Proteasome inhibitors in the clinical setting: benefits and strategies to overcome multiple myeloma resistance to proteasome inhibitors.
The majority of intracellular proteins undergo degradation through the ubiquitin-proteasome pathway. The proteasome pathway has a role in regulating cell proliferation, differentiation, survival and apoptosis. The naturally occurring proteasome inhibitor lactacystin was the first proteasome inhibitor noted to induce apoptosis in vitro. Compared with first-generation proteasome inhibitors, bortezomib (PS-341), a dipeptide boronic acid, has exhibited higher potency and specificity, and has been approved for the treatment of relapsed or refractory myeloma. However, there are some patients who do not respond to therapy or who respond briefly and then relapse. It is becoming increasingly clear that myeloma cells respond to the stress caused by proteasome inhibitors (bortezomib) via rapidly up-regulating pathways that suppress apoptosis, thus attenuating its antitumour activity. The delineation of these molecular pathways and mechanisms to circumvent them are needed to allow this important class of agents to remain vital in the armamentarium of the management of multiple myeloma and other malignancies.
Cheriyath
Venugopalan
V
The Cleveland Clinic Foundation, Taussig Cancer Center, Center for Hematology and Oncology Molecular Therapeutics, Cleveland, Ohio, USA.
Jacobs
Barbara S
BS
Hussein
Mohamad A
MA
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008954:Models, Biological; D009101:Multiple Myeloma / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex