QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fini, L. Articles by Ricciardiello, L. Search for Related Content PubMed PubMed Citation Articles by Fini, L. Articles by Ricciardiello, L.

---

Biochemical, Molecular, and Genetic Mechanisms

Annurca Apple Polyphenols Have Potent Demethylating Activity and Can Reactivate Silenced Tumor Suppressor Genes in Colorectal Cancer Cells^1,2

³ GI Cancer Research Laboratory, Department of Internal Medicine, Sammons Cancer Center, and Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75246; ⁴ Internal Medicine Department, Catholic University of Sacred Heart Gemelli Hospital, 00168 Rome, Italy; ⁵ Department of Nutrition Sciences, University of Naples, 80138 Naples, Italy; ⁶ Division of Gastroenterology, Second University of Naples, 80138 Naples, Italy; and ⁷ Institute for Health Care Research and Improvement, Baylor Health Care System, Dallas, TX 75246

^* To whom correspondence should be addressed. E-mail: luigir{at}baylorhealth.edu or rickbo{at}baylorhealth.edu.

The CpG island methylator phenotype is characterized by DNA hypermethylation in the promoters of tumor suppressor genes with silencing of transcription. Hypermethylation of the promoter of hMLH1 and subsequent microsatellite instability occurs in 12% of sporadic colorectal cancers (CRC). Annurca apple, a variety of southern Italy, is rich in polyphenols that are associated with anticancer properties. Populations in southern Italy have lower incidences of CRC than elsewhere in the western world. We evaluated the mechanisms of putative anticancer effects of Annurca polyphenol extract (APE) in in vitro models of CRC. We extracted polyphenols from Annurca apples and treated RKO, SW48, and SW480 cells with APE and assessed the cell viability, apoptosis, and cell cycle. DNA methylation of selected tumor suppressor genes was evaluated after treatment with APE and was compared with the synthetic demethylating agent 5-aza-2'deoxycytidine (5-aza-2dC). DNA methyltransferase (DNMT)-1 and -3b levels were evaluated. Decreased cell viability and induction of apoptosis was evident after treatment. We found no significant changes in cell cycle dynamics. We observed significant increases of p53 protein expression in RKO after treatment. APE treatment strongly reduced DNA methylation in the promoters of hMLH1, p14^ARF, and p16^INK4a with consequent restoration of normal expression. These effects were qualitatively comparable with those obtained with 5-aza-2dC. We observed a significant reduction in expression of DNMT proteins after treatment without changes in messenger RNA. In conclusion, APE have potent demethylating activity through the inhibition of DNMT proteins. The lack of toxicity in Annurca extracts makes them excellent candidates for the chemoprevention of CRC.

This article has been cited by other articles:

				K. Nosho, K. Shima, N. Irahara, S. Kure, Y. Baba, G. J. Kirkner, L. Chen, S. Gokhale, A. Hazra, D. Spiegelman, et al. DNMT3B Expression Might Contribute to CpG Island Methylator Phenotype in Colorectal Cancer Clin. Cancer Res., June 1, 2009; 15(11): 3663 - 3671. [Abstract] [Full Text] [PDF]

				A. Hadnagy, R. Beaulieu, and D. Balicki Histone tail modifications and noncanonical functions of histones: perspectives in cancer epigenetics Mol. Cancer Ther., April 1, 2008; 7(4): 740 - 748. [Abstract] [Full Text] [PDF]