Proteasome inhibition as a therapeutic strategy for hematologic malignancies.
The ubiquitin-proteasome pathway is a principal intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies since several cell cycle regulators and modulators of apoptosis are degraded through this pathway. The current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the US Food and Drug Administration for the treatment of advanced multiple myeloma, is reviewed. Particular emphasis is placed on the preclinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and an appraisal of possible uses in other hematologic malignancies, such as non-Hodgkin's lymphomas.
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA, USA. Constantine_Mitsiades@dfci.harvard.edu
Constantine S
CS
Mitsiades
Nicholas
N
Mitsiades
Teru
T
Hideshima
Paul G
PG
Richardson
Kenneth C
KC
Anderson
D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D002986:Clinical Trials as Topic; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D025801:Ubiquitin / Q000378:metabolism*
D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D025801:Ubiquitin; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex