title: Anti-proliferative activity of the NPM1 interacting natural product avrainvillamide in acute myeloid leukemia.
abstract: Mutated nucleophosmin 1 (NPM1) acts as a proto-oncogene and is present in ~30% of patients with acute myeloid leukemia (AML). Here we examined the in vitro and in vivo anti-leukemic activity of the NPM1 and chromosome region maintenance 1 homolog (CRM1) interacting natural product avrainvillamide (AVA) and a fully syntetic AVA analog. The NPM1-mutated cell line OCI-AML3 and normal karyotype primary AML cells with NPM1 mutations were significantly more sensitive towards AVA than cells expressing wild-type (wt) NPM1. Furthermore, the presence of wt p53 sensitized cells toward AVA. Cells exhibiting fms-like tyrosine kinase 3 (FLT3) internal tandem duplication mutations also displayed a trend toward increased sensitivity to AVA. AVA treatment induced nuclear retention of the NPM1 mutant protein (NPMc+) in OCI-AML3 cells and primary AML cells, caused proteasomal degradation of NPMc+ and the nuclear export factor CRM1 and downregulated wt FLT3 protein. In addition, both AVA and its analog induced differentiation of OCI-AML3 cells together with an increased phagocytotic activity and oxidative burst potential. Finally, the AVA analog displayed anti-proliferative activity against subcutaneous xenografted HCT-116 and OCI-AML3 cells in mice. Our results demonstrate that AVA displays enhanced potency against defined subsets of AML cells, suggesting that therapeutic intervention employing AVA or related compounds may be feasible.
authors.affiliation: Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Vibeke
authors.initials: V
authors.lastname: Andresen
authors.affiliation: Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Bjarte S
authors.initials: BS
authors.lastname: Erikstein
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Herschel
authors.initials: H
authors.lastname: Mukherjee
authors.affiliation: Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: André
authors.initials: A
authors.lastname: Sulen
authors.affiliation: KinN Therapeutics, Bergen, Norway.|Department of Internal Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Popa
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Steinar
authors.initials: S
authors.lastname: Sørnes
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Håkon
authors.initials: H
authors.lastname: Reikvam
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.|Institute of Chemical and Engineering Sciences, Agency for Science, Technology, and Research (A*STAR), Singapore 138667, Singapore.
authors.forename: Kok-Ping
authors.initials: KP
authors.lastname: Chan
authors.affiliation: Centre of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Randi
authors.initials: R
authors.lastname: Hovland
authors.affiliation: Department of Internal Medicine, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.affiliation: Department of Internal Medicine, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Myers
authors.affiliation: Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Internal Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Bjørn T
authors.initials: BT
authors.lastname: Gjertsen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000494:pharmacology*; D020126:Brefeldin A / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D028884:Karyopherins / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D010587:Phagocytosis / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism; D000097606:Exportin 1 Protein
chemical_list: D001688:Biological Products; D020126:Brefeldin A; D007211:Indoles; D028884:Karyopherins; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D000090063:Proto-Oncogene Mas; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D051941:fms-Like Tyrosine Kinase 3; D000097606:Exportin 1 Protein; C000715470:MAS1 protein, human; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; C480558:avrainvillamide; C497970:FLT3 protein, human