Zebularine exerts its antiproliferative activity through S phase delay and cell death in human malignant mesothelioma cells

Takemura, Yukie; Satoh, Motohiko; Hatanaka, Kenichi; Kubota, Shunichiro

doi:10.1080/09168451.2018.1459466

Cited by 11 publications

(7 citation statements)

References 35 publications

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“…However, with the addition of ZEB administration, the demethylation effect could be maintained [84]. Therefore, it also combines with azacytidine and decitabine and displays much safer in various cancer treatments, such as AML and EBV-positive Burkitt's lymphoma [95].…”

Section: Dnmt Inhibitors (Dnmtis)mentioning

confidence: 99%

Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy

et al. 2020

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Epigenetics is dynamic and heritable modifications to the genome that occur independently of DNA sequence. It requires interactions cohesively with various enzymes and other molecular components. Aberrant epigenetic alterations can lead to inappropriate onset of genetic expressions and promote tumorigenesis. As the epigenetic modifiers are susceptible to extrinsic factors and reversible, they are becoming promising targets in multiple cancer therapies. Recently, various epi-drugs have been developed and implicated in clinical use. The use of epi-drugs alone, or in combination with chemotherapy or immunotherapy, has shown compelling outcomes, including augmentation of anti-tumoral effects, overcoming drug resistance, and activation of host immune response.

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Section: Dnmt Inhibitors (Dnmtis)mentioning

confidence: 99%

Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy

et al. 2020

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“…It displays high stability as it inhibits both DNMTs and cytidine deaminase, and it is stable in acidic and neutral pH, enabling oral administration [ 71 ]. Moreover, zebularine has low cytotoxicity, which might translate into longer treatments with low doses to maintain a demethylated state [ 71 ], as well as an apparent specificity for cancer cells and not fibroblasts [ 72 , 73 ]. Zebularine leads to S-phase delay and cell death in mesothelioma cells [ 72 ], causes formation of replication-dependent double-strand DNA breaks [ 74 ], and enhances colon cancer cell immunogenicity [ 75 ].…”

Section: Dnmt Inhibitorsmentioning

confidence: 99%

“…Moreover, zebularine has low cytotoxicity, which might translate into longer treatments with low doses to maintain a demethylated state [ 71 ], as well as an apparent specificity for cancer cells and not fibroblasts [ 72 , 73 ]. Zebularine leads to S-phase delay and cell death in mesothelioma cells [ 72 ], causes formation of replication-dependent double-strand DNA breaks [ 74 ], and enhances colon cancer cell immunogenicity [ 75 ]. Nevertheless, high concentrations of zebularine are needed to achieve demethylation levels similar to those of DAC since it forms a reversible complex with DNMTs, with slow dissociation kinetics [ 76 ], hindering the transition to clinical practice [ 57 , 71 ].…”

Section: Dnmt Inhibitorsmentioning

confidence: 99%

DNA Methylation as a Therapeutic Target for Bladder Cancer

Nunes

Henrique

Jerónimo

et al. 2020

Cells

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Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted by the current treatment options. Thus, the development of new therapeutic strategies, either alternative or complementary to the current ones, is of major importance. The disruption of normal epigenetic mechanisms, namely, DNA methylation, is a known early event in cancer development. Consequently, DNA methyltransferase (DNMT) inhibitors constitute a promising therapeutic target for the treatment of BC. Although these inhibitors, mainly nucleoside analogues such as 5-azacytidine (5-aza) and decitabine (DAC), cause re-expression of tumor suppressor genes, inhibition of tumor cell growth, and increased apoptosis in BC experimental models and clinical trials, they also show important drawbacks that prevent their use as a valuable option for the treatment of BC. However, their combination with chemotherapy and/or immune-checkpoint inhibitors could aid in their implementation in the clinical practice. Here, we provide a comprehensive review of the studies exploring the effects of DNA methylation inhibition using DNMTs inhibitors in BC, from in vitro and in vivo studies to clinical trials.

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“…Zebularine was developed to counter the shortcomings of DNMTI 5-azacytidine. Zebularine was reported to be safer than 5-azacytidine for the treatment of cancers in Epstein–Barr Virus (EBV) carriers and proposed to be used against tumors possessing EBV (Takemura et al, 2018).…”

Section: Regulation Of Colorectal Cancer By Epigenetic Mechanismmentioning

confidence: 99%

“…These studies indicated that zebularine could effectively target both DNMT inhibitors and non-DNMT inhibitors. In lymphoma cells, zebularine reactivates silenced E-cadherin, which suggests its capacity to reverse the EMT (Takemura et al, 2018).…”

Section: Regulation Of Colorectal Cancer By Epigenetic Mechanismmentioning

confidence: 99%

Drugs Targeting Epigenetic Modifications and Plausible Therapeutic Strategies Against Colorectal Cancer

Patnaik

Anupriya

2019

Front. Pharmacol.

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Genetic variations along with epigenetic modifications of DNA are involved in colorectal cancer (CRC) development and progression. CRC is the fourth leading cause of cancer-related deaths worldwide. Initiation and progression of CRC is the cumulation of a variety of genetic and epigenetic changes in colonic epithelial cells. Colorectal carcinogenesis is associated with epigenetic aberrations including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. Recently, epigenetic modifications have been identified like association of hypermethylated gene Claudin11 (CLDN11) with metastasis and prognosis of poor survival of CRC. DNA methylation of genes CMTM3, SSTR2, MDF1, NDRG4 and TGFB2 are potential epigenetic biomarkers for the early detection of CRC. Tumor suppressor candidate 3 (TUSC3) mRNA expression is silenced by promoter methylation, which promotes epidermal growth factor receptor (EGFR) signaling and rescues the CRC cells from apoptosis and hence leading to poor survival rate. Previous scientific evidences strongly suggest epigenetic modifications that contribute to anticancer drug resistance. Recent research studies emphasize development of drugs targeting histone deacetylases (HDACs) and DNA methyltransferase inhibitors as an emerging anticancer strategy. This review covers potential epigenetic modification targeting chemotherapeutic drugs and probable implementation for the treatment of CRC, which offers a strong rationale to explore therapeutic strategies and provides a basis to develop potent antitumor drugs.

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Zebularine exerts its antiproliferative activity through S phase delay and cell death in human malignant mesothelioma cells

Cited by 11 publications

References 35 publications

Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy

Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy

DNA Methylation as a Therapeutic Target for Bladder Cancer

Drugs Targeting Epigenetic Modifications and Plausible Therapeutic Strategies Against Colorectal Cancer

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