help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Adams, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Adams, J.
The Oncologist, Vol. 7, No. 1, 9-16, February 2002
© 2002 AlphaMed Press

Development of the Proteasome Inhibitor PS-341

Julian Adams

Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA

Correspondence: Julian Adams, Ph.D., Millennium Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, Massachusetts 02139, USA. Telephone: 617-551-3674; Fax: 617-679-7370; e-mail: jadams{at}mpi.com


   ABSTRACT
Top
 Abstract
Introduction
 The Proteasome and Proteasome...
 Preclinical Studies with PS-341
 Pharmacology of PS-341
 Clinical Studies with PS-341
 Conclusion
 References
 
Over the last decade, the critical role of the proteasome in cell-cycle regulation has become increasingly apparent. The proteasome, a multicatalytic protease present in all eukaryotic cells, is the primary component of the protein degradation pathway of the cell. By degrading regulatory proteins (or their inhibitors), the proteasome serves as a central conduit for many cellular regulatory signals and, thus, is a novel target for therapeutic drugs. PS-341 is a small molecule that is a potent and selective inhibitor of the proteasome. In vitro and mouse xenograft studies of PS-341 have shown antitumor activity in a variety of tumor types, including myeloma, chronic lymphocytic leukemia, prostate cancer, pancreatic cancer, and colon cancer, among others. Although PS-341 rapidly leaves the vascular compartment, a novel pharmacodynamic assay has shown that inhibition of proteasome—the biologic target—is dose dependent and reversible. These studies provided the rationale for a twice-weekly dosing schedule employed in ongoing clinical studies. Phase I trials in a variety of tumor types have shown PS-341 to be well tolerated, and phase II trials in several hematologic malignancies and solid tumor types are now in progress. Efficacy and safety data from the most advanced of these, a phase II multicenter trial in myeloma, will be available in early 2002.

Key Words. Antineoplastic agents • Boronic acids • Enzyme inhibitors (administration and dose) • NF-{kappa}B (antagonists and inhibitors) • Hematologic neoplasms (drug therapy) • Multienzyme complexes (antagonists and inhibitors) • 26S Proteasome • Multiple myeloma


   INTRODUCTION
Top
 Abstract
 Introduction
The Proteasome and Proteasome...
 Preclinical Studies with PS-341
 Pharmacology of PS-341
 Clinical Studies with PS-341
 Conclusion
 References
 
In addition to the recycling of damaged or obsolete proteins, protein degradation is a mechanism for controlling the availability of regulatory proteins in the cell. The 26S proteasome is a primary component of the protein degradation pathway of the cell (over 80% of all cellular proteins are processed by this enzyme), and the proteasome's rapid and irreversible elimination of targeted proteins is key to the activation or repression of many cellular processes, including cell-cycle progression and apoptosis. This fundamental role for the proteasome singles it out as a unique target for anticancer therapy, and PS-341 is the first proteasome inhibitor to enter human trials. In preclinical studies, this potent and specific inhibitor has shown significant antitumor activity as a single agent and in combination with other cytotoxic drugs [1–6]. PS-341 treatment has also proven to be well tolerated in phase I trials at doses that result in significant proteasome inhibition and show preliminary evidence of biologic activity, justifying a large-scale phase II program in a variety of tumor types, both solid and hematologic [7,8]. This review provides a summary of the clinical experience with PS-341, as well as the preclinical rationale that supports the potential of PS-341 as a novel treatment for hematologic and solid tumor malignancies.


   THE PROTEASOME AND PROTEASOME INHIBITION
Top
 Abstract
 Introduction
 The Proteasome and Proteasome...
Preclinical Studies with PS-341
 Pharmacology of PS-341
 Clinical Studies with PS-341
 Conclusion
 References
 
The proteasome is a large, multiprotein particle—present in both the cytoplasm and the nucleus of all eukaryotic cells—composed of two functional components: a 20S core catalytic complex and a 19S regulatory subunit. Proteins that are to be degraded are marked with ubiquitin chains, which bind to a receptor on the 19S complex (Fig. 1Go). Once recognized by the regulatory complex, the ubiquitin chain is removed and the protein denatured in preparation for degradation. The protease activity resides in a channel at the center of the 20S complex, which is formed from four stacked, multiprotein rings. The outer {alpha} subunit rings form a narrow channel that allows only denatured proteins to enter the catalytic chamber formed by the central ß subunit rings [9–11]. Inside the catalytic chamber, proteins are surrounded by six protease-active sites (three on each ß subunit ring). The proteasome protease functions similarly to serine proteases but is unique since it relies on a threonine residue in the active site. Proteins processed by the proteasome are reduced to small polypeptides 3 to 22 residues in length [12].



View larger version (16K):
[in this window]
[in a new window]
  		Figure 1. Ubiquitin-proteasome protein degradation. Prior to degradation, doomed proteins are first marked on specific lysine residues with a polyubiquitin chain. Marking the protein is a three-step process in which ubiquitin is activated by a ubiquitin-activating enzyme (E1), then transferred to a ubiquitin-conjugating enzyme (E2). E3s (the ubiquitin-protein ligases) recognize degradation motifs on specific substrates, and catalyze the transfer of ubiquitin from the E2 to the target. These polyubiquitinated substrates are then recognized and degraded by the 26S proteasome.

 
Proteolysis by the 26S proteasome is a fundamental metabolic process, and complete blockade of the proteasome activity with an inhibitor results in death for cells and organisms. Many laboratories have demonstrated the effects of proteasome inhibition on the stability of various cell-cycle regulatory proteins, especially those that are short lived [1,5,13–15]. Cyclins, cyclin-dependent kinase inhibitors, and tumor suppressors (e.g., cyclin B1, p21Waf1/Cip1, p27, p53) are all substrates for the ubiquitin-proteasome pathway (Table 1Go), and inhibiting their requisite degradation has been clearly implicated in sensitizing cells to apoptosis [16–18]. Camptothecin-bound topoisomerase I cleavable complexes are also substrates for the proteasome [19]; inhibition of the proteasome thus stabilizes these complexes and improves the effectiveness of camptothecin treatment [3].


View this table:
[in this window]
[in a new window]
  		Table 1. Cell cycle–related proteins degraded by the proteasome and their functionsa
 
However, not all cells respond in the same way to proteasome inhibition, and those studying proteasome inhibitors soon discovered that transformed cells are much more sensitive to blockade of the proteasome than are normal cells. Although actively dividing cells are more sensitive to proteasome-induced apoptosis than are nonproliferating cells [20], this effect is not simply a consequence of the high replication rate of malignant cells. When confronted with the disruption in cell cycle–regulator turnover that accompanies proteasome inhibition, checkpoint mechanisms arrest cell division in normal cells and allow division to resume only after proteasome activity has been restored. However, in malignant cells, the genetic changes that accompany transformation disable these protective checkpoint mechanisms. Thus, the pro-apoptotic effect of lactacystin (a proteasome-specific protease inhibitor) was more pronounced in malignant lymphocytes harvested from chronic lymphocytic leukemia (CLL) patients than in their normal counterparts from healthy individuals [21]. While the exact mechanism for this differential susceptibility is not fully understood, proteasome inhibition may reverse some of the changes that permit proliferation and suppress apoptosis in malignant cells. For example, the cyclin-dependent kinase inhibitor p27 is degraded by the proteasome [18], and the decreased protein levels observed in some malignant cells are achieved by upregulation of proteasome-mediated p27 degradation [22]. When simian-virus-40-transformed fibroblasts are treated with a proteasome inhibitor, p27 levels increase substantially and apoptosis ensues [23].

The NF-{kappa}B signaling pathway may also be a critical target for proteasome inhibitors. Transcription by NF-{kappa}B is prevented in quiescent cells through binding of a specific inhibitor protein, I{kappa}B, which sequesters the NF-{kappa}B p50/p65 heterodimer in the cytoplasm [24]. This repression is released in response to cellular stresses (including chemotherapy and radiation; Fig. 2Go), which cause targeted degradation of I{kappa}B: phosphorylation of specific serine residues in the N-terminus of I{kappa}B prompt ubiquitination of internal lysine residues [25–27]; ubiquitinated I{kappa}B is then recognized and degraded by the proteasome, and NF-{kappa}B is released [28–32]. Once the transcription factor is released, it is rapidly translocated to the nucleus where it binds cognate sites in the promoter regions of genes encoding cytokines (e.g., tumor necrosis factor, interleukin-1, interleukin-6), stress response enzymes (COX2, NO, 5-LO), and cell adhesion molecules (intracellular adhesion molecule, vascular cell adhesion molecule, E-selectin) and can increase the expression of anti-apoptotic proteins (inhibitor of apoptosis and the Bcl-2 family) [33–36]. Importantly, NF-{kappa}B also drives its own transcription and the transcription of I{kappa}B, effectively acting as a molecular amplifier that maintains its own transcriptional activity [37]. Dysregulation of NF-{kappa}B signaling is an important feature of some malignancies [38,39], and activation of this pathway can stimulate proliferation and/or reduce the effectiveness of chemotherapy or radiation [40]. These observations of the consequences of NF-{kappa}B activation in tumor cells led several investigators to test the effect of preventing NF-{kappa}B activation in transformed cells, usually through inhibition of I{kappa}B degradation. Cusack et al. [41] used an engineered form of I{kappa}B that is not ubiquitinated (i.e., the serines that are recognized by ubiquitinating enzymes were mutated to alanines) and, therefore, cannot be degraded by the proteasome; this superrepressor maintains inhibition of NF-{kappa}B under circumstances that would otherwise lead to its activation. In colorectal cancer cells transfected with the I{kappa}B superrepressor, apoptosis is induced by SN38 (the active metabolite of CPT-11) to a greater extent than in the untransfected parental cell line. Masdehors et al. demonstrated the potential clinical benefits of NF-{kappa}B repression through treatment with a proteasome inhibitor using lymphocytes isolated from CLL patients at diagnosis [21]. These samples included both radiation-resistant and radiation-sensitive isolates, but when treated with lactacystin, all isolates were equally sensitive.



View larger version (30K):
[in this window]
[in a new window]
  		Figure 2. NF-{kappa}B activation pathway. Viruses, growth factors, antigens, radiation, or chemotherapeutic drugs activate signaling pathways that lead to the degradation of I{kappa}B by the proteasome. Once released from I{kappa}B inhibition, NF-{kappa}B translocates to the nucleus to activate transcription of genes that protect the cell from apoptosis and promote cell growth and differentiation. The synthesis of growth factors, cell-adhesion molecules, angiogenesis factors, and antiapoptotic factors is increased.

 

   PRECLINICAL STUDIES WITH PS-341
Top
 Abstract
 Introduction
 The Proteasome and Proteasome...
 Preclinical Studies with PS-341
Pharmacology of PS-341
 Clinical Studies with PS-341
 Conclusion
 References
 
Initial screening of the National Cancer Institute's (NCI) tumor cell lines revealed that PS-341 is active against a broad range of tumor types [1], prompting further exploration of the activity of PS-341 in cell culture and in murine and human xenograft models. In these models, PS-341 exhibited many of the properties seen in preclinical studies of other proteasome inhibitors such as lactacystin: activity as a single agent, enhancement of apoptosis induced by chemotherapy or radiation, and specificity for transformed cells. In cell culture, PC-3 prostate cancer cells undergo growth arrest and apoptosis when treated with PS-341, and PS-341 reduces the growth of PC-3 tumors on nude mice [1]. Additionally, combination therapy with PS-341 increases the effectiveness of CPT-11 (Fig. 3Go) or radiation in colon tumor xenografts (Fig. 4Go) [42]; and in pancreatic tumor xenografts, significant tumor responses are observed when PS-341 is used in combination with gemcitabine [2] or CPT-11 [5]. In each of these studies, the authors were able to identify changes in the expression of proteasome targets, including p21Waf1/Cip1 [1,3], I{kappa}B [5], and NF-{kappa}B [42]. Finally, the 50% inhibitory concentration (IC50) of myeloma cells isolated from patients was reached at PS-341 concentrations that had no effect on the peripheral blood mononuclear cells from healthy volunteers. Cultured bone marrow stromal cells (BMSCs) were equally unresponsive to PS-341: the IC50 of BMSCs was at least 170 times that of the myeloma cells used in this experiment [4].



View larger version (17K):
[in this window]
[in a new window]
  		Figure 3. PS-341 activity in combination CPT-11. CPT-11 treatment triggers I{kappa}B degradation and activation of NF-{kappa}B transcription, resulting in decreased effectiveness of this compound. Blockade of NF-{kappa}B activation by PS-341 should increase the cytotoxicity of CPT-11. To test this hypothesis, LOVO colon cancer xenografts were grown in the flanks of nude mice; after these tumors were established, the mice were treated twice weekly (indicated by arrows) with PS-341 or saline before administration of CPT-11. Either treatment, when given as a single agent, results in a slight reduction in tumor growth. In contrast, the combination of PS-341 and CPT-11 actually reduces the size of the tumor [3].

 


View larger version (105K):
[in this window]
[in a new window]
  		Figure 4. PS-341 activity in combination with radiation. PS-341 treatment, in combination with radiation, significantly reduces the growth of LOVO colorectal cancer xenografts in nude mice. The mouse on the left received a single saline injection, while the mouse on the right received a single injection of PS-341 (1 mg/kg). Tumors on the right flank (marked with arrows) of each mouse were then irradiated (6 Gy). The combination of PS-341 and radiation resulted in greater antitumor activity than PS-341 or radiation treatment alone [42].

 
Another observation that arose from preclinical studies is the infrequency of resistance to PS-341 and the drug's effectiveness even in the presence of known drug resistance factors [4, and D. McConkey, personal communication]. A systematic check of multidrug resistance transporters revealed that PS-341 is a poor substrate for this class of proteins, and Hideshima et al. recently showed that PS-341 can arrest the growth of multiple myeloma cells that are resistant to conventional therapies [4]. Other mechanisms that result in drug resistance are also insufficient to forestall PS-341-induced apoptosis. PC-3 cells are sensitive to PS-341 even though they do not express p53 [1], and overexpression of Bcl-2 also appears to be incapable of preventing PS-341-induced apoptosis (Fig. 5Go) [D. McConkey, personal communication].



View larger version (14K):
[in this window]
[in a new window]
  		Figure 5. Apoptosis in cells that overexpress Bcl-2. Expression of Bcl-2 reduces the fraction of cells that undergo apoptosis following gemcitabine or paclitaxel treatment (compare MIA-PaCa-2 with MIA-Bcl-2.7). In contrast, PS-341 retains most of its activity even in cells expressing Bcl-2 [D. McConkey, personal communication].

 

   PHARMACOLOGY OF PS-341
Top
 Abstract
 Introduction
 The Proteasome and Proteasome...
 Preclinical Studies with PS-341
 Pharmacology of PS-341
Clinical Studies with PS-341
 Conclusion
 References
 
In initial pharmacokinetic studies, PS-341 was found to rapidly exit the plasma compartment (>90% is cleared within 15 minutes of i.v. administration) [43, and Millennium data on file]. To allow for accurate dosing in phase I trials, a rapid and reliable bioassay has been developed to measure residual proteasome activity following PS-341 treatment [44]; for convenience, proteasome activity can be determined from whole blood or white blood cells, but biopsied tissues can also be used to determine the effect of the drug at the tumor site. Using this assay on samples from healthy volunteers, proteasome activity was found to be similar among study participants, and intrasubject variation was minimal [Millennium data on file]. Furthermore, this assay and whole-body autoradiography of [14C]PS-341–treated rats revealed that most organs received roughly the same amount of drug; the central nervous system, testes, and eyes, however, are protected from PS-341 [1].

The proteasome bioassay facilitated pharmacologic and toxicity studies in animals. In all species studied, baseline proteasome activity was restored within 48 to 72 hours of PS-341 treatment. Toxicology studies conducted in rodents and primates indicated that gastrointestinal side effects (anorexia, emesis, and diarrhea) were the primary adverse events associated with PS-341 treatment. Notably, bone marrow toxicity was not observed in primates [1]. The gastrointestinal toxicity is dose related, and overall, treatment is well tolerated until 80% proteasome inhibition is exceeded. In primates, gastrointestinal toxicity becomes significantly more pronounced, and changes in blood pressure and heart rate occur at proteasome inhibition greater than 80%.

In human studies, the ex vivo proteasome bioassay is an integral part of the phase I and phase II protocols. In Figure 6Go, proteasome activity following PS-341 treatment is plotted. The dose-related inhibitory effect of PS-341 is shown, and the dose that would result in 80% proteasome inhibition (the maximum safe level of inhibition identified in preclinical experiments) can be estimated to be 1.96 mg/m2. Further characterization of the response to PS-341 treatment using the bioassay reveals that proteasome inhibition is dose dependent and varies very little, even among the diverse phase I patient population. Given the consistency of this response, the bioassay will probably be unnecessary outside of the clinical trial setting.



View larger version (15K):
[in this window]
[in a new window]
  		Figure 6. Combined 20S proteasome activity from phase I study centers. Proteasome activity was determined in blood samples taken from study participants 1 hour after PS-341 treatment. A semi-log plot of the data fits to a theoretical binding isotherm, and there is a clear dose-dependent inhibitory effect. Using these data, proteasome inhibition would exceed 80% at doses above 1.96 mg/m2. Abbreviations: MDACC = M. D. Anderson Cancer Center; MSKCC = Memorial Sloan-Kettering Cancer Center; Mayo = Mayo Clinic; NYU = New York University; Wisconsin = University of Wisconsin; UNC = University of North Carolina; DFCI = Dana-Farber Cancer Institute; Cortes (M. D. Anderson Cancer Center).

 

   CLINICAL STUDIES WITH PS-341
Top
 Abstract
 Introduction
 The Proteasome and Proteasome...
 Preclinical Studies with PS-341
 Pharmacology of PS-341
 Clinical Studies with PS-341
Conclusion
 References
 
Six phase I clinical trials for PS-341 in hematologic cancers or solid tumors have been completed or are in progress, and the safety and efficacy of PS-341 treatment for refractory multiple myeloma and refractory CLL is being tested in two ongoing phase II trials. Additional phase II trials are planned for solid tumor indications. The NCI is also sponsoring 19 additional trials through the Cancer Therapy Evaluation Program. The first phase I trial, conducted at M.D. Anderson Cancer Center, used a conservative dosing regimen of once-weekly PS-341 for 4 weeks, followed by a 2-week rest. This study continues to accrue patients, and the maximum tolerated dose has not yet been reached [45]. Additional phase I trials were designed to evaluate twice-weekly PS-341 treatments.

Approximately 200 patients have now been treated in the phase I setting, and PS-341 has been well tolerated. Patients experience low-grade fever and/or fatigue after several cycles of PS-341 at doses above 1.0 mg/m2. Thrombocytopenia is also observed, but this toxicity has not been dose limiting or required supportive transfusions. As predicted from animal studies, some patients develop low-grade diarrhea that can be averted with prophylactic loperamide treatment. In addition, several patients have experienced peripheral neuropathy (PN); however, most of these patients had been treated previously with platinum or taxane regimens. Participants in ongoing trials are being closely monitored to determine whether prior neurotoxic chemotherapy can sensitize patients to PN during PS-341 treatment. Skin rash has also been reported infrequently.

Because phase I trials are not designed to test efficacy, tumor responses in these trials can only be considered anecdotal. Nevertheless, the preclinical data, combined with the tolerability of PS-341 in phase I trials, provide a compelling rationale for further clinical development of PS-341. On the once-weekly treatment regimen, several patients with androgen-independent prostate cancer experienced a decrease in prostate-specific antigen levels [8]. A patient with non-small-cell lung cancer achieved a partial response (>50% reduction in tumor mass) on twice-weekly PS-341 at a dose of 1.56 mg/m2 [7]. At a dose that results in 68% proteasome inhibition, lung metastases in two melanoma patients also responded to a lower dose of PS-341 given on the twice-weekly treatment regimen [46]. Significant activity has also been evident in multiple myeloma, with patients showing significant reductions in myeloma-related immunoglobulins and marrow plasmacytosis [47]; a 7-month remission was achieved in one of these patients after four cycles of therapy.


   CONCLUSION
Top
 Abstract
 Introduction
 The Proteasome and Proteasome...
 Preclinical Studies with PS-341
 Pharmacology of PS-341
 Clinical Studies with PS-341
 Conclusion
References
 
PS-341 represents the first of a potentially promising class of agents. In addition to antitumor effects, proteasome inhibitors may also have applications for diseases caused or exacerbated by inflammation, as the mediators of inflammation are often affected by proteasome-mediated protein degradation. The proteasome, which was largely an unknown enzyme until very recently, is thus proving to be an attractive target for drug development. In addition, the regulatory events upstream of the proteasome—those that control the phosphorylation and ubiquitination of proteasome substrates—are actively being explored as potential drug targets. The utility of drugs whose development is based on the elucidation of these pathways is currently unknown but is potentially far reaching.


   REFERENCES
Top
 Abstract
 Introduction
 The Proteasome and Proteasome...
 Preclinical Studies with PS-341
 Pharmacology of PS-341
 Clinical Studies with PS-341
 Conclusion
 References
 

  1. Adams J, Palombella VJ, Sausville EA et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999;59:2615–2622.[Abstract/Free Full Text]
  2. Bold RJ, Virudachalam S, McConkey DJ. Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res 2001;100:11–17.[CrossRef][Medline]
  3. Cusack JC Jr, Liu R, Houston M et al. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-{kappa}B inhibition. Cancer Res 2001;61:3535–3540.[Abstract/Free Full Text]
  4. 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.[Abstract/Free Full Text]
  5. Shah SA, Potter MW, McDade TP et al. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem 2001;82:110–122.[CrossRef][Medline]
  6. Williams SA, Papandreou C, McConkey D. Preclinical effects of proteasome inhibitor PS-341 in combination chemotherapy for prostate cancer. Proc Am Soc Clin Oncol 2001;20:169b.
  7. Aghajanian C, Soignet S, Dizon DS et al. A phase I trial of the novel proteasome inhibitor PS-341 in advanced solid tumor malignancies. Proc Am Soc Clin Oncol 2001;20:85a.
  8. Logothetis CJ, Yang H, Daliani D et al. Dose dependent inhibition of 20S proteasome results in serum Il-6 and PSA decline in patients (PTS) with androgen-independent prostate cancer (AI PCa) treated with the proteasome inhibitor PS-341. Proc Am Soc Clin Oncol 2001;20:186a.
  9. Groll M, Ditzel L, Lowe J et al. Structure of 20S proteasome from yeast at 2.4 Å resolution. Nature 1997;386:463–471.[CrossRef][Medline]
  10. Lowe J, Stock D, Jap B et al. Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 Å resolution. Science 1995;268:533–539.[Abstract/Free Full Text]
  11. Stock D, Ditzel L, Baumeister W et al. Catalytic mechanism of the 20S proteasome of Thermoplasma acidophilum revealed by X-ray crystallography. Cold Spring Harb Symp Quant Biol 1995;60:525–532.[Abstract/Free Full Text]
  12. Nussbaum AK, Dick TP, Keilholz W et al. Cleavage motifs of the yeast 20S proteasome ß subunits deduced from digests of enolase 1. Proc Natl Acad Sci USA 1998;95:12504–12509.[Abstract/Free Full Text]
  13. An WG, Hwang SG, Trepel JB et al. Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. Leukemia 2000;14:1276–1283.[CrossRef][Medline]
  14. Dietrich C, Bartsch T, Schanz F et al. p53-dependent cell cycle arrest induced by N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal in platelet-derived growth factor-stimulated human fibroblasts. Proc Natl Acad Sci USA 1996;93:10815–10819.[Abstract/Free Full Text]
  15. Wu Y, Luo H, Kanaan N et al. The proteasome controls the expression of a proliferation-associated nuclear antigen Ki-67. J Cell Biochem 2000;76:596–604.[CrossRef][Medline]
  16. Dulic V, Kaufmann WK, Wilson SJ et al. p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell 1994;76:1013–1023.[CrossRef][Medline]
  17. King RW, Deshaies RJ, Peters JM et al. How proteolysis drives the cell cycle. Science 1996;274:1652–1659.[Abstract/Free Full Text]
  18. Pagano M, Tam SW, Theodoras AM et al. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 1995;269:682–685.[Abstract/Free Full Text]
  19. Desai SD, Liu LF, Vazquez-Abad D et al. Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. J Biol Chem 1997;272:24159–24164.[Abstract/Free Full Text]
  20. Drexler HC. Activation of the cell death program by inhibition of proteasome function. Proc Natl Acad Sci USA 1997;94:855–860.[Abstract/Free Full Text]
  21. Masdehors P, Omura S, Merle-Beral H et al. Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Br J Haematol 1999;105:752–757.[CrossRef][Medline]
  22. Chiarle R, Budel LM, Skolnik J et al. Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma. Blood 2000;95:619–626.[Abstract/Free Full Text]
  23. An B, Goldfarb RH, Siman R et al. Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts. Cell Death Differ 1998;5:1062–1075.[CrossRef][Medline]
  24. Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-{kappa}B. J Clin Invest 2001;107:241–246.[CrossRef][Medline]
  25. Scherer DC, Brockman JA, Chen Z et al. Signal-induced degradation of I{kappa}B{alpha} requires site-specific ubiquitination. Proc Natl Acad Sci USA 1995;92:11259–11263.[Abstract/Free Full Text]
  26. Spencer E, Jiang J, Chen ZJ. Signal-induced ubiquitination of I{kappa}B{alpha} by the F-box protein Slimb/ß-TrCP. Genes Dev 1999;13:284–294.[Abstract/Free Full Text]
  27. Winston JT, Strack P, Beer-Romero P et al. The SCFß-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in I{kappa}B{alpha} and ß-catenin and stimulates I{kappa}B{alpha} ubiquitination in vitro. Genes Dev 1999;13:270–283.[Abstract/Free Full Text]
  28. Alkalay I, Yaron A, Hatzubai A et al. Stimulation-dependent I{kappa}B{alpha} phosphorylation marks the NF-{kappa}B inhibitor for degradation via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 1995;92:10599–10603.[Abstract/Free Full Text]
  29. Baldi L, Brown K, Franzoso G et al. Critical role for lysines 21 and 22 in signal-induced, ubiquitin-mediated proteolysis of I{kappa}B{alpha}. J Biol Chem 1996;271:376–379.[Abstract/Free Full Text]
  30. Chen Z, Hagler J, Palombella VJ et al. Signal-induced site-specific phosphorylation targets I{kappa}B{alpha} to the ubiquitin-proteasome pathway. Genes Dev 1995;9:1586–1597.[Abstract/Free Full Text]
  31. Lin YC, Brown K, Siebenlist U. Activation of NF-{kappa}B requires proteolysis of the inhibitor I{kappa}B-{alpha}: signal-induced phosphorylation of I{kappa}B-{alpha} alone does not release active NF-{kappa}B. Proc Natl Acad Sci USA 1995;92:552–556.[Abstract/Free Full Text]
  32. Roff M, Thompson J, Rodriguez MS et al. Role of I{kappa}B{alpha} ubiquitination in signal-induced activation of NF-{kappa}B in vivo. J Biol Chem 1996;271:7844–7850.[Abstract/Free Full Text]
  33. Chen C, Edelstein LC, Gelinas C. The Rel/NF-{kappa}B family directly activates expression of the apoptosis inhibitor Bcl-xL. Mol Cell Biol 2000;20:2687–2695.[Abstract/Free Full Text]
  34. Wang CY, Mayo MW, Korneluk RG et al. NF-{kappa}B antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 1998;281:1680–1683.[Abstract/Free Full Text]
  35. Wang CY, Guttridge DC, Mayo MW et al. NF-{kappa}B induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol Cell Biol 1999;19:5923–5929.[Abstract/Free Full Text]
  36. Zong WX, Edelstein LC, Chen C et al. The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-{kappa}B that blocks TNF{alpha}-induced apoptosis. Genes Dev 1999;13:382–387.[Abstract/Free Full Text]
  37. Brown K, Park S, Kanno T et al. Mutual regulation of the transcriptional activator NF-{kappa}B and its inhibitor, I{kappa}B-{alpha}. Proc Natl Acad Sci USA 1993;90:2532–2536.[Abstract/Free Full Text]
  38. Kordes U, Krappmann D, Heissmeyer V et al. Transcription factor NF-{kappa}B is constitutively activated in acute lymphoblastic leukemia cells. Leukemia 2000;14:399–402.[CrossRef][Medline]
  39. Tricot G. New insights into role of microenvironment in multiple myeloma. Lancet 2000;355:248–250.[CrossRef][Medline]
  40. Patel NM, Nozaki S, Shortle NH et al. Paclitaxel sensitivity of breast cancer cells with constitutively active NF-{kappa}B is enhanced by I{kappa}B{alpha} super-repressor and parthenolide. Oncogene 2000;19:4159–4169.[CrossRef][Medline]
  41. Cusack JC, Liu R, Baldwin AS. NF-{kappa}B and chemoresistance: potentiation of cancer drugs via inhibition of NF-{kappa}B. Drug Resist Updat 1999;2:271–273.[CrossRef][Medline]
  42. Russo SM, Tepper JE, Baldwin AS Jr et al. Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-{kappa}B. Int J Radiat Oncol Biol Phys 2001;50:183–193.[CrossRef][Medline]
  43. Nix D, Pien C, Newman R et al. Clinical development of a proteasome inhibitor, PS-341, for the treatment of cancer. Proc Am Soc Clin Oncol 2001;20:86a.
  44. Lightcap ES, McCormack TA, Pien CS et al. Proteasome inhibition measurements: clinical application. Clin Chem 2000;46:673–683.[Abstract/Free Full Text]
  45. Papandreou C, Daliani D, Millikan RE et al. Phase I study of intravenous (I.V.) proteasome inhibitor PS-341 in patients (pts) with advanced malignancies. Proc Am Soc Clin Oncol 2001;20:86a.
  46. Hamilton AL, Eder J, Pavlick AC et al. PS-341: phase I study of a novel proteasome inhibitor with pharmacodynamic endpoints. Proc Am Soc Clin Oncol 2001;20:85a.
  47. Stinchcombe TE, Mitchell BS, Depcik-Smith N et al. PS-341 is active in multiple myeloma: preliminary report of a phase I trial of the proteasome inhibitor PS-341 in patients with hematologic malignancies. Blood 2000;96:516a.
Received October 5, 2001; accepted for publication November 21, 2001.




This article has been cited by other articles:


Home page
 Molecular Cancer TherapeuticsHome page
A. Marten, N. Zeiss, S. Serba, S. Mehrle, M. von Lilienfeld-Toal, and J. Schmidt
Bortezomib is ineffective in an orthotopic mouse model of pancreatic adenocarcinoma
Mol. Cancer Ther., November 1, 2008; 7(11): 3624 - 3631.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
G. Gao, J. Zhang, X. Si, J. Wong, C. Cheung, B. McManus, and H. Luo
Proteasome inhibition attenuates coxsackievirus-induced myocardial damage in mice
Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H401 - H408.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
W. Bensinger
Stem-Cell Transplantation for Multiple Myeloma in the Era of Novel Drugs
J. Clin. Oncol., January 20, 2008; 26(3): 480 - 492.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
L. Li, C. S. Gondi, D. H. Dinh, W. C. Olivero, M. Gujrati, and J. S. Rao
Transfection with Anti-p65 Intrabody Suppresses Invasion and Angiogenesis in Glioma Cells by Blocking Nuclear Factor-{kappa}B Transcriptional Activity
Clin. Cancer Res., April 1, 2007; 13(7): 2178 - 2190.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. Dreicer, D. Petrylak, D. Agus, I. Webb, and B. Roth
Phase I/II Study of Bortezomib Plus Docetaxel in Patients with Advanced Androgen-Independent Prostate Cancer
Clin. Cancer Res., February 15, 2007; 13(4): 1208 - 1215.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M.-V. Mateos, J.-M. Hernandez, M.-T. Hernandez, N.-C. Gutierrez, L. Palomera, M. Fuertes, J. Diaz-Mediavilla, J.-J. Lahuerta, J. de la Rubia, M.-J. Terol, et al.
Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study
Blood, October 1, 2006; 108(7): 2165 - 2172.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
F. Teraishi, W. Guo, L. Zhang, F. Dong, J. J. Davis, T. Sasazuki, S. Shirasawa, J. Liu, and B. Fang
Activation of Sterile20-Like Kinase 1 in Proteasome Inhibitor Bortezomib-Induced Apoptosis in Oncogenic K-ras-Transformed Cells.
Cancer Res., June 15, 2006; 66(12): 6072 - 6079.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
C Kersting, J Packeisen, B Leidinger, B Brandt, R von Wasielewski, W Winkelmann, P J van Diest, G Gosheger, and H Buerger
Pitfalls in immunohistochemical assessment of EGFR expression in soft tissue sarcomas
J. Clin. Pathol., June 1, 2006; 59(6): 585 - 590.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. A. Sosman and I. Puzanov
Molecular targets in melanoma from angiogenesis to apoptosis.
Clin. Cancer Res., April 1, 2006; 12(7): 2376s - 2383s.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. Dublet, A. Ruello, M. Pederzoli, E. Hajjar, M. Courbebaisse, S. Canteloup, N. Reuter, and V. Witko-Sarsat
Cleavage of p21/WAF1/CIP1 by Proteinase 3 Modulates Differentiation of a Monocytic Cell Line: MOLECULAR ANALYSIS OF THE CLEAVAGE SITE
J. Biol. Chem., August 26, 2005; 280(34): 30242 - 30253.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
Y. Dai, M. Rahmani, X.-Y. Pei, P. Dent, and S. Grant
Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms
Blood, July 15, 2004; 104(2): 509 - 518.
[Abstract] [Full Text] [PDF]

Home page
 J. Thorac. Cardiovasc. Surg.Home page
C. E. Denlinger, M. D. Keller, M. W. Mayo, R. M. Broad, and D. R. Jones
Combined proteasome and histone deacetylase inhibition in non-small cell lung cancer
J. Thorac. Cardiovasc. Surg., April 1, 2004; 127(4): 1078 - 1086.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. Helbig, K. W. Christopherson II, P. Bhat-Nakshatri, S. Kumar, H. Kishimoto, K. D. Miller, H. E. Broxmeyer, and H. Nakshatri
NF-{kappa} B Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor CXCR4
J. Biol. Chem., June 6, 2003; 278(24): 21631 - 21638.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
A. V. Lee, R. Schiff, X. Cui, D. Sachdev, D. Yee, A. P. Gilmore, C. H. Streuli, S. Oesterreich, and D. L. Hadsell
New Mechanisms of Signal Transduction Inhibitor Action: Receptor Tyrosine Kinase Down-Regulation and Blockade of Signal Transactivation
Clin. Cancer Res., January 1, 2003; 9(1): 516S - 523S.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
J. Baselga
Why the Epidermal Growth Factor Receptor? The Rationale for Cancer Therapy
Oncologist, August 15, 2002; 7(90004): 2 - 8.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
M. Ranson
ZD1839 (IressaTM): For More Than Just Non-Small Cell Lung Cancer
Oncologist, August 15, 2002; 7(90004): 16 - 24.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Adams, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Adams, J.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS