The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells

• Published in: Leukemia Vol. 21; no. 2; pp. 248 - 252
• Main Authors: TEN CATE, B, SAMPLONIUS, D. F, BIJMA, T, DE LEIJ, L. F. M. H, HELFRICH, W, BREMER, E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01-02-2007; Nature Publishing Group
• Subjects: Acids; Aminoglycosides - therapeutic use; Antibodies; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Anticonvulsants - toxicity; Antigens; Antigens, CD - blood; Antigens, Differentiation, Myelomonocytic - blood; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Calicheamicin; Caspase; Cell Line, Tumor; Cell lines; Chromatin; Clinical medicine; Deoxyribonucleic acid; DNA; DNA damage; DNA structure; DNA, Neoplasm - drug effects; Drug Synergism; Gemtuzumab ozogamicin; Genetic aspects; Hematologic and hematopoietic diseases; Histone deacetylase; Histone Deacetylase Inhibitors; Histones; Humans; Immunology; Inhibitors; Intercalating agents; Intercalating Agents - pharmacology; Intercalation; Internalization; Laboratories; Leukemia; Leukemia, Myeloid, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Selectivity; Sialic Acid Binding Ig-like Lectin 3; Side effects; Stem cells; Toxicity; U937 Cells; Valproic acid; Valproic Acid - toxicity; Netherlands; United States > US; Antineoplastic agent; Immunochemotherapy; synergy; Monoclonal antibody; Ozogamicin; Synergism; CD33-restricted; Mylotarg; gemtuzumab ozogamicin; AML; 4-Aminobutyrate transaminase; Hematology; Enzyme; Transferases; Acute; Enzyme inhibitor; Malignant hemopathy; Valproic acid; Myeloid cell; Chemotherapy; Histone deacetylase inhibitor; Treatment; Cell death; Transaminases; Apoptosis; Acute myelocytic leukemia
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2404477

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.