Flavaglines target primitive leukemia cells and enhance anti-leukemia drug activity

Abstract

Identification of agents that target human leukemia stem cells (LSCs) is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally defined LSCs while sparing normal stem and progenitor cells. In addition to efficacy as single agents, flavaglines sensitize leukemia cells to several anti-cancer compounds, including front-line chemotherapeutic drugs used to treat leukemia patients. Mechanistic studies indicate that flavaglines strongly inhibit protein synthesis, leading to the reduction of short-lived anti-apoptotic proteins. Notably though, treatment with flavaglines alone or in combination with other drugs, yields a much stronger cytotoxic activity towards leukemia cells than the translational inhibitor temsirolimus. These results indicate that the underlying cell death mechanism of flavaglines is more complex than simply inhibiting general protein translation. Global gene expression profiling and cell biological assays identified Myc inhibition and the disruption of mitochondrial integrity to be features of flavaglines, which we propose contribute to their efficacy in targeting leukemia cells. Together, these findings indicate that rocaglamide and silvestrol are distinct from clinically available translational inhibitors and represent promising candidates for the treatment of leukemia.

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

“…This would also address the question of whether there are transcripts uniquely sensitive to silvestrol and not other translation initiation inhibitors. Consistent with this idea is a recent study reporting that silvestrol was a more potent cytotoxic reagent towards leukemia cells than the rapalog, temsirolimus [156].…”

“…In an investigation assessing the effects of silvestrol in a mouse hepatocellular carcinoma model, silvestrol was found to improve median survival in tumor-bearing mice without inducing damage to normal hepatocytes [148]. Along with solid tumors, several groups have shown that silvestrol is effective in the treatment of lymphomas and leukemia, with increased selectivity for malignant B cells compared to nontransformed T cells, suggesting that there may be a favorable therapeutic index for treatment of B cell malignancies [149,[155][156][157][158]. Moreover, silvestrol can re-sensitize chemoresistent B cell lymphomas to doxorubicin, suggesting a potential use in combination therapy [49].…”

Novel flavagline‐like compounds with potent Fli‐1 inhibitory activity suppress diverse types of leukemia

“…1A). RocA was shown to possess potent anticancer activity, but the connection to Fli-1 status is not known, nor do we fully understand its underlying mechanism [28][29][30]. A1544 and A1545 inhibited luciferase activity of FB-Luc driven by Fli-1 or EWS-FLI1 in a dose-dependent manner ( Fig.…”

Molecular mechanisms and anti‐cancer aspects of the medicinal phytochemicals rocaglamides (=flavaglines)

“…Recently, Roc‐A was also shown to sensitize leukemia cells toward anticancer compounds that have distinct actions, e.g . drugs that inactivate Bcl‐2 proteins, inhibit heat‐shock protein 90 or induce reactive oxygen species . Interestingly, Roc‐A showed a much stronger effect compared to Temsirolimus, a translation inhibitor that specifically inhibits mTOR.…”

“…drugs that inactivate Bcl-2 proteins, inhibit heat-shock protein 90 or induce reactive oxygen species. 78 Interestingly, Roc-A showed a much stronger effect compared to Temsirolimus, a translation inhibitor that specifically inhibits mTOR. This feature indicates that Rocs-mediated synergy may involve multiple mechanisms rather than only inhibition of general protein synthesis.…”