Open Access
Review
Development of Proteasome Inhibitors for Cancer Therapy
Xu Chen†
, Xuan Wu†
, Linyan Li
, Xiaoming Zhu*
Author Information
Submitted: 12 Jan 2024 | Accepted: 19 Feb 2024 | Published: 18 Mar 2024
Abstract
The ubiquitin proteasome system (UPS) is considered a crucial degradation machinery in cellular processes of protein quality control and homeostasis. Dysregulation of the UPS is closely associated with many diseases. The proteasome is a key core component of the UPS, which can prevent the accumulation of misfolded proteins and regulate various cellular processes such as cell cycle, apoptosis, and immune responses. In the past two decades, a total of three proteasome inhibitors have been approved for the treatment of hematological malignancies, including bortezomib, carfilzomib, and ixazomib. Additionally, accumulating reports have suggested that some natural product-derived proteasome inhibitors have been developed as anti-cancer drug candidates. In this review, we summarize the development of proteasome inhibitors as well as the mechanisms involved, clinical application progress, and drug resistance. The natural products of proteasome inhibitors and their future perspectives will also be discussed.
References
1.
Labbadia, J.; Morimoto, R.I. The biology of proteostasis in aging and disease. Annu. Rev. Biochem. 2015, 84, 435‒464.
2.
Hipp, M.S.;P. Kasturi, P.; Hartl, F.U. The proteostasis network and its decline in ageing. Nat. Rev. Mol. Cell Biol. 2019, 20, 421‒435.
3.
Liang, R.; Tan, H.B.; Jin, H.J.; et al. The tumour-promoting role of protein homeostasis: Implications for cancer immunotherapy. Cancer Lett. 2023, 573, 216354.
4.
Dikic, I. Proteasomal and autophagic degradation systems. Annu. Rev. Biochem. 2017, 86, 193‒224.
5.
Chen, J.L.; Wu, X.; Yin, D.; et al. Autophagy inhibitors for cancer therapy: small molecules and nanomedicines. Pharmacol. Ther. 2023, 249, 108485.
6.
Kwon, Y.T.; Ciechanover, A. The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem. Sci. 2017, 42, 873‒886.
7.
Finley, D. Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu. Rev. Biochem. 2009, 78, 477‒513.
8.
Huang, H.; Weng, H.; Dong, B.; et al. Oridonin triggers chaperon-mediated proteasomal degradation of BCR-ABL in leukemia. Sci. Rep. 2017, 27, 415‒425.
9.
Narayanan, S.; Cai, C.Y.; Assaraf, Y.G.; et al. Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance. Drug Resistance Updates. 2020, 48, 100663.
10.
Fricker, L.D. Proteasome inhibitor drugs. Annu. Rev. Pharmacol. Toxicol., 2020, 60, 457‒476.
11.
Dou, Q.P.; Landis-Piwowar, K.R.; Chen, D.; et al. Green tea polyphenols as a natural tumour cell proteasome inhibitor. Inflammopharmacology 2008, 16, 208‒212.
12.
Chen, D.; Daniel, K.G.; Chen, M.S.; et al. Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. Biochem. Pharmacol. 2005, 69, 1421‒1432.
13.
Yang, H.; Chen, D.; Cui, Q.C.; et al. Celastrol, a triterpene extracted from the Chinese “Thunder of god vine,” is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res. 2006, 66, 4758‒4765.
14.
Margarucci, L.; Monti, M.C.; Tosco, A.; et al. Chemical proteomics discloses petrosapongiolide M, an antiinflammatory marine sesterterpene, as a proteasome inhibitor. Angew. Chem., Int. Ed. Engl. 2010, 49, 3960‒3963.
15.
Collins, G.A.; Goldberg, A.L. The logic of the 26S proteasome. Cell 2017, 169, 792‒806.
16.
Nunes, A.T.; Annunziata, C.M. Proteasome inhibitors: structure and function. Semin. Oncol. 2017, 44, 377‒380.
17.
Bard, J.A.M.; Goodall, E.A.; Greene, E.R.; et al. Structure and function of the 26S proteasome. Annu. Rev. Biochem. 2018, 87, 697‒724.
18.
Adams, J. The proteasome: structure, function, and role in the cell. Cancer Treat. Rev. 2003, 29, 3‒9.
19.
Nussbaum, A.K.; Dick, T.P.; Keilholz, W.; et al. Cleavage motifs of the yeast 20S proteasome beta subunits deduced from digests of enolase 1. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 12504‒12509.
20.
Manasanch, E.E.; Orlowski, R.Z. Proteasome inhibitors in cancer therapy. Nat. Rev. Clin. Oncol. 2017, 14, 417‒433.
21.
Murata, S.; Takahama, Y.; Kasahara, M.; et al. The immunoproteasome and thymoproteasome: functions, evolution and human disease. Nat. Immunol. 2018, 19, 923‒931.
22.
Deshmukh, F.K.; Yaffe, D.; Olshina, M.A.; et al. The contribution of the 20S proteasome to proteostasis. Biomolecules 2019, 9, 190.
23.
Adams, J.; Palombella, V.J.; Sausville, E.A.; et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999, 59, 2615‒2622.
24.
Yamamoto, Y.; Gaynor, R.B. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J. Clin. Invest. 2001, 107, 135‒142.
25.
Adams, J. The development of proteasome inhibitors as anticancer drugs. Cancer Cell 2004, 5, 417‒421.
26.
Hartl, F.U.; Hayer-Hartl, M. Converging concepts of protein folding in vitro and in vivo. Nat. Struct. Mol. Biol. 2009, 16, 574‒581.
27.
Chen, X.; Cubillos-Ruiz, J.R. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat. Rev. Cancer 2021, 21, 71‒88.
28.
Nikesitch, N.; Lee, J.M.; Ling, S.; et al. Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance. Clin. Transl. Immunol. 2018, 7, e1007.
29.
Brnjic, S.; Mazurkiewicz, M.; Fryknäs, M.; et al. Induction of tumor cell apoptosis by a proteasome deubiquitinase inhibitor is associated with oxidative stress. Antioxid. Redox Signaling 2014, 21, 2271‒2285.
30.
Fribley, A.; Wang, C.Y. Proteasome inhibitor induces apoptosis through induction of endoplasmic reticulum stress. Cancer Biol. Ther. 2006, 5, 745‒748.
31.
Lee, K.H.; Lee, J.; Woo, J.; et al. Proteasome inhibitor-induced IkappaB/NF-kappaB activation is mediated by Nrf2-dependent light chain 3B induction in lung cancer cells. Mol. Cells 2018，41, 1008‒1015.
32.
Kim, C.; Lee, J.H.; Ko, J.H.; et al. Formononetin regulates multiple oncogenic signaling cascades and enhances sensitivity to bortezomib in a multiple myeloma mouse model. Biomolecules 2019, 9, 262.
33.
Zou, T.; Lin, Z. The involvement of ubiquitination machinery in cell cycle regulation and cancer progression. Int. J. Mol. Sci. 2021, 22, 5754.
34.
Halasi, M.; Pandit, B.; Gartel, A.L. Proteasome inhibitors suppress the protein expression of mutant p53. Cell Cycle 2014, 13, 3202‒3206.
35.
Thibaudeau, T.A.; Smith, D.M. A practical review of proteasome pharmacology. Pharmacol. Rev. 2019, 71, 170‒197.
36.
Wu, P.; Oren, O.; Gertz, M.A.; et al. Proteasome inhibitor-related cardiotoxicity: mechanisms, diagnosis, and management. Curr. Oncol. Rep. 2020, 22, 66.
37.
Orlowski, R.Z.; Stinchcombe, T.E.; Mitchell, B.S.; et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J. Clin. Oncol. 2002, 20, 4420‒4427.
38.
Chauhan, D.; Singh, A.; Brahmandam, M.; et al. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 2008, 111, 1654‒1664.
39.
Pérez-Galán, P.; Roué G.; Villamor, N.; et al. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and noxa activation independent of p53 status. Blood 2006, 107, 257‒264.
40.
Strauss, S.J.; Higginbottom, K.; Jüliger, S.; et al. The proteasome inhibitor bortezomib acts independently of p53 and induces cell death via apoptosis and mitotic catastrophe in B-cell lymphoma cell lines. Cancer Res. 2007, 67, 2783‒2790.
41.
Hideshima, T.; Richardson, P.; Chauhan, D.; et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001, 61, 3071‒3076.
42.
LeBlanc, R.; Catley, L.P.; Hideshima, T.; et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res. 2002, 62, 4996‒5000.
43.
Cowan, A.J.; Green, D.J.; Kwok, M.; et al. Diagnosis and management of multiple myeloma: a review. JAMA 2022, 327, 464‒477.
44.
Durie, B.G.M.; Hoering, A.; Abidi, M.H.; et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017, 389, 519‒527.
45.
Chang, J.E.; Li, H.; Smith, M.R.; et al. Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an eastern cooperative oncology group study (E1405). Blood 2014, 123, 1665‒1673.
46.
Chang, J.E.; Carmichael, L.L.; Kim, K.; et al. VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a wisconsin oncology network study. Br. J. Haematol. 2011, 155, 190‒197.
47.
Richardson, P.G.; Sonneveld, P.; Schuster, M.; et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007, 110, 3557‒3560.
48.
Robak, T.; Jin, J.; Pylypenko, H.; et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018, 19, 1449‒1458.
49.
Dimopoulos, M.A.; Goldschmidt, H.; Niesvizky, R.; et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017, 18, 1327‒1337.
50.
Kuhn, D.J.; Chen, Q.; Voorhees, P.M.; et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 2007, 110, 3281‒3290.
51.
Wang, H.; Guan, F.; Chen, D.; et al. An analysis of the safety profile of proteasome inhibitors for treating various cancers. Expert Opin. Drug Saf. 2014, 13, 1043‒1054.
52.
Siegel, D.S.; Martin, T.; Wang, M.; et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012, 120, 2817‒2825.
53.
Vij, R.; Wang, M.; Kaufman, J.L.; et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood 2012, 119, 5661‒5670.
54.
Stewart, A.K.; Rajkumar, S.V.; Dimopoulos, M.A.; et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 2015, 372, 142‒152.
55.
Vesole, D.H.; Bilotti, E.; Richter, J.R.; et al. Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Br. J. Haematol. 2015, 171, 52‒59.
56.
Lendvai, N.; Hilden, P.; Devlin, S.; et al. A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma. Blood 2014, 124, 899‒906.
57.
Papadopoulos, K.P.; Siegel, D.S.; Vesole, D.H.; et al. Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J. Clin. Oncol. 2015, 33, 732‒739.
58.
Korde, N.; Roschewski, M.; Zingone, A.; et al. Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol. 2015, 1, 746‒754.
59.
Gandolfi, S.; Laubach, J.P.; Hideshima, T.; et al. The proteasome and proteasome inhibitors in multiple myeloma. Cancer Metastasis Rev. 2017, 36, 561‒584.
60.
Kupperman, E.; Lee, E.C.; Cao, Y.; et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010, 70, 1970‒1980.
61.
Liu, R.; Fu, C.; Sun, J.; et al. A new perspective for osteosarcoma therapy: proteasome inhibition by MLN9708/2238 successfully induces apoptosis and cell cycle arrest and attenuates the invasion ability of osteosarcoma cells in vitro. Cell. Physiol. Biochem. 2017, 41, 451‒465.
62.
Chauhan, D.; Tian, Z.; Zhou, B.; et al. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin. Cancer Res. 2011, 17, 5311‒5321.
63.
Richardson, P.G.; Kumar, S.K.; Masszi, T.; et al. Final overall survival analysis of the TOURMALINE-MM1 phase III trial of ixazomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J. Clin. Oncol. 2021, 39, 2430‒2442.
64.
Kale, A.J.; Moore, B.S. Molecular mechanisms of acquired proteasome inhibitor resistance. J. Med. Chem. 2012, 55, 10317‒10327.
65.
Chauhan, D.; Singh, A.V.; Ciccarelli, B.; et al. Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. Blood 2010, 115, 834‒845.
66.
Singh, A.V.; Palladino, M.A.; Lloyd, G.K.; et al. Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI-0052 (marizomib) in a human plasmacytoma xenograft murine model. Br. J. Haematol. 2010, 149, 550‒559.
67.
Spencer, A.; Harrison, S.; Zonder, J.; et al. A phase 1 clinical trial evaluating marizomib, pomalidomide and low-dose dexamethasone in relapsed and refractory multiple myeloma (NPI-0052-107): final study results. Br. J. Haematol. 2018, 180, 41‒51.
68.
Hari, P.; Matous, J.V.; Voorhees, P.M.; et al. Oprozomib in patients with newly diagnosed multiple myeloma. Blood Cancer, J. 2019, 9, 66.
69.
Shah, J.; Usmani, S.; Stadtmauer, E.A.; et al. Oprozomib, pomalidomide, and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Clin. Lymphoma Myeloma Leuk. 2019, 19, 570‒578.
70.
Sanderson, M.P.; Friese-Hamim, M.; Walter-Bausch, G.; et al. M3258 Is a selective inhibitor of the immunoproteasome subunit LMP7 (beta5i) delivering efficacy in multiple myeloma models. Mol. Cancer Ther. 2021, 20, 1378‒1387.
71.
Manton, C.A.; Johnson, B.; Singh, M.; et al. Induction of cell death by the novel proteasome inhibitor marizomib in glioblastoma in vitro and in vivo. Sci. Rep. 2016, 6, 18953.
72.
Rentsch, A.; Landsberg, D.; Brodmann, T.; et al. Synthesis and pharmacology of proteasome inhibitors. Angew. Chem., Int. Ed. Engl. 2013, 52, 5450‒5488.
73.
Manach, C.; Scalbert, A.; Morand, C.; et al. Polyphenols: food sources and bioavailability. Am. J. Clin. Nutr. 2004, 79, 727‒747.
74.
Smith, D.M.; Wang, Z.; Kazi, A.; et al. Synthetic analogs of green tea polyphenols as proteasome inhibitors. Mol Med. 2002, 8, 382‒392.
75.
Smith, D.M.; Daniel, K.G.; Wang, Z.; et al. Docking studies and model development of tea polyphenol proteasome inhibitors: applications to rational drug design. Proteins 2003, 54, 58‒70.
76.
Nam, S.; Smith, D.M.; Dou, Q.P. Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo. J. Biol. Chem. 2001, 276, 13322‒13330.
77.
Chen, D.; Landis-Piwowar, K.R.; Chen, M.S.; et al. Inhibition of proteasome activity by the dietary flavonoid apigenin is associated with growth inhibition in cultured breast cancer cells and xenografts. Breast Cancer Res. 2007, 9, R80.
78.
Singh, V.; Sharma, V.; Verma, V.; et al. Apigenin manipulates the ubiquitin-proteasome system to rescue estrogen receptor-β from degradation and induce apoptosis in prostate cancer cells. Eur. J. Nutr. 2014, 54, 1255‒1267.
79.
Liu, F.T.; Agrawal, S.G.; Movasaghi, Z.; et al. Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib. Blood 2008, 112, 3835‒3846.
80.
Tsalikis, J.; Abdel-Nour, M.; Farahvash, A.; et al. Isoginkgetin, a natural biflavonoid proteasome inhibitor, sensitizes cancer cells to apoptosis via disruption of lysosomal homeostasis and impaired protein clearance. Mol. Cell. Biol. 2019, 9, e00489‒e00418.
81.
Yin, R.; Li, T.; Tian, J.X.; et al. Ursolic acid, a potential anticancer compound for breast cancer therapy. Crit. Rev. Food Sci. Nutr. 2018, 58, 568‒574.
82.
Li, S.; Kuo, H.D.; Yin, R.; et al. Epigenetics/epigenomics of triterpenoids in cancer prevention and in health. Biochem. Pharmacol. 2020, 175, 113890.
83.
Ahmad, M.F. Ganoderma lucidum:a rational pharmacological approach to surmount cancer. J. Ethnopharmacol. 2020, 260, 113047.
84.
Dai, Y.; Desano, J.; Tang, W.; et al. Natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and NF-kappaB. PLoS One 2010, 5, e14153.
85.
Walcott, S.E.; Heikkila, J.J. Celastrol can inhibit proteasome activity and upregulate the expression of heat shock protein genes, hsp30 and hsp70, in Xenopus laevis A6 cells. Comp. Biochem. Physiol., Part A: Mol. Integr. Physiol. 2010, 156, 285‒293.
86.
Wang, W.B.; Feng, L.X.; Yue, Q.X.; et al. Paraptosis accompanied by autophagy and apoptosis was induced by celastrol, a natural compound with influence on proteasome, ER stress and Hsp90. J. Cell. Physiol. 2012, 227, 2196‒2206.
87.
Sethi, G.; Ahn, K.S.; Pandey, M.K.; et al. Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-κB-regulated gene products and TAK1-mediated NF-κB activation. Blood. 2006, 109, 2727‒2735.
88.
Yang, H.; Shi, G.; Dou, Q.P. The tumor proteasome is a primary target for the natural anticancer compound withaferin A isolated from “Indian Winter Cherry”. Mol. Pharmacol. 2007, 71, 426‒437.
89.
Vanden Berghe, W.; Sabbe, L.; Kaileh, M.; et al. Molecular insight in the multifunctional activities of withaferin, A. Biochem. Pharmacol. 2012, 84, 1282‒1291.
90.
Vanden Berghe, W.; Sabbe, L.; Kaileh, M.; et al. Development of withaferin A analogs as probes of angiogenesis. Bioorg. Med. Chem. Lett. 2006, 16, 2603‒2607.
91.
Tsukamoto, S.; Tane, K.; Ohta, T.; et al. Four new bioactive pyrrole-derived alkaloids from the marine sponge axinella brevistyla. J. Nat. Prod. 2001, 64, 1576‒1578.
92.
Tsukamoto, S.; Tatsuno, M.; van Soest, R.W.; et al. New polyhydroxy sterols: proteasome inhibitors from a marine sponge acanthodendrilla sp. J. Nat. Prod. 2003, 66, 1181‒1185.
93.
Tsukamoto, S.; Yamanokuchi, R.; Yoshitomi, M.; et al. Aaptamine, an alkaloid from the sponge aaptos suberitoides, functions as a proteasome inhibitor. Bioorg. Med. Chem. Lett. 2010, 20, 3341‒3343.
94.
da Silva, D.C.; Andrade, P.B.; Valentão, P.; et al. Neurotoxicity of the steroidal alkaloids tomatine and tomatidine is RIP1 kinase- and caspase-independent and involves the eIF2α branch of the endoplasmic reticulum. J. Steroid Biochem. Mol. Biol. 2017, 171, 178‒186.
95.
Mohamed, I.E.; Kehraus, S.; Krick, A., et al. Mode of action of epoxyphomalins A and B and characterization of related metabolites from the marine-derived fungus paraconiothyrium sp. J. Nat. Prod. 2010, 73, 2053‒2056.
96.
Goel, U.; Usmani. S.; Kumar, S. Current approaches to management of newly diagnosed multiple myeloma. Am. J. Hematol. 2022, 97(S1), S3‒S25.
97.
Zhang, L.; Wu, M.; Su, R., et al. The efficacy and mechanism of proteasome inhibitors in solid tumor treatment. Recent Pat. Anticancer Drug Discov. 2022, 17, 268‒283.
98.
Roeten, M.S.F.; Cloos, J.; Jansen, G. Positioning of proteasome inhibitors in therapy of solid malignancies. Cancer Chemother. Pharmacol. 2017, 81, 227‒243.
99.
Li, K.; Crews, C.M. PROTACs: past, present and future. Chem. Soc. Rev. 2022, 51, 5214‒5236.
Issue
Volume 3, Issue 1How to Cite
Chen, X., Wu, X., Li, L., & Zhu, X. (2024). Development of Proteasome Inhibitors for Cancer Therapy. International Journal of Drug Discovery and Pharmacology, 3(1), 100004. https://doi.org/10.53941/ijddp.2024.100004
RIS
BibTex
Copyright & License
Copyright (c) 2024 by the authors.
This work is licensed under a This work is licensed under a Creative Commons Attribution 4.0 International License.