title: Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells.
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.
authors.affiliation: The Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Hsing-Chen
authors.initials: HC
authors.lastname: Tsai
authors.forename: Huili
authors.initials: H
authors.lastname: Li
authors.forename: Leander
authors.initials: L
authors.lastname: Van Neste
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.forename: Carine
authors.initials: C
authors.lastname: Robert
authors.forename: Feyruz V
authors.initials: FV
authors.lastname: Rassool
authors.forename: James J
authors.initials: JJ
authors.lastname: Shin
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Harbom
authors.forename: Robert
authors.initials: R
authors.lastname: Beaty
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Pappou
authors.forename: James
authors.initials: J
authors.lastname: Harris
authors.forename: Ray-Whay Chiu
authors.initials: RW
authors.lastname: Yen
authors.forename: Nita
authors.initials: N
authors.lastname: Ahuja
authors.forename: Malcolm V
authors.initials: MV
authors.lastname: Brock
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.forename: David
authors.initials: D
authors.lastname: Feller-Kopman
authors.forename: Lonny B
authors.initials: LB
authors.lastname: Yarmus
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Lin
authors.forename: Alana L
authors.initials: AL
authors.lastname: Welm
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Issa
authors.forename: Il
authors.initials: I
authors.lastname: Minn
authors.forename: William
authors.initials: W
authors.lastname: Matsui
authors.forename: Yoon-Young
authors.initials: YY
authors.lastname: Jang
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Sharkis
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Zahnow
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004249:DNA Damage; D019175:DNA Methylation / Q000187:drug effects*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D020868:Gene Silencing; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine