Finally, tumors belonging to the basal like sub group express high levels of basal

Chymotrypsin like ac tivity at proteasome B5 subunit is associated with the rate limiting step of proteolysis, It is conformationally flexible with active catalytic sites lo cated on the inner surface of the cylinder where protein substrates bind, Another form of the proteasome that is primarily expressed in cells of hematopoietic 17-AAG 価格 origin and cells exposed to inflammatory cytokines, known as the immunoproteasome, has the three catalytic ac tivities represented by LMP7, LMP2, and MECL1, which are more efficient in regulating antigen processing, Inhibition of the proteasome results in perturbation of intracellular protein homeostasis by accumulation of the poly ubiquitinated proteins, subsequently inducing cellular stress and apoptosis. Numerous proteasome inhibitors have been developed and described.<br><br> Bortezomib, a boronic dipeptide which reversibly inhibit the chymotrypsin like activity at the B5 subunit and to a lesser extent inhibit the trypsin like activity at the B1 subunit, is the first proteasome inhibitor approved by FDA of the United States. Bortezomib induces Adriamycin Doxorubicin apoptosis in a wide va riety of cancer cell lines and other transformed cells, yet has relatively few toxic effects on normal cells, Clinical studies have demonstrated the safety and promi sing efficacy of bortezomib as the single agent or com bined with other drugs against multiple myeloma, as well as in several non Hodgkins lymphoma sub types, Bortezomib can also potentiate leukemia cell apoptosis and has a potential therapeutic role against leukemia, either alone or in combination with chemothe rapy, However, there are some patients who do not respond to therapy or respond briefly, then relapse.<br><br> Here we will review the development of study in resistance mecha nisms of bortezomib. Point mutation or over expression A66 ic50 of PSMB5 gene To shed light on the mechanisms of acquired resistance to bortezomib after drug exposure, we established pyrazine 2 carboxyl side chain of bortezomib and residues of the PSMB5 specific pocket, In the case of the chymotryptic like active site, the carbonyl oxygen of bortezomib interact with PSMB5 Ala49 N and PSMB5 Ala50 N by a tight hydrogen bonding network. Computer modeling of the Ala49Thr mutated PSMB5 protein resulting from the G322A mutation suggests that a con formation change occurs that may disrupt contacts be tween the chymotrypsin like active site and bortezomib.<br><br> The G322A, C323 T mutation and the G322A, C326 T conjoined mutation causes amino acid substitutions at position 108 and or 109 of precursor PSMB5 protein, which translates to Ala49Thr and or Ala50Val of functional PSMB5 protein. So Ala49 and Ala50 of the PSMB5 protein are key positions relative to the inhibitory effect of bortezomib on chymotrypsin like activity. Mutations in the PSMB5 gene that result in substitutions of these amino acid residues can confer va rying bortezomib resistance, Following our study, Oerlemans et al. also confirmed G322A PSMB5 mutation which resulted in Ala49Thr bortezomib resistant lymphoblastic lymphoma leukemia cells JurkatB, from the parental Jurkat cell line by repeated drug exposure and selection. First we confirmed G322A point mutation of PSMB5 gene confer bortezomib resist ance to JurkatB cells. The inhibition rate of chymotrypsin like activity in JurkatB cells was significantly decreased compared with parental Jurkat cells after bortezomib treatment.