title: Combined effects of FLT3 and NF-κB selective inhibitors on acute myeloid leukemia in vivo.
abstract: FMS-like tyrosine kinase 3 (FLT3) is an independent poor prognostic marker of acute myeloid leukemia (AML), and strategies that specifically target FLT3 are therefore of substantial interest. However, previous studies with FLT3 inhibitors as single agents in patients with AML showed few clinical responses. In the present study, combined effects of FLT3 selective inhibitor (SC-203048) and NF-κB selective inhibitor (Parthenolide, PTL) on AML xenograft tumor growth in vivo were examined, and the possible antitumor mechanisms by which SC-203048 and PTL affect AML xenograft tumor growth were also detected. Results showed that the tumor growth was strongly inhibited, and increased cell apoptosis was also observed after treatments, especially in the combination group; meanwhile, the expressions of FLT3, p65, cyclin D1, and Bc1-2 decreased significantly, and the expression of nuclear Silencing mediator for retinoic acid and thyroid hormone receptors (SMRT) increased notably. All results indicate that synergism exists between FLT3 and NF-κB inhibitors, and inhibitors combination treatment may be a potential strategy for AML.
authors.affiliation: Department of Pediatrics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wang
authors.forename: Songting
authors.initials: S
authors.lastname: Bai
authors.forename: Yingchao
authors.initials: Y
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Guangyao
authors.initials: G
authors.lastname: Sheng
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000008:administration & dosage; D013876:Thiophenes / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001549:Benzamides; C530104:CCND1 protein, human; C539130:NCOR2 protein, human; D016328:NF-kappa B; D056985:Nuclear Receptor Co-Repressor 2; D019253:Proto-Oncogene Proteins c-bcl-2; C572332:SC-203048; D012717:Sesquiterpenes; D013876:Thiophenes; D019938:Cyclin D1; C002669:parthenolide; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3