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

Hsing Chen Tsai, Huili Li, Leander Van Neste, Yi Cai, Carine Robert, Feyruz V. Rassool, James J. Shin, Kirsten M. Harbom, Robert Beaty, Emmanouil Pappou, James Harris, Ray Whay Chiu Yen, Nita Ahuja, Malcolm V. Brock, Vered Stearns, David Feller-Kopman, Lonny B. Yarmus, Yi Chun Lin, Alana L. Welm, Jean Pierre IssaIl Minn, William Matsui, Yoon Young Jang, Saul J. Sharkis, Stephen B. Baylin, Cynthia A. Zahnow

Research output: Contribution to journalArticlepeer-review

Abstract

Reversal 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.

Original languageEnglish (US)
Pages (from-to)430-446
Number of pages17
JournalCancer cell
Volume21
Issue number3
DOIs
StatePublished - Mar 20 2012

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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