title: NT1721, a novel epidithiodiketopiperazine, exhibits potent in vitro and in vivo efficacy against acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) is an aggressive malignancy characterized by heterogeneous genetic and epigenetic changes in hematopoietic progenitors that lead to abnormal self-renewal and proliferation. Despite high initial remission rates, prognosis remains poor for most AML patients, especially for those harboring internal tandem duplication (ITD) mutations in the fms-related tyrosine kinase-3 (FLT3). Here, we report that a novel epidithiodiketopiperazine, NT1721, potently decreased the cell viability of FLT3-ITD+ AML cell lines, displaying IC50 values in the low nanomolar range, while leaving normal CD34+ bone marrow cells largely unaffected. The IC50 values for NT1721 were significantly lower than those for clinically used AML drugs (i.e. cytarabine, sorafenib) in all tested AML cell lines regardless of their FLT3 mutation status. Moreover, combinations of NT1721 with sorafenib or cytarabine showed better antileukemic effects than the single agents in vitro. Combining cytarabine with NT1721 also attenuated the cytarabine-induced FLT3 ligand surge that has been linked to resistance to tyrosine kinase inhibitors. Mechanistically, NT1721 depleted DNA methyltransferase 1 (DNMT1) protein levels, leading to the re-expression of silenced tumor suppressor genes and apoptosis induction. NT1721 concomitantly decreased the expression of EZH2 and BMI1, two genes that are associated with the maintenance of leukemic stem/progenitor cells. In a systemic FLT3-ITD+ AML mouse model, treatment with NT1721 reduced tumor burdens by > 95% compared to the control and significantly increased survival times. Taken together, our results suggest that NT1721 may represent a promising novel agent for the treatment of AML.
authors.affiliation: Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Kowolik
authors.affiliation: Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Chemistry, University of California, Irvine, CA 92697, USA.
authors.forename: Larry E
authors.initials: LE
authors.lastname: Overman
authors.affiliation: Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Horne
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000032:analysis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D063150:Polycomb Repressive Complex 1 / Q000032:analysis; D000077157:Sorafenib
chemical_list: C069077:BMI1 protein, human; D008565:Membrane Proteins; D010671:Phenylurea Compounds; D010879:Piperazines; C583251:epidithiodiketopiperazine; C084881:flt3 ligand protein; D003561:Cytarabine; D009536:Niacinamide; D000077157:Sorafenib; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; D063150:Polycomb Repressive Complex 1
keywords: BMI1; DNMT1; ETP; FLT3 ligand; FLT3-ITD