The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines

• Published in: Blood 2002-11, Vol.100 (9), p.3319-3324
• Main Authors: Batova, Ayse, Shao, Li-en, Diccianni, Mitchell B., Tanaka, Alice L.Yu, Tetsuya, Rephaeli, Ada, Nudelman, Abraham, Yu, John
• Format: Article
• Language: English
• Subjects: Acetylation - drug effects; Acute Disease; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Butyrates - pharmacology; Cell Division - drug effects; Chemotherapy; Child; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - biosynthesis; Cyclins - genetics; Doxorubicin - pharmacology; Drug Resistance, Multiple - genetics; Drug Resistance, Neoplasm - genetics; Drug Screening Assays, Antitumor; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Leukemic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Genes, MDR; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - enzymology; Histone Deacetylase Inhibitors; Histones - metabolism; HL-60 Cells - drug effects; Humans; Infant; Inhibitory Concentration 50; Leukemia - enzymology; Leukemia - genetics; Leukemia - pathology; Leukemia, Myeloid - enzymology; Leukemia, Myeloid - genetics; Leukemia, Myeloid - pathology; Leukemia-Lymphoma, Adult T-Cell - enzymology; Leukemia-Lymphoma, Adult T-Cell - genetics; Leukemia-Lymphoma, Adult T-Cell - pathology; Medical sciences; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - enzymology; Pharmacology. Drug treatments; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - enzymology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein Processing, Post-Translational - drug effects; Transfection; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - enzymology; Tumor Stem Cell Assay
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-02-0567

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 (IC50) of 45.8 ± 4.1 μM. 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 IC50 of 50 μM 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 IC50values of 25 μM and 17 μM, 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.