title: The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines.
abstract: The novel prodrug of butyric acid, pivaloyloxymethyl butyrate (AN-9), a histone deacetylase inhibitor, shows great promise as an effective and relatively nontoxic anticancer agent for solid malignancies. However, little is known about its effects on hematopoietic malignancies. In this study, we show that 21 primary samples of acute leukemia were sensitive to the antiproliferative effects of AN-9, with a 50% inhibitory concentration (IC(50)) of 45.8 +/- 4.1 microM. In colony-forming assays, primary T-cell acute lymphoblastic leukemia (T-ALL) cells were 3-fold more sensitive to AN-9 than the normal hematopoietic progenitors, erythroid burst-forming units and granulocyte/monocyte colony-forming units. AN-9 induced apoptosis in the T-ALL cell line CEM. A common problem with cancer is chemoresistance, which is often typical of relapsed cancers. Remarkably, a T-ALL sample at diagnosis and an acute myeloid leukemia sample at relapse that were resistant to doxorubicin in vitro were sensitive to AN-9, with an IC(50) of 50 microM for both samples. More strikingly, samples from 2 infants with t(4;11) ALL obtained at diagnosis and relapse each were the most sensitive to AN-9, with IC(50) values of 25 microM and 17 microM, respectively. Furthermore, a doxorubicin-resistant clone of HL60, HL60/ADR, obtained by the transfection of the MDR-1 gene, was equally sensitive to AN-9 cytotoxicity as the parental cells. AN-9 induced the expression of p21 in an infant leukemia sample with 11q23 rearrangement, but not in T- or B-precursor ALL. Collectively, our results suggest that AN-9 is a selective agent for hematopoietic malignancies that can circumvent the mechanisms of chemoresistance limiting most conventional chemotherapy.
authors.affiliation: Division of Pediatric Hematology/Oncology, Department of Pediatrics, Medical Center, University of California-San Diego, 200 West Arbor Drive, San Diego, CA 92103-8447, USA.
authors.forename: Ayse
authors.initials: A
authors.lastname: Batova
authors.forename: Li-en
authors.initials: LE
authors.lastname: Shao
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Diccianni
authors.forename: Alice L
authors.initials: AL
authors.lastname: Yu
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tanaka
authors.forename: Ada
authors.initials: A
authors.lastname: Rephaeli
authors.forename: Abraham
authors.initials: A
authors.lastname: Nudelman
authors.forename: John
authors.initials: J
authors.lastname: Yu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002648:Child; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019450:Genes, MDR; D018922:HL-60 Cells / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D007223:Infant; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D014410:Tumor Stem Cell Assay
chemical_list: D002087:Butyrates; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009363:Neoplasm Proteins; C070441:pivalyloxymethyl butyrate; D004317:Doxorubicin