Molecular and clinical aspects of proteasome inhibition in the treatment of cancer.
The proteasome is a multicatalytic threonine protease responsible for intracellular protein turnover in eukaryotic cells, including the processing and degradation of several proteins involved in cell cycle control and the regulation of apoptosis. Preclinical studies have shown that the treatment with proteasome inhibitors results in decreased proliferation, induction of apoptosis, and sensitization of tumor cells against conventional chemotherapeutic agents and irradiation. The effects were conferred to stabilization of p21, p27, Bax, p53, I-KB, and the resulting inhibition of the nuclear factor-KB (NF-KB) activation. Bortezomib is the first proteasome inhibitor that has 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, Millennium Pharmaceuticals, Cambridge, MA, USA) for the treatment of relapsed multiple myeloma. At present, clinical trials are examining the activity in a variety of solid tumors and hematological malignancies.
Zavrski
Ivana
I
Department of Hematology and Oncology, Charité Universitätsmedizin Berlin, Germany.
Jakob
Christian
C
Kaiser
Martin
M
Fleissner
Claudia
C
Heider
Ulrike
U
Sezer
Orhan
O
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D061988:Proteasome Inhibitors
D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors