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Closed Access item Chemical Blockage of the Proteasome Inhibitory Function of Bortezomib
Miller, Thomas P.
Esteban, J. A.
Bengston, Audrey L.
Soengas, María S.
|Keywords:||Bortezomib, Tiron, L-N-acetyl-cysteine|
|Publisher:||American Society for Biochemistry and Molecular Biology|
|Citation:||Journal of Biological Chemistry 281: 1107-1118 (2006)|
|Abstract:||The proteasome inhibitor bortezomib is emerging as a potent
anti-cancer agent. Still, recent clinical trials have revealed a significant
secondary toxicity of bortezomib. Consequently, there is
much interest in dissecting the mechanism of action of this compound
to rationally improve its therapeutic index. The cytotoxic
effect of bortezomib is frequently characterized by interfering with
downstream events derived from the accumulation of proteasomal
targets. Here we identify the first chemical agent able to act
upstream of the proteasome to prevent cell killing by bortezomib.
Specifically, we show that the polyhydroxyl compound Tiron can
function as a competitive inhibitor of bortezomib. This effect of
Tiron was surprising, since it is a classical radical spin trap and was
expected to scavenge reactive oxygen species produced as a consequence
of bortezomib action. The inhibitory effect of Tiron against
bortezomib was selective, since it was not shared by other antioxidants,
such as vitamin E, MnTBAP, L-N-acetyl-cysteine, and
FK-506. Comparative analyses with nonboronated proteasome
inhibitors (i.e. MG132) revealed a specificity of Tiron for bortezomib.
We exploited this novel feature of Tiron to define the
“point of no return” of proteasome inhibition in melanoma cells and
to block cell death in a three-dimensional model of human skin.
Cells from T-cell lymphoma, breast carcinoma, and non-small cell
lung cancer were also responsive to Tiron, suggesting a broad
impact of this agent as a bortezomib blocker. These results may have
important implications for the analysis of bortezomib in vivo and
for the design of drug mixtures containing proteasome inhibitors.|
|Publisher version (URL):||http://dx.doi.org/10.1074/jbc.M511607200|
|Appears in Collections:||(CBM) Artículos|
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