Decitabine

Gore, Steven D.; Jones, C.A.; Kirkpatrick, Peter

doi:10.1038/nrd2180

Cited by 98 publications

(69 citation statements)

References 15 publications

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“…This implies that an intact P53 pathway is not critical to respond to AZA+RA treatment. Thus, combined AZA+RA treatment shows efficacy in NB cells with different combinations of severe genetic aberrations associated with high-risk NB: 1p36 AZA is already in clinical use for treatment of myelodysplasive syndrome (11) and in several clinical trials for different types of tumors (33). In a phase I case study, a patient who suffered from relapsed stage 4 NB received AZA treatment combined with dendritic cell vaccine, which resulted in complete remission (34).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we show that treatment with the demethylating agent 5-Aza-deoxycytidine (AZA) can restore RA responsiveness in high-risk NB. Thus, growth of xenografted NB tumors, which fail to respond to RA treatment, can be thwarted with a combined systemic delivery of two FDA-approved drugs (AZA+RA) (10,11). We show that the AZA+RA-dependent inhibition of tumor growth rapidly induces a HIF2α-associated hypoxia-like response in the treated xenografts.…”

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confidence: 91%

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Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

Westerlund

Shi

Toskas

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNAdemethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genomewide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.neuroblastoma | differentiation | retinoic acid | 5-Aza-dC | HIF2a

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 91%

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

Westerlund

Shi

Toskas

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous reports outlined agents and methods that could possibly selectively induce apoptosis in cancer cells, and be potentially useful in cancer therapy (reviewed in [13,24,25,[30][31][32] To date, however, only a small number of therapies directly targeting the apoptotic pathways have advanced to clinical testing, and none have yet achieved FDA approval. Most of the clinical trials using such agents were hampered by low efficacy (e.g., [33]), toxicity (e.g., [34]), the presence of decoy receptors (e.g., DcR1, DcR2, and osteoprotegerin) which bind TRAIL and inhibit apoptosis [35], and concerns about inducing immunodeficiency with hypogammaglobulinemia and the predisposition to develop lymphomas [36].…”

Section: Mechanisms Of Apoptosismentioning

confidence: 99%

P2X₇-mediated chemoprevention of epithelial cancers

Gorodeski

2009

Expert Opinion on Therapeutic Targets

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The growing understanding of mechanisms of P2X(7)-mediated apoptosis has generated a novel strategy for targeting directly and specifically skin neoplasia. The data link directly, for the first time, upregulation of apoptosis with cancer chemoprevention. Striking antitumor efficacy has been achieved in the rodent cancer model, and it is likely that the recently gained wealth of knowledge about the mechanisms of P2X(7)-control of apoptosis will eventually be translated into new clinical therapies for epithelial cancers.

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“…Since the first therapeutics based on modified nucleosides ( Fig. 1) have been employed clinically [4][5][6][7], the interest in research directed towards the preparation of even more effective anticancer drugs has significantly increased. Various structural modifications of nucleobase or furanose units as well as of both fragments simultaneously have been examined.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Cytotoxicity of a New Series of Isoxazolidine Based Nucleoside Analogues

Piotrowska

Cieślak

Królewska

et al. 2011

Archiv der Pharmazie

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5-Arylisoxazolidin-3-yl-3-diethoxyphosphonates have been synthesized from N-methyl-C-diethoxyphosphorylnitrone and vinyl aryls in good yields and their transformation into the respective phosphonic acids has been accomplished via dealkylation procedure using trimethylsilyl bromide. Phosphonates having 1- and 2-naphthyl substituents at C5 in the isoxazolidine ring as well as the respective phosphonic acids have been found cytotoxic to HeLa and K562 cells with IC(50) in the 0.1-0.3 mM range. Preliminary studies on mechanism of action imply that intercalation to DNA is not responsible for their cytotoxic properties.

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Decitabine

Cited by 98 publications

References 15 publications

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

P2X₇-mediated chemoprevention of epithelial cancers

Design, Synthesis and Cytotoxicity of a New Series of Isoxazolidine Based Nucleoside Analogues

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Decitabine

Cited by 98 publications

References 15 publications

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

P2X7-mediated chemoprevention of epithelial cancers

Design, Synthesis and Cytotoxicity of a New Series of Isoxazolidine Based Nucleoside Analogues

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Product

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P2X₇-mediated chemoprevention of epithelial cancers