{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:22:40Z","timestamp":1791256960092,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2004,12,17]],"date-time":"2004-12-17T00:00:00Z","timestamp":1103241600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2005,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The DNA methylation inhibitor 5\u2010Aza\u20102\u2032\u2010deoxycytidine (5\u2010Aza\u2010CdR) has significant therapeutic value for the treatment of patients with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). The demethylating effect of 5\u2010Aza\u2010CdR has been well characterized. In contrast, less is known about the molecular events downstream of the methylation inhibition. Here, 5\u2010Aza\u2010CdR induced apoptosis in AML cells (both p53 mutant and wild\u2010type) but not in epithelial or normal PBMCs. Cell death was accompanied by activation of the mitochondrial apoptosis pathway, as shown by release of cytochrome <jats:italic>c<\/jats:italic> and AIF and loss of mitochondrial membrane potential (\u0394\u03a8m). Activation of caspase\u20103 (but not \u22126 and \u22128) was detectable using Western blot analysis and measurement of caspase enzymatic activity. 5\u2010Aza\u2010CdR treatment resulted in the induction of p21, which correlated with the arrest of AML cells in the G<jats:sub>1<\/jats:sub> cell cycle phase. Induction of p21 expression was independent of its promoter methylation status but mediated by 5\u2010Aza\u2010CdR\u2010induced reexpression of the tumor\u2010suppressor p73, a known upstream regulator of p21. The p73 promoter was hypermethylated in AML cell lines and in primary AML cells but not in epithelial cells, which were resistant toward 5\u2010Aza\u2010CdR. Therefore, 5\u2010Aza\u2010CdR\u2010mediated specific killing of myeloid cells might be dependent on its ability to revert p73 promoter methylation and to reexpress p73 mRNA. In addition, exogenous expression of p73 rendered epithelial cells sensitive to apoptosis induced by 5\u2010Aza\u2010CdR or other cytostatic drugs. We therefore conclude that p73 is a relevant target for methylation\u2010dependent efficacy of 5\u2010Aza\u2010CdR in AML cells. \u00a9 2004 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.20797","type":"journal-article","created":{"date-parts":[[2004,12,17]],"date-time":"2004-12-17T22:52:00Z","timestamp":1103323920000},"page":"683-695","source":"Crossref","is-referenced-by-count":98,"title":["5\u2010Aza\u20102\u2032\u2010deoxycytidine induces p21<sup>WAF<\/sup> expression by demethylation of p73 leading to p53\u2010independent apoptosis in myeloid leukemia"],"prefix":"10.1002","volume":"114","author":[{"given":"Karin","family":"Schmelz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"D\u00f6rken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Tamm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,2,18]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg816"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204341"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2000.18.5.956"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.11543"},{"key":"e_1_2_6_6_2","first-page":"6","article-title":"Phase 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