The ubiquitin-proteasome pathway is the major quality-control pathway for newly synthesized proteins in every eukaryotic cell (Coux et al., 1996
; Hershko and Ciechanover, 1998
). Furthermore, through specific targeted destruction of regulatory proteins, this pathway participates in the regulation of numerous cellular and physiological functions. For example, cell-cycle progression is impossible without timely degradation of cyclins and cyclin-dependent kinase inhibitors (cdk) by the ubiquitin-proteasome pathway (King et al., 1996
). This finding suggested that proteasome inhibitors should block this process and so prevent malignant cells from proliferating. Although proteasome inhibitors were initially developed as anti-inflammatory agents (see Goldberg, 2010
, for a detailed account of bortezomib development), when cultured cells derived from different cancers were treated with proteasome inhibitors, it was quickly discovered that this treatment caused rapid apoptosis. Furthermore, apoptosis was selective for transformed cells, reducing concerns that proteasome inhibitors would be too toxic due to inhibition of the protein quality control functions of the ubiquitin-proteasome pathway in normal cells (see for review Adams, 2004
, and Kisselev and Goldberg, 2001
Bortezomib was found to have a unique cytotoxicity pattern against an NCI panel of 60 cell lines derived from different cancers (Adams et al., 1999
). In animal studies, bortezomib reduced the growth rate of xenograft tumors and showed a remarkable ability to block angiogenesis (LeBlanc et al., 2002
) and reduce metastasis (Teicher et al., 1999
), providing a rationale for clinical trials. Accordingly, phase I clinical trials were conducted on a variety of solid tumors (Aghajanian et al., 2002
) and hematologic malignancies (Orlowski et al., 2002
). Several responses were observed in patients with MM (Orlowski et al., 2002
). This led to focused phase II trials and rapid FDA approval based on the results of those trials (Richardson et al., 2003
), initially (in 2003) as a third-line treatment for a relapsed and refractory disease and then (in 2008) as front-line treatment for a newly diagnosed MM patients.
For years it was not clear why MM is so responsive to bortezomib. Initially, it was thought that transcription factor NF-κB is its main target (Adams, 2004
; Chauhan et al., 2005b
). MM cells are transformed plasma cells residing in the bone marrow (BM), and NF-κB activity is important for the maintenance of interactions between MM and BM stromal cells. This factor regulates expression of IL-6 and IGF-1, which promote growth, survival, and chemoresistance of MM cells in the BM milieu (Chauhan et al., 2005b
). Activation of NF-κB involves up to two proteasome-dependent steps (Palombella et al., 1994
), so inhibition of NF-κB activation contributes to bortezomib activity in MM; however, this is not the major factor responsible for bortezomib’s antineoplastic activity, and inhibition of NF-κB signaling has a much milder effect on myeloma cells than does inhibition of proteasomes (Hideshima et al., 2002
). NF-κB plays an important role in the proliferation and chemo-resistance of many solid tumors. Bortezomib has no efficacy in these malignancies.
As already noted, a main function of the ubiquitin-proteasome pathway is quality control of newly synthesized proteins. MM cells are the most protein secretors of all cell types. They synthesize and secrete large amounts of IgG or IgA (Bianchi et al., 2009
; Cenci et al., 2011
), one of the most complex protein molecules to synthesize. IgG is a four-chain protein that contains multiple disulfide bonds. Individual IgG chains that fail to properly fold or assemble are degraded by proteasomes via the endoplasmic reticulum (ER)-degradation pathway, so a high rate of IgG biosynthesis in MM cells places an unusually high burden on the proteasomes. MM cells are therefore under permanent ER stress and can be easily induced, by proteasome inhibition, into the unfolded protein response (Obeng et al., 2006
). Moreover, increased production of IgG by MM cells increases their sensitivity to proteasome inhibitors (Meister et al., 2007
). As a result, partial inhibition of proteasomes in vivo by bortezomib, which is not toxic to patients’ normal cells, is sufficient to kill MM cells. Proteasome inhibitor-induced apoptosis always involves upregulation of a proapoptotic BH3 only member of Bcl-2 family (Fennell et al., 2008
), most frequently NOXA (Chen et al., 2010
; Fernández et al., 2005
; Qin et al., 2005
). NOXA expression in hematologic malignancies is controlled by a transcription factor ATF3 (Chen et al., 2010
; Wang et al., 2009
), which is induced by ER stress.
The success of bortezomib has stimulated interest in proteasomes as targets in oncology, and today at least five other compounds—two peptide boronates, two peptide epoxyketones, and one marine natural product, β-lactone—are at various stages of clinical development ().
Proteasome Inhibitors Used Clinically or in Clinical Trials for the Treatment of Multiple Myeloma