The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells.
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.
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Laboratory for Tumor Immunology, Department of Pathology and Laboratory Medicine, Groningen University Institute for Drug Exploration, Section Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Samplonius
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Bijma
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de Leij
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Helfrich
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Bremer
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E
D000617:Aminoglycosides / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000927:Anticonvulsants / Q000633:toxicity; D015703:Antigens, CD / Q000097:blood; D015214:Antigens, Differentiation, Myelomonocytic / Q000097:blood; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D000079982:Gemtuzumab; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D063268:Sialic Acid Binding Ig-like Lectin 3; D020298:U937 Cells; D014635:Valproic Acid / Q000633:toxicity*
D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000927:Anticonvulsants; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; C571163:CD33 protein, human; D004273:DNA, Neoplasm; D056572:Histone Deacetylase Inhibitors; D007364:Intercalating Agents; D063268:Sialic Acid Binding Ig-like Lectin 3; D014635:Valproic Acid; D000079982:Gemtuzumab