Zebularine induces replication-dependent double-strand breaks which are preferentially repaired by homologous recombination

Orta, Manuel Luís; Pastor, Nuria; Burgos-Morón, Estefanía; Domı́nguez, I.; Calderón-Montaño, José Manuel; Castaño, Carlos Huertas; López‐Lázaro, Miguel; Helleday, Thomas; Mateos, Santiago

doi:10.1016/j.dnarep.2017.07.002

Cited by 16 publications

(16 citation statements)

References 47 publications

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“…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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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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“…Zebularine is more selective for malignant cells and this makes it's a likely anticancer drug. 32 Azacytidine was the first hypomethylation agent for the treatment of the MDS patients, and has been approved on May 19, 2004. Decitabine is also beneficial in the treatment of MDS patients and has been approved by the FDA on May 2, 2006.…”

Section: Nucleoside Analog Dna Methyltransferases Inhibitorsmentioning

confidence: 99%

“…35 Zebularine is a powerful inhibitor of both cytidine deaminase and DNA cytosine methyltransferase and, today, it is thought to be a general DNA methylation inhibitor. 32 Nonnucleoside Analog DNA Methyltransferases Inhibitors This type of DNA methylation inhibitors involves (-)-epigallocatechin-3-gallate (EGCG), procaine, procainamide, hydralazine, and mitoxantrone. They inhibit DNA methylation without requiring DNA to be incorporated.…”

Section: Nucleoside Analog Dna Methyltransferases Inhibitorsmentioning

confidence: 99%

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Cancer Treatment: An Epigenetic View

Aydin

Kalkan

2020

Global Medical Genetics

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Cancer can be identified as an uncontrolled growth and reproduction of cell. Accumulation of genetic aberrations (mutations of oncogenes and tumor-suppressor genes and epigenetic modifications) is one of the characteristics of cancer cell. Increasing number of studies highlighted importance of the epigenetic alterations in cancer treatment and prognosis. Now, cancer epigenetics have a huge importance for developing novel biomarkers and therapeutic target for cancer. In this review, we will provide a summary of the major epigenetic changes involved in cancer and preclinical results of epigenetic therapeutics.

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“…As a result, their stability in the blood is limited and their use as cytotoxic agents in solid cancers proved unsuccessful [19]. The second-generation DNMTis guadecitabine and zebularine are more stable in the liquid environment and allow for a longer effective half-life [19–21]. While hypomethylation induced by the first-generation DNMTis in in vitro studies [22–24] brings evidence of effectivity of these agents, down-regulating the DNA methylation with guadecitabine in cancer xenograft models [25] provided proof that the unfavorable pharmacokinetic profile of first-generation DNMTis can be overcome.…”

Section: Targeting Dna Methylation With Dna Methyltransferase (Dnmt) mentioning

confidence: 99%

Incorporating DNA Methyltransferase Inhibitors (DNMTis) in the Treatment of Genitourinary Malignancies: A Systematic Review

et al. 2017

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Inhibition of DNA methyltransferases (DNMTs) has emerged as a novel treatment strategy in solid tumors. Aberrant hypermethylation in promoters of critical tumor suppressor genes is the basis for the idea that treatment with hypomethylating agents may lead to the restoration of a "normal" epigenome and produce clinically meaningful therapeutic outcomes. The aim of this review article is to summarize the current state of knowledge of DNMT inhibitors in the treatment of genitourinary malignancies. The efficacy of these agents in genitourinary malignancies was reported in a number of studies and suggests a role of induced DNA hypomethylation in overcoming resistance to conventional cytotoxic treatments. The clinical significance of these findings should be further investigated.

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Zebularine induces replication-dependent double-strand breaks which are preferentially repaired by homologous recombination

Cited by 16 publications

References 47 publications

DNA Methylation as a Therapeutic Target for Bladder Cancer

DNA Methylation as a Therapeutic Target for Bladder Cancer

Cancer Treatment: An Epigenetic View

Incorporating DNA Methyltransferase Inhibitors (DNMTis) in the Treatment of Genitourinary Malignancies: A Systematic Review

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