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Proteasome Inhibitors: A Novel Class of Potent and Effective Antitumor Agents

ProScript, Inc., Cambridge, Massachusetts 02139 [J. A., V. J. P., A. D., D. D. L., C. S. P., P. J. E.]; Hoechst Marion Roussel, D-60486 Frankfurt am Main, Germany [J. M.]; Hoechst Marion Roussel, Bridgewater, New Jersey 08807 [S. P.]; and Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland 20892 [E. A. S., J. J.]

The ubiquitin-proteasome pathway plays a critical role in the regulated degradation of proteins involved in cell cycle control and tumor growth. Dysregulating the degradation of such proteins should have profound effects on tumor growth and cause cells to undergo apoptosis. To test this hypothesis, we developed a novel series of proteasome inhibitors, exemplified by PS-341, which we describe here. As determined by the National Cancer Institute in vitro screen, PS-341 has substantial cytotoxicity against a broad range of human tumor cells, including prostate cancer cell lines. The PC-3 prostate cell line was, therefore, chosen to further examine the antitumor activity of PS-341. In vitro, PS-341 elicits proteasome inhibition, leading to an increase in the intracellular levels of specific proteins, including the cyclin-dependent kinase inhibitor, p21. Moreover, exposure of such cells to PS-341 caused them to accumulate in the G₂-M phase of the cell cycle and subsequently undergo apoptosis, as indicated by nuclear condensation and poly(ADP-ribose) polymerase cleavage. Following weekly i.v. treatment of PS-341 to mice bearing the PC-3 tumor, a significant decrease (60%) in tumor burden was observed in vivo. Direct injection of PS-341 into the tumor also caused a substantial (70%) decrease in tumor volume with 40% of the drug-treated mice having no detectable tumors at the end of the study. Studies also revealed that i.v. administration of PS-341 resulted in a rapid and widespread distribution of PS-341, with highest levels identified in the liver and gastrointestinal tract and lowest levels in the skin and muscle. Modest levels were found in the prostate, whereas there was no apparent penetration of the central nervous system. An assay to follow the biological activity of the PS-341 was established and used to determine temporal drug activity as well as its ability to penetrate tissues. As such, PS-341 was shown to penetrate PC-3 tumors and inhibit intracellular proteasome activity 1.0 h after i.v. dosing. These data illustrate that PS-341 not only reaches its biological target but has a direct effect on its biochemical target, the proteasome. Importantly, the data show that inhibition of this target site by PS-341 results in reduced tumor growth in murine tumor models. Together, the results highlight that the proteasome is a novel biochemical target and that inhibitors such as PS-341 represent a unique class of antitumor agents. PS-341 is currently under clinical evaluation for advanced cancers.

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				V. Chung, B. Zhou, X. Liu, L. Zhu, L. M. Boo, H.-V. Nguyen, D. K. Ann, J. Song, Y. Chen, and Y. Yen SUMOylation plays a role in gemcitabine- and bortezomib-induced cytotoxicity in human oropharyngeal carcinoma KB gemcitabine-resistant clone. Mol. Cancer Ther., March 1, 2006; 5(3): 533 - 540. [Abstract] [Full Text] [PDF]

				J. Codony-Servat, M. A. Tapia, M. Bosch, C. Oliva, J. Domingo-Domenech, B. Mellado, M. Rolfe, J. S. Ross, P. Gascon, A. Rovira, et al. Differential cellular and molecular effects of bortezomib, a proteasome inhibitor, in human breast cancer cells. Mol. Cancer Ther., March 1, 2006; 5(3): 665 - 675. [Abstract] [Full Text] [PDF]

				E. T. Efuet and K. Keyomarsi Farnesyl and Geranylgeranyl Transferase Inhibitors Induce G1 Arrest by Targeting the Proteasome Cancer Res., January 15, 2006; 66(2): 1040 - 1051. [Abstract] [Full Text] [PDF]

				Y. Fernandez, T. P. Miller, C. Denoyelle, J. A. Esteban, W.-H. Tang, A. L. Bengston, and M. S. Soengas Chemical Blockage of the Proteasome Inhibitory Function of Bortezomib: IMPACT ON TUMOR CELL DEATH J. Biol. Chem., January 13, 2006; 281(2): 1107 - 1118. [Abstract] [Full Text] [PDF]

				A. M. Roccaro, T. Hideshima, N. Raje, S. Kumar, K. Ishitsuka, H. Yasui, N. Shiraishi, D. Ribatti, B. Nico, A. Vacca, et al. Bortezomib Mediates Antiangiogenesis in Multiple Myeloma via Direct and Indirect Effects on Endothelial Cells Cancer Res., January 1, 2006; 66(1): 184 - 191. [Abstract] [Full Text] [PDF]

				H. Y. Yamada and G. J. Gorbsky Inhibition of TRIP1/S8/hSug1, a component of the human 19S proteasome, enhances mitotic apoptosis induced by spindle poisons Mol. Cancer Ther., January 1, 2006; 5(1): 29 - 38. [Abstract] [Full Text] [PDF]

				W. Zou, P. Yue, N. Lin, M. He, Z. Zhou, S. Lonial, F. R. Khuri, B. Wang, and S.-Y. Sun Vitamin C Inactivates the Proteasome Inhibitor PS-341 in Human Cancer Cells Clin. Cancer Res., January 1, 2006; 12(1): 273 - 280. [Abstract] [Full Text] [PDF]

				S. T. Nawrocki, J. S. Carew, K. Dunner Jr., L. H. Boise, P. J. Chiao, P. Huang, J. L. Abbruzzese, and D. J. McConkey Bortezomib Inhibits PKR-Like Endoplasmic Reticulum (ER) Kinase and Induces Apoptosis via ER Stress in Human Pancreatic Cancer Cells Cancer Res., December 15, 2005; 65(24): 11510 - 11519. [Abstract] [Full Text] [PDF]

				S. A.J. Vaziri, J. Hill, K. Chikamori, D. R. Grabowski, N. Takigawa, M. Chawla-Sarkar, L. R. Rybicki, A. V. Gudkov, T. Mekhail, R. M. Bukowski, et al. Sensitization of DNA damage-induced apoptosis by the proteasome inhibitor PS-341 is p53 dependent and involves target proteins 14-3-3{sigma} and survivin Mol. Cancer Ther., December 1, 2005; 4(12): 1880 - 1890. [Abstract] [Full Text] [PDF]

				B. J. Krawiec, R. A. Frost, T. C. Vary, L. S. Jefferson, and C. H. Lang Hindlimb casting decreases muscle mass in part by proteasome-dependent proteolysis but independent of protein synthesis Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E969 - E980. [Abstract] [Full Text] [PDF]

				S. Lonial, E. K. Waller, P. G. Richardson, S. Jagannath, R. Z. Orlowski, C. R. Giver, D. L. Jaye, D. Francis, S. Giusti, C. Torre, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma Blood, December 1, 2005; 106(12): 3777 - 3784. [Abstract] [Full Text] [PDF]

				X. Yu, S. Huang, E. Patterson, M. W. Garrett, K. M. Kaufman, J. P. Metcalf, M. Zhu, S. T. Dunn, and D. C. Kem Proteasome degradation of GRK2 during ischemia and ventricular tachyarrhythmias in a canine model of myocardial infarction Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1960 - H1967. [Abstract] [Full Text] [PDF]

				P. G. G. Richardson, B. Barlogie, J. Berenson, S. Singhal, S. Jagannath, D. Irwin, S. V. Rajkumar, T. Hideshima, H. Xiao, D. Esseltine, et al. Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma Blood, November 1, 2005; 106(9): 2977 - 2981. [Abstract] [Full Text] [PDF]

				S. R. Alberts, N. R. Foster, R. F. Morton, J. Kugler, P. Schaefer, M. Wiesenfeld, T. R. Fitch, P. Steen, G. P. Kim, and S. Gill PS-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group (NCCTG) randomized phase II study Ann. Onc., October 1, 2005; 16(10): 1654 - 1661. [Abstract] [Full Text] [PDF]

				G. Saunders Overview of drug therapy for multiple myeloma Journal of Oncology Pharmacy Practice, September 1, 2005; 11(3): 83 - 100. [Abstract] [PDF]

				A.L. Hamilton, J.P. Eder, A.C. Pavlick, J.W. Clark, L. Liebes, R. Garcia-Carbonero, A. Chachoua, D.P. Ryan, V. Soma, K. Farrell, et al. Proteasome Inhibition With Bortezomib (PS-341): A Phase I Study With Pharmacodynamic End Points Using a Day 1 and Day 4 Schedule in a 14-Day Cycle J. Clin. Oncol., September 1, 2005; 23(25): 6107 - 6116. [Abstract] [Full Text] [PDF]

				P.-P. Kuang and R. H. Goldstein Regulation of elastin gene transcription by proteasome dysfunction Am J Physiol Cell Physiol, September 1, 2005; 289(3): C766 - C773. [Abstract] [Full Text] [PDF]

				A. A. Adjei and M. Hidalgo Intracellular Signal Transduction Pathway Proteins As Targets for Cancer Therapy J. Clin. Oncol., August 10, 2005; 23(23): 5386 - 5403. [Abstract] [Full Text] [PDF]

				E. W. Newcomb, M. A. Ali, T. Schnee, L. Lan, Y. Lukyanov, M. Fowkes, D. C. Miller, and D. Zagzag Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1{alpha} expression in human glioma cells by a proteasome-independent pathway: Implications for in vivo therapy Neuro-oncol, July 1, 2005; 7(3): 225 - 235. [Abstract] [PDF]

				T. Pekol, J. S. Daniels, J. Labutti, I. Parsons, D. Nix, E. Baronas, F. Hsieh, L.-S. Gan, and G. Miwa HUMAN METABOLISM OF THE PROTEASOME INHIBITOR BORTEZOMIB: IDENTIFICATION OF CIRCULATING METABOLITES Drug Metab. Dispos., June 1, 2005; 33(6): 771 - 777. [Abstract] [Full Text] [PDF]

				F. Pajonk, A. van Ophoven, and W. H. McBride Hyperthermia-Induced Proteasome Inhibition and Loss of Androgen Receptor Expression in Human Prostate Cancer Cells Cancer Res., June 1, 2005; 65(11): 4836 - 4843. [Abstract] [Full Text] [PDF]

				L. M. Lashinger, K. Zhu, S. A. Williams, M. Shrader, C. P.N. Dinney, and D. J. McConkey Bortezomib Abolishes Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Resistance via a p21-Dependent Mechanism in Human Bladder and Prostate Cancer Cells Cancer Res., June 1, 2005; 65(11): 4902 - 4908. [Abstract] [Full Text] [PDF]

				U. Fischer and K. Schulze-Osthoff New Approaches and Therapeutics Targeting Apoptosis in Disease Pharmacol. Rev., June 1, 2005; 57(2): 187 - 215. [Abstract] [Full Text] [PDF]

				T. H. Landowski, C. J. Megli, K. D. Nullmeyer, R. M. Lynch, and R. T. Dorr Mitochondrial-Mediated Disregulation of Ca2+ Is a Critical Determinant of Velcade (PS-341/Bortezomib) Cytotoxicity in Myeloma Cell Lines Cancer Res., May 1, 2005; 65(9): 3828 - 3836. [Abstract] [Full Text] [PDF]

				I. M. Ghobrial, T. E. Witzig, and A. A. Adjei Targeting Apoptosis Pathways in Cancer Therapy CA Cancer J Clin, May 1, 2005; 55(3): 178 - 194. [Abstract] [Full Text] [PDF]

				G. K. Dy, J. P. Thomas, G. Wilding, L. Bruzek, S. Mandrekar, C. Erlichman, D. Alberti, K. Binger, H. C. Pitot, S. R. Alberts, et al. A Phase I and Pharmacologic Trial of Two Schedules of the Proteasome Inhibitor, PS-341 (Bortezomib, Velcade), in Patients with Advanced Cancer Clin. Cancer Res., May 1, 2005; 11(9): 3410 - 3416. [Abstract] [Full Text] [PDF]

				R. Z. Orlowski, P. M. Voorhees, R. A. Garcia, M. D. Hall, F. J. Kudrik, T. Allred, A. R. Johri, P. E. Jones, A. Ivanova, H. W. Van Deventer, et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies Blood, April 15, 2005; 105(8): 3058 - 3065. [Abstract] [Full Text] [PDF]