title: Proteasome as an emerging therapeutic target in cancer.
abstract: The 26S proteasome is a multicatalytic intracellular protease expressed in eukaryotic cells. It is responsible for selective degradation of intracellular proteins that are responsible for cell proliferation, growth, regulation of apoptosis and transcription of genes involved in execution of key cellular functions. Thus proteasome inhibition is a potential treatment option for cancer and diseases due to aberrant inflammation condition. Treatment with proteasome inhibitors results in stabilization and accumulation proteasome substrates, a phenomenon that may result in confounding signals in cells, cell cycle arrest and activation of apoptotic programs. The inhibition of the transcriptional factor nuclear factor kappaB (NF-kappaB) activation was found as one of crucial mechanisms in induction of apoptosis, overcoming resistance mechanisms and inhibition of immune response and inflammation mechanisms. Bortezomib (PS-341) and PS-519 are the first proteasome inhibitors that have entered clinical trials. In multiple myeloma, both the FDA (United States Food and Drug Administration) and EMEA (European Medicine Evaluation Agency) granted an approval for the use of bortezomib (Velcade) for the treatment of relapsed multiple myeloma. At present, several phase II and phase III trials in hematological malignancies and solid tumors are ongoing. PS-519 that focuses on inflammation, reperfusion injury and ischemia is currently under evaluation for the indication of acute stroke.
authors.affiliation: Department of Hematology and Oncology, Charité--Universitätsmedizin Berlin, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Zavrski
authors.forename: L
authors.initials: L
authors.lastname: Kleeberg
authors.forename: M
authors.initials: M
authors.lastname: Kaiser
authors.forename: C
authors.initials: C
authors.lastname: Fleissner
authors.forename: U
authors.initials: U
authors.lastname: Heider
authors.forename: J
authors.initials: J
authors.lastname: Sterz
authors.forename: C
authors.initials: C
authors.lastname: Jakob
authors.forename: O
authors.initials: O
authors.lastname: Sezer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods* / Q000639:trends; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D011480:Protease Inhibitors / Q000008:administration & dosage; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors
chemical_list: D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex