avrainvillamide and Leukemia--Myeloid--Acute

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.

Topics: Animals; Apoptosis; Biological Products; Brefeldin A; Cell Cycle Checkpoints; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Exportin 1 Protein; fms-Like Tyrosine Kinase 3; Humans; Indoles; Inhibitory Concentration 50; Karyopherins; Leukemia, Myeloid, Acute; Mice, Inbred BALB C; Mice, Nude; Mutation; Nuclear Proteins; Nucleophosmin; Phagocytosis; Proto-Oncogene Mas; Reactive Oxygen Species; Receptors, Cytoplasmic and Nuclear; Respiratory Burst; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays