ArticleAnti-cancer agents in medicinal chemistry2020
The Killing of Human Neuroblastoma Cells by the Small Molecule JQ1 Occurs in a p53-Dependent Manner.
Article in Anti-cancer agents in medicinal chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 14 citations in OpenAlex.
- MTHFD1 regulates the NADPH redox homeostasis in MYCN-amplified neuroblastoma.Cell death & disease · 2024Article
- The Oncolytic Activity of Zika Viral Therapy in Human Neuroblastoma In Vivo Models Confers a Major Survival Advantage in a CD24-dependent Manner.Cancer research communications · 2024Article
- Combination bromo- and extraterminal domain and poly (ADP-ribose) polymerase inhibition synergistically enhances DNA damage and inhibits neuroblastoma tumorigenesis.Discover oncology · 2022Article
- BRD4 inhibitor GNE987 exerts anti-cancer effects by targeting super-enhancers in neuroblastoma.Cell & bioscience · 2022Article
- Deciphering the PTM codes of the tumor suppressor p53.Journal of molecular cell biology · 2022Review
- Chaperonin containing TCP-1 (CCT/TRiC) is a novel therapeutic and diagnostic target for neuroblastoma.Frontiers in oncology · 2022Article
- Targeting bromodomain and extra-terminal proteins to inhibit neuroblastoma tumorigenesis through regulating MYCN.Frontiers in cell and developmental biology · 2022Review
- Neuroblastoma and the epigenome.Cancer metastasis reviews · 2021Review
- Molecular Mechanisms ofFrontiers in oncology · 2020Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMYCN amplification is a prognostic biomarker associated with poor prognosis of neuroblastoma in children. The overall survival of children with MYCN-amplified neuroblastoma has only marginally improved within the last 20 years. The Bromodomain and Extra-Terminal motif (BET) inhibitor, JQ1, has been shown to downregulate MYCN in neuroblastoma cells.
objectiveTo determine if JQ1 downregulation of MYCN in neuroblastomas can offer a target- specific therapy for this, difficult to treat, pediatric cancer.
methodsSince MYCN-amplified neuroblastoma accounts for as much as 40 to 50 percent of all high-risk cases, we compared the effect of JQ1 on both MYCN-amplified and non-MYCN-amplified neuroblastoma cell lines and investigated its mechanism of action.
resultsIn this study, we show that JQ1 can specifically target MYCN for downregulation, though this effect is not specific to only MYCN-amplified cells. And although we can confirm that the loss of MYCN alone can induce apoptosis, the exogenous rescue of MYCN expression can abrogate much of this cytotoxicity. More fascinating, however, was the discovery that the JQ1-induced knockdown of MYCN, which led to the loss of the human double minute 2 homolog (HDM2) protein, also led to the accumulation of tumor protein 53 (also known as TP53 or p53), which ultimately induced apoptosis. Likewise, the knockdown of p53 also blunted the cytotoxic effects of JQ1.
conclusionThese data suggest a mechanism of action for JQ1 cytotoxicity in neuroblastomas and offer a possible prognostic target for determining its efficacy as a therapeutic.
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