Mechanism of inhibition of DNA methyltransferases by cytidine analogs in cancer therapy

Gowher, Humaira; Jeltsch, Albert

doi:10.4161/cbt.3.11.1308

Cited by 90 publications

(57 citation statements)

References 64 publications

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“…This is surprising given the absence of the NH 2 group at the 4 position of the pyrimidine ring, which results in one less hydrogen bond for the G:Z pairing relative to the G:C pairing ( Figures 3A and 4A). Such a high degree of incorporation suggests effective recognition by the polymerase when bound to the primed template G. This supports the role of zebularine as a demethylating agent and potential chemotherapeutic, because in order to block the activity of DNA methyltransferase, zebularine must first be specifically incorporated into DNA in place of cytosine (21,39).…”

supporting

confidence: 54%

Incorporation of Zebularine from its 2′-Deoxyribonucleoside Triphosphate Derivative and Activity as a Template-Coding Nucleobase

Dowd

Sutch

Haworth

et al. 2008

Nucleosides, Nucleotides and Nucleic Acids

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Zebularine (1-(β-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one) was studied as both a 2'-deoxyribosyl 5'-triphosphate derivative and as a template incorporated into an oligonucleotide.Using a novel Pyrosequencing assay zebularine acted as cytosine analog and was incorporated into DNA with a template pairing profile most similar to cytosine, pairing with greatest efficiency opposite guanine in the template strand. Guanine was incorporated with greater affinity than adenine opposite a zebularine in the template strand. Computer modeling of basepairing structures supported a better fit of zebularine opposite guanine than adenine. Zebularine

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supporting

confidence: 54%

Incorporation of Zebularine from its 2′-Deoxyribonucleoside Triphosphate Derivative and Activity as a Template-Coding Nucleobase

Dowd

Sutch

Haworth

et al. 2008

Nucleosides, Nucleotides and Nucleic Acids

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“…At low doses that do not inhibit proliferation, these drugs are effective hypomethylating agents and they have shown clinical activity as anticancer agents (see further). Other nucleoside inhibitors include zebularine, which has shown promise in vitro (17) but is not being pursued clinically at this time, and 5-fluoro-2 ¶-deoxycytidine (18), which has entered clinical trials. One limitation of nucleoside analogues is the requirement for DNA incorporation and active DNA synthesis, which limits the activity of the drugs in hypoproliferating cells (including potentially cancer stem cells).…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation as a Therapeutic Target in Cancer

Issa

2007

Clinical Cancer Research

272

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Targeting DNA methylation for cancer therapy has had a rocky history. The first reports on DNA methylation changes in cancer described global loss of methylation, which has been suggested to drive tumorigenesis through activation of oncogenic proteins or induction of chromosomal instability. In this context, reducing DNA methylation was viewed as a tumor-promoting event rather than a promising cancer therapy. The idea of inhibiting DNA methylation therapeutically emerged from subsequent studies showing that, in parallel to global decreases in methylation, several genes (including many critical to the tumor phenotype) displayed gains of methylation in their promoters during tumorigenesis, a process associated with epigenetic silencing of expression and loss of protein function. This led to revival of interest in drugs discovered decades ago to be potent inhibitors of DNA methyltransferases. These drugs have now been approved for clinical use in the United States in the treatment of myelodysplastic syndrome, thus opening the floodgate for a whole new approach to cancer therapyöepigenetic therapy.

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“…Todos esses fármacos são análogos de nucleosídeos, sendo incorporados à molécula de DNA como citosina durante a replicação. Esses análogos ligam-se covalentemente à enzima DNMT, o que inibe a metilação do DNA (GOWHER;JELTSCH, 2004;JONES, 2006).…”

Section: Terapias Epigenéticasunclassified

Epigenética e doenças humanas

Oliveira

2012

Semin. Cienc. Biol. Saude

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The term epigenetics defines heritable changes in gene expression that do not involve DNA sequence changes. DNA methylation and histone modifications are two important related mechanisms. DNA methylation alters chromatin structure and has been shown to have a direct effect on the silencing of genes and transposons. There are many post-traductional modifications on histones and an extra complexity comes from many sites and amino acids that may be modified, what results in multiple matches in a real "histone code" decrypted by different cell factors. The epigenetics mechanisms are complex, and minor failing in the establishment and maintenance causes diseases, as genetics syndromes and cancer. Due to several diseases, an increasing amount of research has been realized to find drugs able to suppress these defects. Nowadays, there have already been described some medicines able to interfere in the action of the enzymes which regulate the epigenetic processes, however, there is still doubt in effectiveness of theses treatment. It is necessary additional research about epigenetics mechanism to, in the future, understand specific pathways and control the effects of these drugs. Keywords: Epigenetics. Diseases. DNA methylation. Histone modifications.O termo epigenética é definido pela alteração herdável na expressão gênica, sem que haja mudança na sequência primária de DNA, sendo a metilação do DNA e a modificação de histonas, importantes mecanismos envolvidos. A metilação do DNA influencia a organização da cromatina, e leva à repressão de genes e elementos transponíveis. As modificações pós-traducionais que podem ocorrem em proteínas histonas são muitas e podem ocorrer em diferentes aminoácidos e diferentes posições, e resultam em uma multiplicidade de combinações em um verdadeiro "código de histona", e elas são interpretadas por diferentes fatores celulares. As marcas epigenéticas atuam simultaneamente para regular a transcrição gênica em um processo complexo, e pequenas falhas no estabelecimento ou manutenção desses podem desencadear o desenvolvimento de patologias, como a encontrada em síndromes genéticas e no câncer. Devido ao grande número de doenças, muitas pesquisas têm sido realizadas na busca de drogas capazes de reverter esses defeitos epigenéticos. Atualmente, já foram descritos alguns agentes capazes de interferir na ação de enzimas que regulam os processos, porém, existem ainda muitas dúvidas na aplicatividade desses tratamentos, se fazendo necessário maiores estudos dos mecanismos epigenéticos para, no futuro, serem mapeadas vias de interferências específicas e um melhor controle de efeitos. Palavras-chave: Epigenética. Doenças. Metilação do DNA. Modificação de histona.

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Mechanism of inhibition of DNA methyltransferases by cytidine analogs in cancer therapy

Cited by 90 publications

References 64 publications

Incorporation of Zebularine from its 2′-Deoxyribonucleoside Triphosphate Derivative and Activity as a Template-Coding Nucleobase

Incorporation of Zebularine from its 2′-Deoxyribonucleoside Triphosphate Derivative and Activity as a Template-Coding Nucleobase

DNA Methylation as a Therapeutic Target in Cancer

Epigenética e doenças humanas

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