There is significant interest
in treating cancers by blocking protein synthesis, to which hematological
malignancies seem particularly sensitive. The translation elongation inhibitor
homoharringtonine (Omacetaxine mepesuccinate) has recently been approved by the
FDA for chronic myeloid leukemia, while the translation initiation inhibitor
silvestrol has shown promise in mouse models of cancer. Precisely how these
compounds induce cell death is unclear, but reduction in Mcl‑1, a labile
pro-survival Bcl‑2 family member, has been proposed to constitute the critical
event. Herein, we demonstrate that primary
B cells and neutrophils are highly sensitive to translation inhibitors, which
trigger the Bax/Bak-mediated apoptotic pathway. However, contrary to
expectations, reduction of Mcl‑1 did not significantly enhance cytotoxicity of
these compounds, suggesting that it does not play a principal role and cautions
that strong correlations do not always signify causality. On the other hand,
the killing of T lymphocytes was less dependent on Bax and Bak, indicating that
translation inhibitors can also induce cell death via alternative mechanisms.
Indeed, loss of clonogenic survival proved to be independent of the
Bax/Bak-mediated apoptosis altogether. Our findings also warn of potential toxicity
since these translation inhibitors are cytotoxic to many differentiated
non-cycling cells.