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Background  Activating mutations [internal tandem duplication (ITD)] or overexpression of the FMS-like tyrosine kinase receptor-3 ( FLT3 ) gene are associated with poor outcome in acute myeloid leukemia (AML) patients, underscoring the need for novel therapeutic approaches. The natural product silvestrol has potent antitumor activity in several malignancies, but its therapeutic impact on distinct molecular high-risk AML subsets remains to be fully investigated. We examined here the preclinical activity of silvestrol in  FLT3 -ITD and  FLT3  wild-type (wt) AML.    Methods  Silvestrol  in vitro  anti-leukemic activity was examined by colorimetric cell viability assay, colony-forming and flow cytometry assays assessing growth inhibition and apoptosis, respectively. Pharmacological activity of silvestrol on  FLT3  mRNA translation, mRNA and protein expression was determined by RNA-immunoprecipitation, qRT-PCR and immunoblot analyses, respectively. Silvestrol  in vivo  efficacy was investigated using MV4-11 leukemia-engrafted mice.    Results  Silvestrol shows antileukemia activity at nanomolar concentrations both in  FLT3 -wt overexpressing (THP-1) and  FLT3 -ITD (MV4-11) expressing AML cell lines (IC 50  = 3.8 and 2.7 nM, respectively) and patients’ primary blasts [IC 50  = ~12 nM ( FLT3 -wt) and ~5 nM ( FLT3 -ITD)]. Silvestrol increased apoptosis (~4fold, P = 0.0001), and inhibited colony-formation (100%, P < 0.0001) in primary blasts. Silvestrol efficiently inhibited  FLT3  translation reducing FLT3 protein expression by 80–90% and decreased  miR-155  levels (~60%), a frequently co-regulated onco-miR in  FLT3 -ITD-positive AML. The median survival of silvestrol-treated vs vehicle-treated mice was 63 vs 29 days post-engraftment, respectively (P < 0.0001).    Conclusions  Silvestrol exhibits significant  in vivo  and  in vitro  antileukemic activities in AML through a novel mechanism resulting in inhibition of  FLT3  and  miR-155  expression. These encouraging results warrant a rapid translation of silvestrol for clinical testing in AML.

Silvestrol exhibits significant in vivo and in vitro antileukemic activities and inhibits FLT3 and miR-155 expressions in acute myeloid leukemia