Translation is regulated predominantly at the initiation phase by several signal transduction pathways that are often usurped in human
cancers, including the PI3K/Akt/mTOR axis. mTOR exerts unique administration over translation by regulating assembly of eukaryotic
initiation factor (
eIF) 4F, a heterotrimeric complex responsible for recruiting 40S ribosomes (and associated factors) to
mRNA 5' cap structures. Hence, there is much interest in targeted
therapies that block
eIF4F activity to assess the consequences on
tumor cell growth and
chemotherapy response. We report here that
hippuristanol (Hipp), a translation initiation inhibitor that selectively inhibits the
eIF4F RNA helicase subunit, eIF4A, resensitizes Eμ-Myc
lymphomas to
DNA damaging agents, including those that overexpress eIF4E-a modifier of
rapamycin responsiveness. As Mcl-1 levels are significantly affected by Hipp, combining its use with the Bcl-2 family inhibitor,
ABT-737, leads to a potent synergistic response in triggering cell death in mouse and human
lymphoma and
leukemia cells. Suppression of eIF4AI using RNA interference also synergized with
ABT-737 in murine
lymphomas, highlighting eIF4AI as a therapeutic target for modulating
tumor cell response to
chemotherapy.