Zebularine induces chemosensitization to methotrexate and efficiently decreases AhR gene methylation in childhood acute lymphoblastic leukemia cells

Andrade, Augusto Faria; Borges, Kleiton Silva; Castro‐Gamero, Angel Mauricio; Silveira, Vanessa da Silva; Suazo, Veridiana Kill; Oliveira, Jaqueline Carvalho de; Moreno, Daniel Antunes; Queiróz, Rosane Gomes de Paula; Scrideli, Carlos Alberto; Tone, Luíz Gonzaga

doi:10.1097/cad.0000000000000028

Cited by 29 publications

(28 citation statements)

References 44 publications

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“…However, epigenetic changes are reversible, in contrast to gene mutations, and there is a potential to reverse gene silencing using DNA methyltransferase (DNMT) inhibitors, which are drugs that prevent hypermethylation by irreversibly binding to the active site of DNMT [43]. These drugs are effective as monotherapy for hematologic malignancy [44, 45], but not in solid cancer. However, effects on solid cancer are likely to be found in combination with other drugs.…”

Section: Utility Of Mirnas In Treatment Of Ovarian Cancermentioning

confidence: 99%

Application of MicroRNA in Diagnosis and Treatment of Ovarian Cancer

Banno

Yanokura

Iida

et al. 2014

BioMed Research International

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Ovarian cancer has a poor prognosis because early detection is difficult and recurrent ovarian cancer is usually drug-resistant. The morbidity and mortality of ovarian cancer are high worldwide and new methods of diagnosis and therapy are needed. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression that are involved in carcinogenesis, metastasis, and invasion. Thus, miRNAs are likely to be useful as diagnostic and prognostic biomarkers and for cancer therapy. Many miRNAs have altered expression in ovarian cancer compared to normal ovarian tissues and these changes may be useful for diagnosis and treatment. For example, deficiencies of enzymes including Dicer and Drosha that are required for miRNA biogenesis may be adverse prognostic factors; miRNAs such as miR-214 and miR-31, which are involved in drug resistance, and the miR-200 family, which is implicated in metastasis, may serve as biomarkers; and transfection of downregulated miRNAs and inhibition of upregulated miRNAs may be effective for treatment of ovarian cancer. Chemotherapy targeting epigenetic mechanisms associated with miRNAs may also be effective to reverse gene silencing.

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Section: Utility Of Mirnas In Treatment Of Ovarian Cancermentioning

confidence: 99%

Application of MicroRNA in Diagnosis and Treatment of Ovarian Cancer

Banno

Yanokura

Iida

et al. 2014

BioMed Research International

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“…The potential use of DNMT inhibitors for the treatment of human T‐ALL has not been extensively evaluated. The T‐ALL cell line JURKAT was found to be sensitive to zebularine, another DNMT inhibitor, with strong synergistic effects in combination with methotrexate . Moreover, DNMT3A mutations occur mostly in early immature T‐ALLs, a poor prognostic subtype of human T‐ALL characterized by a gene expression signature enriched for transcripts found in myeloid progenitors.…”

Section: Epigenetic Opportunities For Targeted Therapy In T‐allmentioning

confidence: 99%

Epigenetics in T‐cell acute lymphoblastic leukemia

Peirs

Meulen

Walle

et al. 2014

Immunological Reviews

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Normal T-cell development is a strictly regulated process in which hematopoietic progenitor cells migrate from the bone marrow to the thymus and differentiate from early T-cell progenitors toward mature and functional T cells. During this maturation process, cooperation between a variety of oncogenes and tumor suppressors can drive immature thymocytes into uncontrolled clonal expansion and cause T-cell acute lymphoblastic leukemia (T-ALL). Despite improved insights in T-ALL disease biology and comprehensive characterization of its genetic landscape, clinical care remained largely similar over the past decades and still consists of high-dose multi-agent chemotherapy potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable side effects, clinical outcome is still extremely poor in a significant subset of T-ALL patients as a result of therapy resistance or hematological relapses. Recent genetic studies have identified recurrent somatic alterations in genes involved in DNA methylation and post-translational histone modifications in T-ALL, suggesting that epigenetic homeostasis is critically required in restraining tumor development in the T-cell lineage. In this review, we provide an overview of the epigenetic regulators that could be implicated in T-ALL disease biology and speculate how the epigenetic landscape of T-ALL could trigger the development of epigenetic-based therapies to further improve the treatment of human T-ALL.

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“…Zebularine preferentially targets cancer cells and exhibits low toxicity toward normal cells and mice [81, 82]. Zebularine induces apoptosis and decreases clonogenic capacity of acute lymphoblastic leukemia cell lines in a dose-dependent manner [83]. Although it is orally available and more stable than FDA-approved Vidaza and Decitabine, its clinical benefit is yet to be evaluated.…”

Section: Introductionmentioning

confidence: 99%

The IGF signalling pathway in Wilms tumours - A report from the ENCCA Renal Tumours Biology-driven drug development workshop

et al. 2014

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It is hypothesised that Wilms tumour (WT) results from aberrant renal development due to its embryonic morphology, associated undifferentiated precursor lesions (termed nephrogenic rests) and embryonic kidney-like chromatin and gene expression profiles. From the study of overgrowth syndrome-associated WT, germline dysregulation was identified in the imprinted region at 11p15 affecting imprinted genes IGF2 and H19. This is also detected in ~70% sporadic cases, making this the most common somatic molecular aberration in WT. This review summarises the critical discussion at an international workshop held under the auspices of The European Network for Cancer Research in Children and Adolescents (ENCCA) consortium, where the potential for drug development to target IGF2 and the WT epigenome was debated. Here, we consider current cancer treatments which include targeting the IGF pathway and the use of methylation agents alone or in combination with other drugs in clinical trials of paediatric cancers. Finally, we discuss the possibility of the use of these drugs to treat patients with WT.

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Zebularine induces chemosensitization to methotrexate and efficiently decreases AhR gene methylation in childhood acute lymphoblastic leukemia cells

Cited by 29 publications

References 44 publications

Application of MicroRNA in Diagnosis and Treatment of Ovarian Cancer

Application of MicroRNA in Diagnosis and Treatment of Ovarian Cancer

Epigenetics in T‐cell acute lymphoblastic leukemia

The IGF signalling pathway in Wilms tumours - A report from the ENCCA Renal Tumours Biology-driven drug development workshop

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