ReviewPost ScreenBuilding on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy
Introduction
Inhibition of the proteasome has emerged as a clinically effective anti-cancer therapeutic approach over the past decade [1]. This has been primarily for hematologic malignancies – including multiple myeloma (MM) [2], non-Hodgkin's lymphoma (NHL) [3], and Waldenström's macroglobulinemia (WM) – and associated conditions, such as primary systemic amyloidosis. The first-in-class proteasome inhibitor bortezomib (VELCADE®, Millennium Pharmaceuticals, Inc., and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) has demonstrated the feasibility of this approach and validated the concept of proteasome inhibition [1]. Preclinical studies have suggested that proteasome inhibition with bortezomib results in pleiotropic effects, disrupting multiple cellular signaling pathways and inducing tumor cell death 1, 4. Clinical studies have established substantial activity of bortezomib in various malignancies, as reviewed elsewhere 2, 3, and also determined its pharmacokinetics and pharmacodynamics and characterized its safety profile [5].
Some limitations of bortezomib exist, including limited activity in solid tumors [1], emergence of reversible peripheral neuropathy in several patients [6] and the intravenous route of administration. Thus, several new proteasome inhibitors are in development, with the aim of building on the activity seen with bortezomib while improving the safety profile of proteasome inhibition and the convenience of administration. Here, we discuss the key aspects of the development of new proteasome inhibitors, review this second generation of agents and assess the potential pharmacologic impact of the different chemical properties of these agents.
Section snippets
The proteasome as a therapeutic target
The proteasome is a crucial component of the ubiquitin–proteasome system (UPS) 7, 8, 9, which is responsible for regulation and degradation of the majority of intracellular proteins. Consequently, its inhibition affects numerous signaling pathways in cells. UPS substrates include proteins responsible for regulating cellular processes such as the cell cycle, growth and proliferation signaling, and pro-apoptotic and anti-apoptotic signaling.
The 26S proteasome comprises a 20S core (Figure 1)
Mechanism of action of proteasome inhibition
Several putative mechanisms of activity of proteasome inhibition have been determined based upon preclinical studies of bortezomib. Bortezomib induces apoptosis in tumor cells via the intrinsic mitochondrial pathway, the extrinsic death-receptor pathway, and the endoplasmic reticulum stress response pathway 4, 26, 27. This activity has been suggested to result from inhibition of the degradation of various regulatory and pro-apoptotic proteins [4], including: inhibition of nuclear factor (NF)-κB
Preclinical studies and clinical development of the second-generation inhibitors
Bortezomib resulted in substantial anti-tumor activity in in vitro and in vivo studies and, through the multiple pathways affected by proteasome inhibition, demonstrated synergistic activity with various conventional and novel therapeutic agents [10]. Similar findings have been reported from preclinical studies of the second-generation inhibitors, as discussed below, although some preclinical studies have suggested differential effects and differential anti-tumor activity between proteasome
Pharmacologic implications of proteasome abundance and different binding kinetics
The challenge of developing new proteasome inhibitors is not to make them better inhibitors of the proteasome per se; as discussed earlier, bortezomib and the second-generation inhibitors all have low nanomolar IC50 values for the β5 subunit and, therefore, are very effective inhibitors of proteasome activity. Indeed, the small differences in potency between inhibitors seen in vitro might have no effect in vivo owing to the abundance of proteasomes in the human body, as illustrated in Figure 3;
Concluding remarks
The concept of proteasome inhibition as a therapeutic approach in cancer is now well established, and numerous companies are now developing new proteasome inhibitors with the aim of building upon the success of the first-in-class inhibitor bortezomib [62]. Bortezomib and all these second-generation compounds represent highly effective inhibitors of the proteasome, regardless of the type of agent; improving upon bortezomib, therefore, will require modification of the pharmacology of the
Acknowledgments
The authors acknowledge editorial assistance from Steve Hill of FireKite during the development of this publication, which was funded by Millennium Pharmaceuticals, Inc.
References (63)
The development of proteasome inhibitors as anticancer drugs
Cancer Cell
(2004)The proteasome: structure, function, and role in the cell
Cancer Treat. Rev.
(2003)A high molecular weight protease in the cytosol of rat liver. I. Purification, enzymological properties, and tissue distribution
J. Biol. Chem.
(1986)Proteasome inhibitors: from research tools to drug candidates
Chem. Biol.
(2001)CEP-18770: a novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib
Blood
(2008)A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from bortezomib
Cancer Cell
(2005)Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma
Blood
(2007)NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells
Blood
(2007)Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-kappaB regulated gene products
Blood
(2007)Dual targeting of the proteasome regulates survival and homing in Waldenstrom's macroglobulinemia
Blood
(2008)
The novel proteasome inhibitor NPI-0052 induces the expression of Raf-1 kinase inhibitor protein (RKIP) in B-NHL via inhibition of the transcription repressor Snail: roles of Snail and RKIP in sensitization to TRAIL apoptosis
Blood
The novel proteasome inhibitor CEP-18770 inhibits myeloma tumor growth in vitro and in vivo and enhances the anti-MM effects of melphalan
Blood
Induction of sustained early G1 arrest by selective inhibition of CDK4 and CDK6 primes myeloma cells for synergistic killing by proteasome inhibitors carfilzomib and PR-047
Blood
Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma
Blood
The selective proteasome inhibitor carfilzomib in combination with chemotherapeutic agents improves anti-tumor response in solid tumor xenograft models
Eur. J. Cancer
Metabolism, disposition and pharmacokinetics of PR-171, a novel inhibitor of the 20S proteasome
Blood
The selective proteasome inhibitor carfilzomib is well tolerated in experimental animals with dose intensive administration
Blood
Pharmacodynamic and efficacy studies of a novel proteasome inhibitor NPI-0052 in human plasmacytoma xenograft mouse model
Blood
Combination of a novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vivo synergistic cytotoxicity in multiple myeloma
Blood
Inhibition of the pan-Bcl-2 family by the small molecule GX15-070 induces apoptosis in mantle cell lymphoma (MCL) cells and enhances the activity of two proteasome inhibitors (NPI-0052 and bortezomib), and doxorubicin chemotherapy
Blood
Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma
Blood
Proteasome inhibitor associated neuropathy is mechanism based
Blood
Effect of an experimental proteasome inhibitor on the cytoskeleton, cytosolic protein turnover, and induction in the neuronal cells in vitro
Neurotoxicology
Proteasome inhibitors in cancer therapy: lessons from the first decade
Clin. Cancer Res.
Bortezomib in the front-line treatment of multiple myeloma
Expert Rev. Anticancer Ther.
Novel approaches for the treatment of NHL: proteasome inhibition and immune modulation
Leuk. Lymphoma
Proteasome inhibitors: antitumor effects and beyond
Leukemia
Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline
Br. J. Haematol.
The ubiquitin-proteasome pathway: on protein death and cell life
EMBO J.
The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle
Cell Death Differ.
Cited by (251)
The role of proteasomes in tumorigenesis
2024, Genes and DiseasesA review of progress in o-aminobenzamide-based HDAC inhibitors with dual targeting capabilities for cancer therapy
2023, European Journal of Medicinal ChemistryAnti-cancer effect of boron derivatives on small-cell lung cancer
2022, Journal of Trace Elements in Medicine and BiologyInterplay between proteasome inhibitors and NF-κB pathway in leukemia and lymphoma: a comprehensive review on challenges ahead of proteasome inhibitors
2024, Cell Communication and SignalingBortezomib Is Toxic but Induces Neurogenesis and Inhibits TUBB3 Degradation in Rat Neural Stem Cells
2024, Biomolecules and Therapeutics