The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines
| العنوان: | The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines |
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| المؤلفون: | Mitchell B. Diccianni, Ayse Batova, Abraham Nudelman, Alice L. Yu, Tetsuya Tanaka, Ada Rephaeli, Li-en Shao, John Yu |
| المصدر: | Blood. 100:3319-3324 |
| بيانات النشر: | American Society of Hematology, 2002. |
| سنة النشر: | 2002 |
| مصطلحات موضوعية: | Apoptosis, Biochemistry, Histones, chemistry.chemical_compound, Neoplasms, Tumor Cells, Cultured, Leukemia-Lymphoma, Adult T-Cell, Enzyme Inhibitors, Child, Tumor Stem Cell Assay, Acute leukemia, Leukemia, Gene Expression Regulation, Leukemic, Histone deacetylase inhibitor, Myeloid leukemia, Acetylation, Hematology, Drug Resistance, Multiple, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Butyrates, Haematopoiesis, Leukemia, Myeloid, Acute Disease, Neoplastic Stem Cells, Cell Division, medicine.drug, Cyclin-Dependent Kinase Inhibitor p21, medicine.drug_class, HL60, Immunology, HL-60 Cells, Biology, Transfection, Inhibitory Concentration 50, Cyclins, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Acute lymphocytic leukemia, medicine, Humans, Doxorubicin, Infant, Cell Biology, Hematopoietic Stem Cells, medicine.disease, Histone Deacetylase Inhibitors, chemistry, Drug Resistance, Neoplasm, Cancer research, Drug Screening Assays, Antitumor, Genes, MDR, Protein Processing, Post-Translational |
| الوصف: | 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. |
| تدمد: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2002-02-0567 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::554bb2290d19d030d305593c8f4aba77 https://doi.org/10.1182/blood-2002-02-0567 |
| رقم الانضمام: | edsair.doi.dedup.....554bb2290d19d030d305593c8f4aba77 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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| DOI: | 10.1182/blood-2002-02-0567 |