Abstract LB-88: Transient exposure to low-dose decitabine and azacytidine reprograms cancer cells to produce a prolonged antitumor response

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (8_Supplement), p.LB-88-LB-88
• Main Authors: Tsai, Hsing-Chen, Van Neste, Leander, Li, Huili, Cai, Yi, Robert, Carine, Shin, James J., Pappou, Emmanouil, Yen, Ray-Whay, Minn, IL, Ahuja, Nita, Brock, Malcolm V., Rassool, Feyruz V., Jang, Yoon-Young, Sharkis, Saul J., Matsui, William, Zahnow, Cynthia A., Baylin, Stephen B.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-LB-88

Reversing abnormal promoter DNA hypermethylation to induce expression of abnormally silenced genes is an attractive cancer therapeutic strategy. The DNA methylation inhibitors, decitabine (5-aza-2′-deoxycytidine) and azacytidine (5-azacytidine), have proven clinically effective against hematological neoplasms especially with use of low, minimally toxic, doses. While, experimentally, high doses of these drugs induce DNA damage and cytotoxicity, the prolonged time for patient responses does not suggest acute tumor cell lysis. We now separate, for these drugs, cytotoxic effects at high doses from cellular reprogramming effects at low nanomolar doses. These latter subsequently reduce tumorigenicity of human leukemia and solid tumor cells, and for leukemia cells, blunt long term self-renewal. We correlate these effects with sustained, genome wide, promoter DNA de-methylation and gene re-expression, and an anti-tumor reprogramming of multiple central cancer pathways which regulate cell cycle entry, mitosis, proliferation, apoptosis, and dependence upon anaerobic glycolysis. Thus, decitabine and azacytidine represent drugs that can, at low nanomolar doses, simultaneously reverse major cancer pathways each of which are the focus of intense drug targeting efforts. This suggests these drugs are broadly applicable to cancer management. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-88.