Abstract
Studies have documented the potential antitumor activities of oridonin, a compound extracted from medicinal herbs. However, whether oridonin can be used in the selected setting of hematology/oncology remains obscure. Here, we reported that oridonin induced apoptosis of t(8;21) acute myeloid leukemic (AML) cells. Intriguingly, the t(8;21) product AML1-ETO (AE) fusion protein, which plays a critical role in leukemogenesis, was degraded with generation of a catabolic fragment, while the expression pattern of AE target genes investigated could be reprogrammed. The ectopic expression of AE enhanced the apoptotic effect of oridonin in U937 cells. Preincubation with caspase inhibitors blocked oridonin-triggered cleavage of AE, while substitution of Ala for Asp at residues 188 in ETO moiety of the fusion abrogated AE degradation. Furthermore, oridonin prolonged lifespan of C57 mice bearing truncated AE-expressing leukemic cells without suppression of bone marrow or reduction of body weight of animals, and exerted synergic effects while combined with cytosine arabinoside. Oridonin also inhibited tumor growth in nude mice inoculated with t(8;21)-harboring Kasumi-1 cells. These results suggest that oridonin may be a potential antileukemia agent that targets AE oncoprotein at residue D188 with low adverse effect, and may be helpful for the treatment of patients with t(8;21) AML.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Chromosomes, Human, Pair 21 / genetics
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Chromosomes, Human, Pair 8 / genetics
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Core Binding Factor Alpha 2 Subunit / antagonists & inhibitors*
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Core Binding Factor Alpha 2 Subunit / metabolism
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Cytarabine / agonists
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Cytarabine / pharmacology
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Diterpenes / agonists
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Diterpenes / chemistry
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Diterpenes / pharmacology*
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Diterpenes, Kaurane / agonists
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Diterpenes, Kaurane / chemistry
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Diterpenes, Kaurane / pharmacology*
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Drug Screening Assays, Antitumor
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Drug Synergism
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Humans
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Mice
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Mice, Nude
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Oncogene Proteins, Fusion / antagonists & inhibitors*
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Oncogene Proteins, Fusion / metabolism
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Plant Extracts / agonists
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Plant Extracts / chemistry
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Plant Extracts / pharmacology
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Plants, Medicinal / chemistry
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RUNX1 Translocation Partner 1 Protein
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Translocation, Genetic
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U937 Cells
Substances
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AML1-ETO fusion protein, human
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Antineoplastic Agents
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Core Binding Factor Alpha 2 Subunit
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Diterpenes
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Diterpenes, Kaurane
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Oncogene Proteins, Fusion
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Plant Extracts
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RUNX1 Translocation Partner 1 Protein
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Cytarabine
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oridonin