoma cell death is modulated by p53 and mycn through glutathione level.

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Publisher: BioMed Central Ltd.
Document Type: Article
Length: 9,394 words
Lexile Measure: 1420L

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Abstract :

Background Neuroblastoma is the most common extracranial solid tumor in children. This cancer has a low frequency of TP53 mutations and its downstream pathway is usually intact. This study assessed the efficacy of the p53 activator, PRIMA-1.sup.MET, in inducing neuroblastoma cell death. Methods CellTiter 2.0 was used to study susceptibility and specificity of NB cell lines to PRIMA-1.sup.MET. Real-time PCR and western blot were used to assess the most common p53 transactivation targets. Induction of p53 and Noxa, and inhibition of Cas3/7, were used to assess impact on cell death after PRIMA-1.sup.MET treatment. Flow cytometry was used to analyze cell cycle phase and induction of apoptosis, reactive oxygen species, and the collapse of mitochondrial membrane potential. Results Neuroblastoma cell lines were at least four times more susceptible to PRIMA-1.sup.MET than were primary fibroblasts and keratinocyte cell lines. PRIMA-1.sup.MET induced cell death rapidly and in all cell cycle phases. Although PRIMA-1.sup.MET activated p53 transactivation activity, p53's role is likely limited because its main targets remained unaffected, whereas pan-caspase inhibitor demonstrated no ability to prevent cell death. PRIMA-1.sup.MET induced oxidative stress and modulated the methionine/cysteine/glutathione axis. Variations of MYCN and p53 modulated intracellular levels of GSH and resulted in increased/decreased sensitivity of PRIMA-1.sup.MET. PRIMA-1.sup.MET inhibited thioredoxin reductase, but the effect of PRIMA-1.sup.MET was not altered by thioredoxin inhibition. Conclusions PRIMA-1.sup.MET could be a promising new agent to treat neuroblastoma because it demonstrated good anti-tumor action. Although p53 is involved in PRIMA-1.sup.MET-mediated cell death, our results suggest that direct interaction with p53 has a limited role in neuroblastoma but rather acts through modulation of GSH levels. Keywords: Neuroblastoma, PRIMA-1.sup.MET, p53, MYCN, Glutathione

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Gale Document Number: GALE|A581364817