Preferential response of cancer cells to zebularine

Cheng, Jonathan; Yoo, Christine B.; Weisenberger, Daniel J.; Chuang, Jody C.; Wozniak, Chandra; Liang, Gangning; Márquez, Víctor E.; Greer, Sheldon; Ørntoft, Torben F.; Thykjær, Thomas; Jones, Peter A.

doi:10.1016/j.ccr.2004.06.023

Cited by 279 publications

(243 citation statements)

References 34 publications

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“…Treatment of tumorconditioned HUVECs with the DNMT inhibitor DAC significantly restored ICAM-1 protein expression (P < 0.01). A similar effect was observed after treatment with zebularine, a recently discovered DNMT inhibitor that requires higher effective concentrations (22,25), or with the HDAC inhibitor TSA (P < 0.01). Because DNMTs and HDACs cooperate in gene silencing (15), we further treated tumor-conditioned HUVEC with a combination of DAC and TSA (14).…”

Section: Methodssupporting

confidence: 65%

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Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Hellebrekers

Castermans

Viré³

et al. 2006

Cancer Research

141

107

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Tumors can escape from immunity by repressing leukocyte adhesion molecule expression on tumor endothelial cells and by rendering endothelial cells unresponsive to inflammatory activation. This endothelial cell anergy is induced by angiogenic growth factors and results in reduced leukocytevessel wall interactions, thereby attenuating infiltration of leukocytes into the tumor. This report describes a novel mechanism of endothelial cell anergy regulation. We recently reported that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors have angiostatic activity. Here, we studied whether epigenetic mechanisms regulate this angiogenesis-mediated escape from immunity. We found that DNMT inhibitors 5-aza-2 ¶-deoxycytidine and zebularine, as well as HDAC inhibitor trichostatin A, reexpressed intercellular adhesion molecule-1 (ICAM-1) on tumor-conditioned endothelial cells in vitro , resulting in restored leukocyte-endothelial cell adhesion. In addition, treatment with DNMT or HDAC inhibitors in vivo also restored ICAM-1 expression on tumor endothelial cells from two different mouse tumor models. Furthermore, leukocyte-vessel wall interactions in mouse tumors were increased by these compounds, as measured by intravital microscopy, resulting in enhanced leukocyte infiltration. We show that ICAM-1 down-regulation in tumor endothelial cells is associated with ICAM-1 promoter histone H3 deacetylation and loss of histone H3 Lys 4 methylation but not with DNA hypermethylation. In conclusion, our data show that ICAM-1 is epigenetically silenced in tumor endothelial cells by promoter histone modifications, which can be overcome by DNMT and HDAC inhibitors, suggesting a new molecular mechanism based on which novel therapeutic approaches for cancer can be

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Section: Methodssupporting

confidence: 65%

“…14; Sigma, Zwijndrecht, the Netherlands) or zebularine (100 Amol/L; ref. 22; obtained from National Cancer Institute, Bethesda, MD), or with the HDAC inhibitor trichostatin A (TSA; 300 nmol/L; ref. 14; Wako, Neuss, Germany), replacing drugs and culture medium every 24 hours, as described previously (14,19).…”

Section: Methodsmentioning

confidence: 99%

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Hellebrekers

Castermans

Viré³

et al. 2006

Cancer Research

141

107

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“…These three types of tissues were analyzed for methylation, and a considerable amount of demethylation was detected in large and small intestines whereas no decrease in methylation was seen in skin epidermal cells, indicating that the turnover of these cells may be responsible for the tissue-specific demethylation. It would be of interest to determine whether zebularine activity is dependent on the rate of cell division in vivo as it is in vitro (13).…”

Section: Discussionmentioning

confidence: 99%

“…Zebularine, a novel inhibitor of DNA methylation, has been shown to have anticancer properties in vivo and in vitro (12)(13)(14)(15). Unlike 5-azacytidine and 5-aza-2′-deoxycytidine, which are chemically labile, zebularine is stable, making it possible to deliver the drug orally (14).…”

mentioning

confidence: 99%

Long-term Epigenetic Therapy with Oral Zebularine Has Minimal Side Effects and Prevents Intestinal Tumors in Mice

Yoo

Chuang

Byun

et al. 2008

Cancer Prevention Research

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Recent successes in the application of epigenetic drugs for the treatment of myelodysplastic syndrome have raised questions on the safety of long-term administration of DNA methylation inhibitors. We treated preweaned cancer prone Apc Min/+ (Min) mice continuously with the DNA methylation inhibitor zebularine in their drinking water to determine the effects of the drug on normal mouse development as well as cancer prevention. Zebularine caused a tissue-specific reduction in DNA methylation at B1 short interspersed nucleotide elements in the small and large intestines of female Min mice but not in other organs examined after chronic oral treatment. No significant difference in the average weights of mice was observed during the treatment. In addition, analysis of global gene expression of colonic epithelial cells from the females indicated that only 3% to 6% of the genes were affected in their expression. We did not detect toxicity and abnormalities from the histopathologic analysis of liver and intestinal tissues. Lastly, we tested whether prevention of tumorigenesis can be achieved with chronic oral administration of zebularine in Min mice. The average number of polyps in Min females decreased from 58 to 1, whereas the average polyp number remained unaffected in Min males possibly due to differential activity of aldehyde oxidase. Taken together, our results show for the first time that long-term oral administration of zebularine causes a gender-specific abrogation of intestinal tumors while causing a tissuespecific DNA demethylation. Importantly, prolonged treatment of mice with epigenetic drugs resulted in only minor developmental and histologic changes.

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“…The medical importance of CG-X antigens is supported by the observation that vaccine-induced CD8 þ T-cell responses to CG-X antigens, but not to melanoma differentiation antigens, correlates with tumor-free and overall survival in melanoma patients (Reynolds et al, 2003). Treatment with agents that increase the expression of CG-X antigens, including DAC (Karpf et al, 2004;Sigalotti et al, 2004) and zebularine (Cheng et al, 2004), constitute an intriguing therapeutic approach by which antitumor immunity to CG-X antigen-directed vaccines could be improved (Karpf and Jones, 2002;Maio et al, 2003;Guo et al, 2006). However, the toxicity and pleiotropic effects associated with nucleoside analog DNMT inhibitors could be a barrier to the successful clinical implementation of this combination strategy (Karpf and Jones, 2002).…”

Section: Ac-k9mentioning

confidence: 99%

Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b

2006

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We examined the function of two key DNA methyltransferase (DNMT) enzymes in epigenetic regulation of Xlinked cancer/germline (CG-X) antigen genes in human cancer cells, using MAGE-A1, NY-ESO-1, and XAGE-1 as models. In HCT116 cells, genetic knockout of DNMT1 caused moderate activation of CG-X genes, DNMT3b knockout had a negligible effect, and double knockout of both enzymes caused robust gene induction. Similarly, dual DNMT knockout caused dramatic hypomethylation of the MAGE-A1 and NY-ESO-1 promoters, DNMT1 knockout showed moderate hypomethylation, and DNMT3b knockout elicited only slight methylation changes. In contrast, both single and double knockout cells showed significant hypomethylation of the XAGE-1 promoter. RNA interference (RNAi) targeting of DNMT1 in HCT116 cells validated the results seen using genetic knockout cells; however, RNAi targeting of DNMT1 in a different colorectal cancer cell line revealed a greater independent role for DNMT1 in mediating CG-X gene repression and promoter methylation in other cell types. Notably, the histone H3 modification pattern at CG-X promoters was altered following DNMT knockout. DNMT1 or DNMT3b knockout reduced dimethylated lysine-9 (diMe-H3K9) levels, but did not significantly affect dimethylated lysine-4 (diMe-H3K4) or acetylated lysine-9 (Ac-H3-K9) levels. In contrast, dual DNMT1/3b knockout reduced the level of diMe-H3K9 and dramatically increased the levels of diMe-H3K4 and Ac-H3K9 at CG-X gene loci. In summary, DNMT1 and DNMT3b were found to perform both redundant and independent functions in epigenetic regulation of CG-X antigen genes in human cancer cells.

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Preferential response of cancer cells to zebularine

Cited by 279 publications

References 34 publications

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Long-term Epigenetic Therapy with Oral Zebularine Has Minimal Side Effects and Prevents Intestinal Tumors in Mice

Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b

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