The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells
| Autor: | B. ten Cate, Douwe F. Samplonius, Theo Bijma, Wijnand Helfrich, Edwin Bremer, de Louis Leij |
|---|---|
| Přispěvatelé: | Groningen University Institute for Drug Exploration (GUIDE), Targeted Gynaecologic Oncology (TARGON), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL) |
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Myeloid Sialic Acid Binding Ig-like Lectin 3 CD33 synergy THERAPY chemistry.chemical_compound AML hemic and lymphatic diseases gemtuzumab ozogamicin CD33-restricted SPECIFICITY biology INDUCTION Histone deacetylase inhibitor apoptosis Antibodies Monoclonal Drug Synergism DNA Neoplasm U937 Cells Hematology CHEMOTHERAPY Gemtuzumab Intercalating Agents Chromatin Leukemia Myeloid Acute Histone medicine.anatomical_structure TARGET Oncology SAFETY Anticonvulsants lipids (amino acids peptides and proteins) MYLOTARG medicine.drug Gemtuzumab ozogamicin medicine.drug_class Antigens Differentiation Myelomonocytic Antineoplastic Agents Antibodies Monoclonal Humanized Antigens CD valproic acid Cell Line Tumor Calicheamicin medicine Humans MODULATION IN-VITRO EFFICACY Histone Deacetylase Inhibitors Aminoglycosides chemistry Apoptosis biology.protein Cancer research |
| Zdroj: | Leukemia, 21(2), 248-252. Nature Publishing Group |
| ISSN: | 0887-6924 |
| Popis: | Gemtuzumab ozogamicin ( GO) is a calicheamicin-conjugated antibody directed against CD33, an antigen highly expressed on acute myeloid leukemic (AML) cells. CD33-specific binding triggers internalization of GO and subsequent hydrolytic release of calicheamicin. Calicheamicin then translocates to the nucleus, intercalates in the DNA structure and subsequently induces double-strand DNA breaks. GO is part of clinical practice for AML, but is frequently associated with severe side effects. Therefore, combination of GO with other therapeutics is warranted to reduce toxicity, while maximizing therapeutic selectivity. We hypothesized that the histone deacetylase inhibitor valproic acid (VPA) sensitizes AML cells to GO. VPA-induced histone hyperacetylation opens the chromatin structure, whereby the DNA intercalation of calicheamicin should be augmented. We found that clinically relevant concentrations of VPA potently augmented the tumoricidal activity of GO towards AML cell lines and primary AML blasts. Moreover, VPA treatment indeed augmented the DNA intercalation of calicheamicin and enhanced DNA degradation. Importantly, synergy was restricted to CD33-positive AML cells and did not require caspase activation. In conclusion, the synergistic proapoptotic activity of cotreatment of AML cells with VPA and GO indicates the potential value of this strategy for AML. |
| Databáze: | OpenAIRE |
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