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Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice.

ABSTRACT: 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 tissue-specific DNA demethylation. Importantly, prolonged treatment of mice with epigenetic drugs resulted in only minor developmental and histologic changes.

SUBMITTER: Yoo CB

PROVIDER: S-EPMC6959547 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice.

Yoo Christine B CB Chuang Jody C JC Byun Hyang-Min HM Egger Gerda G Yang Allen S AS Dubeau Louis L Long Tiffany T Laird Peter W PW Marquez Victor E VE Jones Peter A PA

Cancer prevention research (Philadelphia, Pa.) 20080319 4

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 B ...[more]

PMID: 19138966

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Project description:Background: Intestinal tumors are the third most common malignant tumors worldwide, accounting for approximately 10% of all new cancer cases worldwide. Cancer prevention is a promising way to limit the intestinal tumor incidence rate; however, challenges remain. Qingchang Wenzhong decoction (QCWZD) can clinically treat mild to moderate ulcerative colitis symptoms. Moreover, the mechanism by which it prevents intestinal tumors has not been clarified. In this study, we explored the mechanism by which QCWZD prevents the occurrence of intestinal tumors. Methods: To study the preventive mechanism of QCWZD on intestinal tumors, we used two model mice with azoxymethane/dextran sodium sulfate (AOM/DSS)- and Apcmin/+-induced intestinal tumor formation. The two models exhibited colitis-associated cancer and familial adenomatous polyposis, respectively. Colon and small intestine tissues were collected and analyzed based on histopathology and immunohistochemistry analyses. Fecal samples were collected, and 16S rRNA sequencing was used to analyze the correlation between intestinal microbiota and the prevention of intestinal tumors. Results: In the AOM/DSS mice, the QCWZD reduced the number and size of tumors, as well as tumor load. Similarly, in the Apcmin/+ mice, QCWZD can also reduce the number of tumors and the tumor load. The results of 16S rRNA sequencing confirmed that QCWZD altered the composition of intestinal microbiota in mice, a phenomenon that may prevent the occurrence of intestinal tumors by aiding the increase in the abundance of beneficial bacteria, such as Ralstonia and Butyricicoccus, and reducing that of pathogenic bacteria, such as Desulfobacterota and Bacteroides, in the intestine. Further, immunohistochemistry reveald that QCWZD can improve the expression of intestinal barrier-related proteins and inhibit pyroptosis-related proteins. Conclusions: QCWZD has the potential to prevent the occurrence of intestinal tumors. The anti-tumor activity may be achieved by regulating the intestinal microbiota, improving the function of the intestinal barrier, and inhibiting GSDME mediated pyroptosis.

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Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice.

Publications

Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice.

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