Novel DNA methyltransferase-1 (DNMT1) depleting anticancer nucleosides, 4-thio-2-deoxycytidine and 5-aza-4-thio-2-deoxycytidine

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• 作者：Jaideep V. Thottassery (1) (3)
  Vijaya Sambandam (1)
  Paula W. Allan (1)
  Joseph A. Maddry (1)
  Yulia Y. Maxuitenko (1)
  Kamal Tiwari (1)
  Melinda Hollingshead (2)
  William B. Parker (1) (3)
  
• 关键词：DNMT1 ; DNA methyltransferase ; Decitabine ; Azacytidine ; Zebularine ; Deoxycytidine
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2014
• 出版时间：August 2014
• 年：2014
• 卷：74
• 期：2
• 页码：291-302
• 全文大小：1,189 KB
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• 作者单位：Jaideep V. Thottassery (1) (3)
  Vijaya Sambandam (1)
  Paula W. Allan (1)
  Joseph A. Maddry (1)
  Yulia Y. Maxuitenko (1)
  Kamal Tiwari (1)
  Melinda Hollingshead (2)
  William B. Parker (1) (3)
  
  1. Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL, 35205, USA
  3. University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, AL, USA
  2. Biological Testing Branch, NCI at Frederick, Frederick, MD, USA
  
• ISSN：1432-0843

文摘

Purpose Currently approved DNA hypomethylating nucleosides elicit their effects?in part by depleting DNA methyltransferase I (DNMT1). However, their low response rates and adverse effects continue to drive the discovery of newer DNMT1 depleting agents. Herein, we identified two novel 2-deoxycytidine (dCyd) analogs, 4-thio-2-deoxycytidine (T-dCyd) and 5-aza-4-thio-2-deoxycytidine (aza-T-dCyd) that potently deplete DNMT1 in both in vitro and in vivo models of cancer and concomitantly inhibit tumor growth. Methods DNMT1 protein levels in in vitro and in vivo cancer models were determined by Western blotting and antitumor efficacy was evaluated using xenografts. Effects on CpG methylation were evaluated using methylation-specific PCR. T-dCyd metabolism was evaluated using radiolabeled substrate. Results T-dCyd markedly depleted DNMT1 in CCRF-CEM and KG1a leukemia and NCI-H23 lung carcinoma cell lines, while it was ineffective in the HCT-116 colon or IGROV-1 ovarian tumor lines. On the other hand, aza-T-dCyd potently depleted DNMT1 in all of these lines indicating that dCyd analogs with minor structural dissimilarities induce different DNMT1 turnover mechanisms. Although T-dCyd was deaminated to 4-thio-2-deoxyuridine, very little was converted to 4-thio-thymidine nucleotides, suggesting that inhibition of thymidylate synthase would be minimal with 4-thio dCyd analogs. Both T-dCyd and aza-T-dCyd also depleted DNMT1 in human tumor xenografts and markedly reduced in vivo tumor growth. Interestingly, the selectivity index of aza-T-dCyd was at least tenfold greater than that of decitabine. Conclusions Collectively, these data show that 4-thio modified dCyd analogs, such as T-dCyd or aza-T-dCyd, could be a new source of clinically effective DNMT1 depleting anticancer compounds with less toxicity.