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

Abstract 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.</jats:p

Abstract 995: Transient low doses of DNA demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells

Abstract Reversal of gene promoter DNA hypermethylation and associated abnormal gene silencing is an attractive approach to cancer therapy. The DNA methylation inhibitors, decitabine (5-aza-2′-deoxycytidine) and azacitidine (5-azacytidine) are proving efficacious clinically for hematological neoplasms, especially at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, but these may not explain the prolonged time to response often seen in patients. We now show that transient exposure of cultured and primary leukemic and epithelial tumor cells to decitabine or azacitidine at clinically-relevant nanomolar doses, without causing immediate cytotoxicity, produces a “memory” for anti-tumor responses, including potent inhibition of subpopulations of cancer, stem-like cells which often resist other therapies. These inhibitory effects are accompanied by sustained decreases in genome-wide promoter DNA methylation with associated gene re-expression, and anti-tumor changes in multiple key cellular regulatory pathways, such as cell cycle events mediated through FOXM1, cell invasion and motility, and granulocyte and breast cancer cell maturation. Notably, most of the key pathways altered by decitabine or azacitidine involve high priority targets for pharmacologic anti-cancer strategies, which provides molecular basis for possible combination therapies. Thus, low dose decitabine and azacitidine regimens may potentially have broad applicability for cancer management. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 995. doi:1538-7445.AM2012-995</jats:p

Transient Low Doses of DNA-Demethylating Agents Exert Durable Antitumor Effects on Hematological and Epithelial Tumor Cells

SummaryReversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged time to response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically relevant nanomolar doses, without causing immediate cytotoxicity, produce an antitumor “memory” response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genomewide promoter DNA methylation, gene reexpression, and antitumor changes in key cellular regulatory pathways. Low-dose decitabine and azacitidine may have broad applicability for cancer management