Bortezomib Amplifies Effect on Intracellular Proteasomes by Changing Proteasome Structure

Abstract

The proteasome inhibitor Bortezomib is used to treat multiple myeloma (MM). Bortezomib inhibits protein degradation by inactivating proteasomes' active-sites. MM cells are exquisitely sensitive to Bortezomib – exhibiting a low-nanomolar IC50 – suggesting that minimal inhibition of degradation suffices to kill MM cells. Instead, we report, a low Bortezomib concentration, contrary to expectation, achieves severe inhibition of proteasome activity in MM cells: the degree of inhibition exceeds what one would expect from the small proportion of active-sites that Bortezomib inhibits. Our data indicate that Bortezomib achieves this severe inhibition by triggering secondary changes in proteasome structure that further inhibit proteasome activity. Comparing MM cells to other, Bortezomib-resistant, cancer cells shows that the degree of proteasome inhibition is the greatest in MM cells and only there leads to proteasome stress, providing an explanation for why Bortezomib is effective against MM but not other cancers.

SNIPER(TACC3) induces cytoplasmic vacuolization and sensitizes cancer cells to Bortezomib

“…Since bortezomib is clinically used to treat multiple myelomas, we then evaluated the anticancer effects of SNIPER(TACC3)‐2 in cancer cells including human multiple myeloma RPMI‐8226 and KMS‐11 cells, human Burkitt's lymphoma Raji cells and U2OS cells. The viability of these cancer cells were reduced by individual treatment of bortezomib and SNIPER(TACC3) in a dose‐dependent manner (Fig.…”

Development of Resistance to Endoplasmic Reticulum Stress-Inducing Agents in Mouse Leukemic L1210 Cells

“…Bortezomib is a high-affinity and specificity inhibitor of the 26S proteasome. It is an N-protected dipeptide, which stands for pyrazinoic acid, phenylalanine and Leucine with a boronic acid instead of a carboxylic acid and is a synthetic anticancer medication approved for the treatment of multiple myeloma and mantle cell lymphoma [26]. MG-132 is a potent, reversible, and cell-permeable 26S proteasome inhibitor [27].…”

Calculations of supramolecular structures of peptidylboronic acid (bortezomib) with ABO blood system antigen

“…Today it is used to treat plasma cell myeloma and passes clinical tests for other types of cancer. Bortezomib is an inhibitor of the 20S proteasome and promotes the apoptosis of cancer cells that have lost the alternative proteasome [2][3][4][5][6].…”