Abstract
Pharmacological targeting of eIF4E in primary CLL lymphocytes
Highlights
Because Ribavirin was not cytotoxic when used alone, we hypothesized that FLU might induce changes in signaling events targeted by Ribavirin
We sought to assess the contribution of eIF4E to fludarabine (FLU) resistance in primary chronic lymphocytic leukemia (CLL) lymphocytes as this nucleoside analog is used as a first-line treatment for the disease.[7]
A clinically achievable concentration of Ribavirin (10 mM), which was not cytotoxic to primary CLL lymphocytes in culture, significantly sensitized 76% of the samples tested to FLU with the sensitization index (R) ranging from 1.25 to eightfold (Figures 1a, Po0.001 and Supplementary Table)
Summary
Blood Cancer Journal (2013) 3, e146; doi:10.1038/bcj.2013.43; published online 13 September 2013. To begin to assess this hypothesis, we monitored the effect of FLU or the combination of FLU and 10 mM Ribavirin on the expression or phosphorylation of eIF4E and AKT and the expression of Bcl[2] and BAX in two samples with R values of five (highly sensitized) and one (not sensitized), respectively (Figure 1c). A representative sample showing AKT phosphorylation (S473) after treatment with vehicle (black line), FLU alone (IC50 concentration, red line) or in combination with 10 mM Ribavirin (FLU þ Rib; green line). FLU-induced AKT phosphorylation and Bcl[2] expression were Importantly, this effect was negated by co-treatment with FLU observed in a TCL-1-positive CLL cell line (c) Nuclear (N, black bars) or cytoplasmic (C, gray bars) eIF4E localization after treatment with vehicle, FLU IC50 or FLU IC50 plus 10 mM Ribavirin is represented as percentage of the fluorescent signal calculated from 15 to 25 cells per condition. The Fisher test indicates that there is a significant difference between the eIF4E nuclear staining patterns after the treatments (**Po0.01, Fisher test). (d) The bars represent the mean sensitization value of CGP57380 on FLU sensitivity in seven M-IgVH and seven U-IgVH samples (open bars) with respect to paired vehicle-treated samples (gray bars) (y axis). eIF4E phosphorylation is shown in representative samples from each group
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