Proteasome inhibitors: antitumor effects and beyond

Abstract

Proteasome inhibitors are emerging as effective drugs for the treatment of multiple myeloma and possibly certain subtypes of non-Hodgkin's lymphoma. Bortezomib (Velcade) is the first proteasome inhibitor proven to be clinically useful and will soon be followed by a second generation of small molecule inhibitors with improved pharmacological properties. Although it is now understood that certain types of malignancies have an exquisite dependence on a functional proteasome for their survival, the underlying reason(s) remain unclear as of now. In this context, addiction to nuclear factor-jB (NF-jB)-induced survival signals, activation of the unfolded protein response as well as a reduced proteasomal activity in differentiated plasma cells have all been proposed to justify proteasome inhibitors' activity in susceptible tissues. The ubiquitin-proteasome pathway and its relevance to cancerThe ubiquitin-proteasome pathway (UPP) mediates the degradation of polyubiquitinated proteins and represents the main protein degradation pathway in eucaryotic cells. 1 It is estimated that more than 80% of intracellular proteins are degraded by the proteasome. Besides carrying out protein turnover, the UPP plays an essential role in regulating protein levels during cell cycle, apoptosis, response to cellular stress (i.e. DNA damage, hypoxia) and intracellular signal transduction, not to mention its importance for the generation of antigenic epitopes to be presented on human leukocyte antigen (HLA) molecules. It is now known that some types of cancer are exquisitely prone to undergo apoptosis in response to inhibition of the UPP pathway, a phenomenon that, at present, still lacks a precise explanation. 2,3 Intracellular proteins are targeted for degradation by the conjugation of polyubiquitin chains to lysine residues of the protein, a process carried out by ubiquitin-conjugating enzymes and antagonized by deubiquitinating proteases (revised by Nijman et al. 4 ). 1 Ubiquitination is performed by three enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (E3). E1 activates ubiquitin monomers by adenylation and transfers them to E2, which in turn works in conjunction with E3 to confer substrate specificity. Whereas E1 only exists in two isoforms derived from alternative splicing of the same messenger at least 25 E2 and hundreds of E3 enzymes exist. 1 A similar complexity is shared by the deubiquitinating enzymes, of which more than 500 are represented in the human genome, thus indicating the high complexity and specificity of this regulatory mechanism. 4 The proteasome is an enzymatic complex that recognizes ubiquitin-tagged proteins and catalyses their proteolytic degradation in an ATP-dependent fashion. 1-3 Proteasomes can be found both in the cytoplasm and in the nucleus of eucaryotic cells. The proteasome typically consists of a 20S component, which is normally associated to a 19S or to an 11S (inducible by interferon-g) regulator component. The 20S proteasome component is compris...

Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

“…The effects of selective absence of NF-kB in CNS resident cells in EAE has been recently investigated by inducible knockdown of IKK2 [36]. Consistent with the inhibitory effect of bortezomib on the activation of NF-kB in different tumor cells [20,23], we here demonstrate that the therapeutic effect of bortezomib in EAE is accompanied by inhibition of NF-kB activation in spleen and spinal cords in vivo. Thus, both the proteasome and NF-kB activity contribute to the pathogenesis of EAE.…”

“…In addition to their anticancer properties, they modulate inflammatory and immune responses by affecting antigen processing, apoptosis, cell cycle, co-stimulation, adhesion and chemotaxis [21,22]. Specifically bortezomib, a boronic acid dipeptide with selective activity as a proteasome inhibitor, has been shown to inhibit NF-kB activity in malignant cells [20,23]. Inhibitors of the proteasome decrease NF-kB activation and have anti-inflammatory activity in vivo [24,25].…”

Cytotoxic effect of trans-cinnamaldehyde on human leukemia K562 cells

“…The use of immunosuppressors against GVHD is not conducive to the absolute depletion of residual leukemic cells. Therefore, the development of appropriate anticancer drugs remains an important goal [2] .…”

Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability

“…Dysfunction of the proteasome pathway can lead to many disorders, including cancers and neurodegenerative diseases (Paul, 2008). Proteasome is crucial for the regulation of cell cycle and apoptosis and its specific inhibition by molecules has emerged as a promising strategy to treat cancers (Nencioni et al, 2007). For example, bortezomib (also known as PS-341 or Velcade) is the first proteasome inhibitor used in the treatment of multiple myeloma (Twombly, 2003).…”