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A phase I trial of antisense oligonucleotides targeting eIF4E has recently been completed. eIF4E binding motif peptides can also interfere with eIF4E FAK pathway inhibitor eIF4G binding, translation initiation, cell cycle, and survi val, providing proof of concept that eIF4E binding small molecule inhibitors may have utility in cancer therapy. A 4E BP1 based peptide fused to a GnRH agonist was shown to be taken up by GnRHRI expressing ovarian cancer cells and inhibit growth in vitro and in vivo. Moerke et al. identified inhibitors of the eIF4E eIF4G interaction in a high throughput screen. The most potent compound exhibited in vitro activity against mul tiple cancer cell lines and appeared to have preferential effect on transformed cells. Cencic et al. reported that eIF4E eIF4G interaction inhibitors can reverse tumor chemoresistance in lymphoma models.
Another potential approach to inhibit translation is by interfering with eIF4E binding to the 7 methyl guano sine cap or by interfering with eIF4E binding to the multidomain adaptor protein eIF4G, thus interfering with assembly of the translation initiation complex eIF4F. Kentsis et al. reported that the antiviral guano sine analog ribovirin binds to eIF4E at the site used by the 7 methyl guanosine cap, competing with eIF4E bind ing and disrupting the transport and translation of mRNAs regulated by eIF4E. Thus, translation initia tion is actively being pursued as a therapeutic target. As activation of translation initiation is a common integral pathway for the malignant phenotype, these approaches may hold promise for a variety of tumor types.
Pdcd4 has been reported to inhibit protein translation by binding to the translation initiation factor eIF4A. As pdcd4 undergoes regulated degradation by b Trcp after phosphorylation at S67 by S6K1, PI3K mTOR pathway inhibitors may increase pdcd4 expression at least in some cancer cell lines. However, targeting eIF4E directly may provide an alternate strategy for pdcd4 low tumors. Pateamine A, a marine natural product with potent antiproliferative and immunosuppressive activ ities, was also found to inhibit protein translation, inhi biting the eukaryotic eIF4A family of RNA helicases. Des methyl, des amino pateamine A, a structurally simplified analogue of pateamine A, was recently shown to have potent antiproliferative activity against a wide variety of human cancer cell lines.
However, it is of note that pdcd4 has other tumor suppressive functions reported such as inhibiting AP 1 transactivation, and thus pdcd4s antitumor effect may not be limited to its effects on translation. eEF2K is phosphorylated and inhibited by SAPK, RSK and S6K1, and phosphorylated and activated by AMPK. Thus eEF2K integrates a variety of diverse signaling pathways, and potentially may be targeted through different strategies.