Emergence of acquired resistance to bor-tezomib and impaired bortezomib-induced accumulation of ubiquitinated proteins in bortezomib-resistant cells. (A) Dose-response curve for bortezomib-induced growth inhibition of wild-type (WT) human monocytic/macrophage THP1 cells and bortezomib (BTZ)–resistant variants THP1/BTZ50, THP1/BTZ100, and THP1/BTZ200, selected for growth in extracellular concentrations of 50 nM, 100 nM, and 200 nM bortezomib, respectively. Results depicted are the mean of 7 to 20 experiments (± SD). Drug exposure time, 72 hours. (B) Accumulation of ubiquitinated proteins in THP1/WT cells and bortezomib-resistant sublines after exposure to bor-tezomib. Bortezomib-resistant cells were allowed a 4-day drug washout period (control) after which they were exposed for 24 hours to their selective concentrations of bortezomib. THP/WT cells were exposed to 10 nM BTZ for 24 hours. (C) Accumulation of ubiquitinated proteins in THP/WT cells after 24-hour exposure to 10 to 100 nM bortezomib and for THP1/BTZ200 cells after 24-hour exposure to bortezomib concentrations beyond selective concentrations (up to 1000 nM). A representative picture of 2 separate experiments is depicted.
