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Papers In Press, published online ahead of print November 8, 2005
Dermatology Dept., University of Michigan. Comprehensive Cancer Center, Ann Arbor, MI 48109
Corresponding Author: soengas{at}umich.edu
The proteasome inhibitor Bortezomib is emerging as a potent anticancer 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 as it was not shared by other antioxidants such as Vitamin E, MnTBAP, L-NAC FK-506. Comparative analyses with non-boronated 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 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 cocktails containing proteasome inhibitors.
J. Biol. Chem, 10.1074/jbc.M511607200
Submitted on October 26, 2005
Accepted on November 8, 2005
Chemical blockage of the proteasome inhibitory function of Bortezomib: Impact on tumor cell death
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