The proteasome: a novel target for cancer chemotherapy

Abstract

The ubiquitin-proteasome system is an important regulator of cell growth and apoptosis. The potential of specific proteasome inhibitors to act as novel anti-cancer agents is currently under intensive investigation. Several proteasome inhibitors exert anti-tumour activity in vivo and potently induce apoptosis in tumour cells in vitro, including those resistant to conventional chemotherapeutic agents. By inhibiting NF-B transcriptional activity, proteasome inhibitors may also prevent angiogenesis and metastasis in vivo and further increase the sensitivity of cancer cells to apoptosis. Proteasome inhibitors also exhibit some level of selective cytotoxicity to cancer cells by preferentially inducing apoptosis in proliferating or transformed cells or by overcoming deficiencies in growth-inhibitory or proapoptotic molecules. High expression of oncogene products like c-Myc also makes cancer cells more susceptible to proteasome inhibitor-induced apoptosis. The induction of apoptosis by proteasome inhibitors varies between cell types but often occurs following an initial accumulation of short-lived proteins such as p53, p27, pro-apoptotic Bcl-2 family members or activation of the stress kinase JNK. These initial events often result in a perturbation of mitochondria with concomitant release of cytochrome c and activation of the Apaf-1 containing apoptosome complex. This results in activation of the apical caspase-9 followed by activation of effector caspases-3 and -7, which are responsible for the biochemical and morphological changes associated with apoptosis.

NanoDrop fluorometry adopted for microassays of proteasomal enzyme activities

“…These results confirm the applicability of NanoDrop fluorometry for enzyme assays in very small samples and, thus, make this method useful for studying precious proteasome inhibitors or effectors [14][15][16]. A small amount of extract (50-100 ll) is more than sufficient to run all three proteasomal enzyme assays, including controls and effectors, and to quantify protein as well.…”

New agents in acute myeloid leukemia and other myeloid disorders

“…83 Covalent attachment of a polyubiquitin chain targets proteins to the proteasome. The proteasome functions as a regulator of metabolic pathways, allowing up-regulation of degradation of certain proteins without affecting the proteolysis of other substrates.…”

“…The proteasome functions as a regulator of metabolic pathways, allowing up-regulation of degradation of certain proteins without affecting the proteolysis of other substrates. 83 Proteasome inhibitors can affect cellular levels of oncogenic proteins differentially. 83 Important substrates for proteasome degradation include cyclins and CDKIs, transcription factors (such as p53, NF B, c-Myc, c-fos, and c-Jun), a number of apoptosis family of proteins, IAPs, and some caspases.…”

“…83 Proteasome inhibitors can affect cellular levels of oncogenic proteins differentially. 83 Important substrates for proteasome degradation include cyclins and CDKIs, transcription factors (such as p53, NF B, c-Myc, c-fos, and c-Jun), a number of apoptosis family of proteins, IAPs, and some caspases. [83][84][85] Bortezomib (PS341) is a specific and potent inhibitor of proteasome.…”

“…83 Important substrates for proteasome degradation include cyclins and CDKIs, transcription factors (such as p53, NF B, c-Myc, c-fos, and c-Jun), a number of apoptosis family of proteins, IAPs, and some caspases. [83][84][85] Bortezomib (PS341) is a specific and potent inhibitor of proteasome. 86 It induces apoptosis and overcomes resistance in a number of cell lines as well as primary cells from patients with CLL.…”