- Mini review
The ubiquitin-proteasome system: A novel target for anticancer and anti-inflammatory drug research
Cellular & Molecular Biology Letters volume 13, pages 353–365 (2008)
The ubiquitin-proteasome system is responsible for the degradation of most intracellular proteins, including those that control cell cycle progression, apoptosis, signal transduction and the NF-κB transcriptional pathway. Aberrations in the ubiquitin-proteasome system underlie the pathogenesis of many human diseases, so both the ubiquitin-conjugating system and the 20S proteasome are important targets for drug discovery. This article presents a few of the most important examples of the small molecule inhibitors and modulators targeting the ubiquitin-proteasome system, their mode of action, and their potential therapeutic relevance in the treatment of cancer and inflammatory-related diseases.
acute myeloid leukemia
acute renal failure
bone marrow stromal cells
β-transducin repeat containing protein
chronic lymphocytic leukemia
human counterpart of Mdm2
hypoxia inducible factor
murine double minute 2
major histocompatibility complex
proteolytic targeting chimeric molecules
phosphorylated von Hippel-Lindau tumor suppressor
reactivation of p53 and induction of tumor cell apoptosis
complex formed by Skp1, cullin and F-box protein
small interfering RNA
S-phase kinase associated protein 2
small molecule proteolysis inducers
tumor necrosis factor
various leukocyte adhesion molecules
vascular endothelial growth factor
Glickman, M.H. and Ciechanover, A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol. Rev. 82 (2001) 373–428.
Ciechanover, A. and Schwartz, A.L. The ubiquitin system: pathogenesis of human diseases and drug targeting. Biochim. Biophys. Acta 1695 (2004) 3–7.
Herrmann, J., Ciechanover, A., Lerman, L.O. and Lerman, A. The ubiquitinproteasome system in cardiovascular diseases-a hypothesis extended. Cardiovasc. Res. 61(2004) 11–21.
Wojcik, C. and Di Napoli M. Ubiquitin-proteasome system and proteasome inhibition: new strategies in stroke therapy. Stroke 35 (2004) 1506–1518.
Nalepa, G., Rolfe, M. and Harper, J.W. Drug discovery in the ubiquitinproteasome system. Nature 5 (2006) 596–623.
Burger, A. and Seth, A.K. The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. Eur. J. Cancer 40 (2004) 2217–2229.
Sun, Y. E3 ubiquitin ligases as cancer targets and biomarkers. Neoplasia 8 (2006) 645–654.
Kisselev, A.F. and Goldberg, A.L. Proteasome inhibitors: from research tools to drug candidates. Chem. Biol. 8 (2001) 739–758.
Delcros, J.G., Floch, M.B., Prigent, C. and Arlot-Bonnemains, Y. Proteasome inhibitors as therapeutic agents: current and future strategies. Curr. Med. Chem. 10 (2003) 479–503.
Joazeiro, C.A.P., Anderson, K.C. and Hunter, T. Proteasome inhibitor drugs on the rise. Cancer Res. 66 (2006) 7840–7842.
Voorhees, P.M. and Orlowski, R.Z. The proteasome and proteasome inhibitors in cancer therapy. Annu. Rev. Pharmacol. Toxicol. 46 (2006) 189–213.
Orlowski, Z. The ubiquitin proteasome pathway from bench to bedside. Hematology 1 (2005) 220–225.
Zhou, P. Targeted protein degradation. Curr. Opin. Chem. Biol. 9 (2005) 51–55.
Michael, D. and Oren, M. The p53-Mdm2 module and the ubiquitin system. Semin. Cancer Biol. 13 (2003) 49–58.
Vassilev, L.T., Vu, B.T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., Fotouhi, N. and Liu, E.A. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303 (2004) 844–848.
Issaeva, N., Bozko, P., Enge, M., Protopopowa, M., Verhoef, L.G., Masucci, M., Pramanik, A. and Selivanova G. Small molecule RITA binds to p53, blocks p53-HDM2 interaction and activates p53 function in tumors. Nature Med. 10 (2004) 1321–1328.
Maerken, T.V., Speleman, F., Vermuelen, J., Lambertz, I., Clercq, S., Smet, E., Yigit, N., Coppens, V., Philippe, J., Paepe, A., Marine, J. and Vandesompele, J. Small-molecule MDM2 antagonists as a new therapy concept for neuroblastoma. Cancer Res. 66 (2006) 9646–9655.
Gstaiger, M., Jordan, R., Lim, M., Catzavelos, C., Mestan, J., Slingerland, J. and Krek, W. Skp2 is oncogenic and overexpressed in human cancers. Proc. Natl. Acad. Sci. (USA) 24 (2001) 5043–5048.
Baldwin, A.S. The transcription factor NF-κB and human diseases. J. Clin. Invest. 107 (2001) 3–6.
Karin, M. Nuclear factor-κB in cancer development and progression. Nature 44 (2006) 431–436.
Yamamoto, Y. and Gaynor, R.B. Therapeutic poteκtial of inhibition of the NF-κB pathway in the treatment of inflammation and cancer. J. Clin. Invest. 107 (2001) 135–142.
Yaron, A., Gonen, H., Alkalay, I., Hatzubai, A., Jung, S., Beyth, S., Mercurio, F., Manning, A.M., Ciechanover, A., Ben-Neriah, Y. Inhibition of NF-κB cellular function via specific targeting of the IκB-ubiquitin ligase. EMBO J. 16 (1997) 6486–6494.
Swinney, D.C., Xu, Y.Z., Scarafia, L.E., Lee, I., Mak, A.Y., Gan, Q.F., Ramesha, C.S., Mulkins, M.A., Dunn, J., So, O.Y., Biegel, T., Dinh, M., Volkel, P., Barnett, J., Dalrymple, S.A., Lee, S. and Huber, M. A small molecule ubiquitination inhibitor blocks NF-κB-dependent cytokine expression in cells and rats. J. Biol. Chem. 277 (2002) 2357–23581.
Adams, J. Proteasome inhibitors as new anticancer drugs. Curr. Opin. Oncol. 14 (2002) 628–634.
Elliott, P.J., Zollner, T.M. and Boehncke, W.H. Proteasome inhibition: a new anti-inflammatory strategy. J. Mol. Med. 81 (2003) 235–245.
Orlowski, M and Wilk, S. Catalytic activities of the 20S proteasome, a multicatalytic proteinase complex. Arch. Biochem. Biophys. 383 (2000) 1–16.
Groll, M. and Huber, R. Inhibitors of eukaryotic 20S proteasome core particle: a structural approach. Biochim. Biophys. Acta 1695 (2004) 33–44.
Kloetzel, P.M. and Ossendorp, F. Proteasome and peptidase function in MHC class I-mediated antigen presentation. Curr. Opin. Immunol. 16 (2004) 76–81.
Groll, M. and Huber, R. Inhibitors of eukaryotic 20S proteasome core particle: a structural approach. Biochim. Biophys. Acta 1695 (2004) 33–44.
Hideshima, T., Richardson, P., Chauhan, D., Palombella, V.J., Elliot, P.J., Adams, J. and Anderson, K.C. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer. Res. 61 (2001) 3071–3076.
Lee, A.H., Iwakoshi, N.N., Anderson, K.C. and Glimcher, L.H. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc. Natl. Acad. Sci (USA) 100 (2003) 9946–9951.
Adams, J. and Kauffman, M. Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest. 22 (2004) 304–11.
Hideshima, T., Mitsiades, C., Akiyama, M., Hayashi, T., Chauhan, D., Richardson, P., Schlossman, R., Podar, K., Munshi, N.C., Mitsiades, N. and Anderson, K.C. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 101 (2003) 1530–1534.
Mitsiades, N., Mitsiades, C.S., Richardson, P.G., Poulaki, V., Tai, Y.Y., Chauhan, D., Fanourakis, G., Gu, X., Bailey, C., Joseph, M., Libermann, T.A., Schlossman, R., Munshi, N.C., Hideshima, T. and Anderson, K.C. The proteasome inhibitor PS-341 potentates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101 (2003) 2377–2380.
Vink J., Cloos, J. and Kaspers, G.J.L. Proteasome inhibition as novel treatment strategy in leukaemia. Brit. J. Haematol. 134 (2006) 253–262.
Feling, R.H., Buchanan, G.O., Mincer, T.J., Kauffman, C.A., Jensen, P.R. and Fenical, W. Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew. Chem. In. Ed. Engl. 42 (2003) 355–357.
Kuhn, D.J., Chen, Q., Voorhees, P.M., Strader, J.S., Shenk, K.D., Sun, C.M., Demo, S.D., Bennet, M.K., Leewen, F.W., Chanan-Khan, A.A. and Orlowski, R.Z. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against pre-clinical models of multiple myeloma. Blood (2007) prepublished online.
Ho, A., Bargagna-Mohan, P., Wehenkel, M., Mohan, R. and Kim, K. LMP2-specific inhibitors: chemical genetic tools for proteasome biology. Chem. Biol. 14 (2007) 419–430.
Chauhan, D., Catley, L., Li, G., Podar, K., Hideshima, T., Velankar, M., Mitsiades, N., Yasui, H., Letai, A., Ovaa, H., Berkers, C., Nicholson, B., Chao, T., Neuteboom, S.T., Richardson, P., Palladino, M.A. and Anderson, C. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from bortezomib. Cancer Cell 8 (2005) 407–419.
Ruiz, S., Krupnik, Y., Keating, M., Chandra, J., Palladino, M. and McConkey, D. The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia. Mol. Cancer Ther. 7 (2006) 1836–1843.
Stapnes, C., Doskeland, A.P., Hatfield, K., Ersvaer, E., Ryningen, A. and Lorens, J.B. The proteasome inhibitors bortezomib and PR-171 have antiproliferative and proapoptotic effects on primary human acute myeloid leukaemia cells. Brit. J. Haematol. 136 (2007) 814–828.
Di Napoli, M. and Papa, F. MLN-519: Milenium/PAION. Curr. Opin. Invest. Drugs 4 (2003) 333–341.
Phillips, J.B., Williams, A.J., Adams, J., Elliott, P.J. and Tortella, F.C. Proteasome inhibitor PS519 reduced infarction and attenuates leukocyte infiltration in a rat model of focal cerebral ischemia. Stroke 31 (2000) 1686–1693.
Zhang, L., Zhang, Z.G., Zhang, R.L., Lu, M., Adams, J., Elliott, P.J. and Chopp, M. Postischemic (6-hour) treatment with recombinant human tissue plasminogen activator and proteasome inhibitor PS-519 reduces infarction in a rat model of embolic focal cerebral ischemia. Stroke 32 (2001) 2926–2931.
Berti, R., Williams, A.J., Velarde, L.C., Moffett, J.R., Elliott, P.J., Adams, J., Yao, C., Dave, J.R. and Tortella, F.C. Effect of the proteasome inhibitor MLN519 on the expression of inflammatory molecules following middle cerebral artery occlusion and reperfusion in the rat. Neurotox. Res. 5 (2003) 505–514.
Williams, A.J., Dave, J.R., Elliot, P.J., Adams, J. and Tortella, F.C. Delayed treatment of ischemic/reperfusion brain injury: extended therapeutic window with the proteasome inhibitor MLN519. Stroke 35 (2004) 1186–1191.
Williams, A.J., Dave, J.R. and Tortella, F.C. Neuroprotection with the proteasome inhibitor MLN519 in focal ischemic brain injury: relation to nuclear factor kappa B (NF-kappaB), inflammatory gene expression, and leukocyte infiltration. Neurochem. Int. 49 (2006) 106–112.
Campbell, B., Adams, J., Shin, Y.K. and Lefer, A.M. Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart. J. Mol. Cell Cardiol. 31 (1999) 467–476.
Pye J., Ardeshirpour, F., McCain, A., Bellinger, D.A., Merricks, E., Adams, J., Elliott, P.J., Pien, C., Fisher, T.H., Baldwin, A.S. and Nichols, T.C. Proteasome inhibition ablates activation of NF-κB in myocardial reperfusion and reduces reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 264 (2003) H919–H926.
Stansfield, W.E., Moss, N.C., Willis, M.S., Tang, R. and Selzman, C.H. Proteasome inhibition attenuates infarct size and preserves cardiac function in a murine model of myocardial ischemia-reperfusion injury. Ann. Thorac. Surg. 84 (2007) 120–125.
Shah, I.M., Lees, K.R. and Elliott, P.J. Early clinical experience with the novel proteasome inhibitor PS-519. Brit. J. Clin. Pharmacol. 54 (2002) 269–276.
Buchan, A.M., Li, H. and Blackburn, B. Neuroprotection achieved with a novel proteasome inhibitor which blocks NF-kappaB activation. Neuroreport 11 (2000) 427–430.
Takaoka, M., Ohkita, M. and Matsumura, Y. Pathophysiological role of proteasome-dependent proteolytic pathway in endothelin-1-related cardiovascular diseases. Curr. Vasc. Pharmacol. 1 (2003) 19–26.
Itoh M., Takaoka, M., Shibata, A., Okhita, M. and Matsumura, Y. Preventive effect of lactacystin, a selective proteasome inhibitor, on ischemic acute renal failure in rats. J. Pharmacol. Exp. Ther. 298 (2001) 501–507.
Ostrowska, J.K., Wojtukiewicz, M.Z., Chabielska, E., Buczko, W. and Ostrowska, H. Proteasome inhibitor prevents experimental arterial thrombosis in renovascular hypertensive rats. Thromb. Haemost. 92 (2004) 171–177.
Morgan, E.N., Pohlman, T.H. and Vocelka, C. Nuclear factor kappa B mediates a procoagulant response in monocytes during extracorporeal circulation. J. Thorac. Cardiovasc. Surg. 125 (2003) 165–171.
Ostrowska-Roszczenko, J.K., Ostrowska, H., Wojtukiewicz, M.Z., Radziwon, P., Szczepanski, M. and Wolczynski, S. Proteasome inhibition prevents tissue factor expression in human endothelial cells exposed to diverse agonists via inhibition of NF-kappaB in cultured endothelial cells. 41st Meeting of the Polish Biochem.Soc., Bialystok, 2006, 200.
Ostrowska, H., Wojcik, C., Omura, S. and Worowski, K. Lactacystin, a specific inhibitor of the proteasome, inhibits human platelet lysosomal cathepsin A-like enzyme. Biochem. Biophys. Res. Commun. 234 (1997) 729–732.
Geier, E., Pfeifer, G., Wilm, M., Lucchiari-Hartz, M., Baumeister, W., Eichmann, K. and Niedermann G. A giant protease with potential to substitute for some functions of the proteasome. Science 283 (1999) 978–981.
Sakamoto, K.M. Kim, K.B., Kumagai, A., Mercurio, F., Crews, C.M. and Deshaies, R.J. Protacs: chimeric molecules that target proteins to the Skp1-cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. 98 (2001) 8554–8559.
Zhang, D., Baek, S.H., Ho, A. and Kim, K. Degradation of target protein in living cells by small-molecule proteolysis inducers. Bioorg. Med. Chem. Lett. 14 (2004) 645–648.
Sakamoto, K.M., Kim, K.B., Verma, R., Ransick, A., Stein, B., Crews, C.M. and Deshaies, R.J. Development of protacs to target cancer-promoting proteins for ubiquitination and degradation. Mol. Cell. Proteomics 2 (2003) 1350–1358.
Paper authored by participants of the international conference: XXXIV Winter School of the Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Zakopane, March 7–11, 2007, “The Cell and Its Environment”. Publication cost was partially covered by the organisers of this meeting.
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Ostrowska, H. The ubiquitin-proteasome system: A novel target for anticancer and anti-inflammatory drug research. Cell Mol Biol Lett 13, 353–365 (2008). https://doi.org/10.2478/s11658-008-0008-7
- E3 ubiquitin ligases
- Therapeutic potential
- Cardiovascular diseases