title: Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo.
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.
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Road II, Shanghai 200025, China. zhou_guangbiao@gibh.org
authors.forename: Guang-Biao
authors.initials: GB
authors.lastname: Zhou
authors.forename: Hui
authors.initials: H
authors.lastname: Kang
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.forename: Feng-Xiang
authors.initials: FX
authors.lastname: Zhang
authors.forename: Xiang-Qin
authors.initials: XQ
authors.lastname: Weng
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Shen
authors.forename: Jue
authors.initials: J
authors.lastname: Chen
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Gu
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
authors.forename: Zhen-Yi
authors.initials: ZY
authors.lastname: Wang
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003561:Cytarabine / Q000819:agonists / Q000494:pharmacology; D004224:Diterpenes / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D045786:Diterpenes, Kaurane / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010936:Plant Extracts / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry; D000075142:RUNX1 Translocation Partner 1 Protein; D014178:Translocation, Genetic; D020298:U937 Cells
chemical_list: C107844:AML1-ETO fusion protein, human; D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; D004224:Diterpenes; D045786:Diterpenes, Kaurane; D015514:Oncogene Proteins, Fusion; D010936:Plant Extracts; D000075142:RUNX1 Translocation Partner 1 Protein; D003561:Cytarabine; C011959:oridonin