This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Orlowski, R. Z. Articles by Kuhn, D. J. Search for Related Content PubMed PubMed Citation Articles by Orlowski, R. Z. Articles by Kuhn, D. J. Related Collections Therapeutics and Targets Therapeutics and Targets: Experimental Therapeutics– Small Molecules Clinical Research: Clinical Trials

Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade

Authors' Affiliations: Departments of ¹ Lymphoma/Myeloma and ² Experimental Therapeutics, Division of Cancer Medicine, University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Robert Z. Orlowski, The University of Texas M. D. Anderson Cancer Center, Department of Lymphoma/Myeloma, 1515 Holcombe Boulevard, Unit 429, Houston, TX 77030. Phone: 713-792-2860; Fax: 713-563-5067; E-mail: rorlowsk{at}mdanderson.org.

Abstract

The ubiquitin-proteasome pathway is involved in intracellular protein turnover, and its function is crucial to cellular homeostasis. First synthesized as probes of proteolytic processes, proteasome inhibitors began to be thought of as potential drug candidates when they were found to induce programmed cell death preferentially in transformed cells. They made their first leap into the clinic to be tested as therapeutic agents 10 years ago, and since then, great strides have been made in defining their mechanisms of action, their clinical efficacy and toxicity, and some of their limitations in the form of resistance pathways. Validation of the ubiquitin-proteasome pathway as a target for cancer therapy has come in the form of approvals of the first such inhibitor, bortezomib, for relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this agent has become a standard of care. Lessons learned from this first-in-class agent are now being applied to the development of a new generation of proteasome inhibitors that hold the promise of efficacy in bortezomib-resistant disease and possibly in a broader spectrum of diseases. This saga provides a salient example of the promise of translational medicine and a paradigm by which other agents may be successfully brought from the bench to the bedside.

View larger version (58K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. The ubiquitin-proteasome pathway. To target proteins for degradation, they must typically be polyubiquitinated (left), a process which begins by activation of ubiquitin (Ub) in an ATP-dependent fashion by an E1 ubiquitin-activating enzyme. The ubiquitin moiety is then transferred to an E2 ubiquitin-conjugating enzyme, preserving the high-energy thiolester bond. An E3 ubiquitin-ligase then often acts as a scaffold in concert with the E2 to promote formation of a polyubiquitin chain after binding of the protein substrate. Polyubiquitin chains are recognized by components of the 19S cap of the 26S proteasome (Fig. 2), ubiquitin is cleaved off and recycled, and the target protein is unwound and fed into the middle of the 20S catalytic chamber, which is shaped like a barrel. Proteases in the 20S particle (Fig. 4) cleave the target into oligopeptides that exit the proteasome and are later digested into amino acidsfor reincorporation into other proteins. In addition to ubiquitin-dependent proteolysis, some proteins may also be subject to ubiquitin-independent turnover (right) without the need for prior ubiquitination. Such proteolysis may occur through either the 26S proteasome or possibly the 20S core particle itself. This figure has been adapted from Voorhees et al. (36) with permission.

View larger version (37K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Proteasome isoforms. The 26S or constitutive proteasome is found in most tissues and consists of a 20S core particle with two 19S cap structures. Each outer ring contains seven nonidentical subunits (green), which are predominantly structural, whereas the two inner rings contain seven nonidentical β subunits (red), some of which encode proteases (Fig. 4). Together, the four rings are stacked one on top of each other around a central chamber where proteolysis occurs. A second proteasome isoform is the immunoproteasome, which is expressed in a more tissue-specific manner and can also be induced by some cytokines, such as -IFN. Immunoproteasomes contain two different regulatory cap structures known as 11S particles at each end. Also, six of the β subunits from the 26S proteasome are replaced by two copies each of three new proteases (purple) that slightly change the substrate preferences and cleavage patterns of the immunoproteasome. These modifications may allow the immunoproteasome to more efficiently generate antigenic peptides for presentation in the context of MHC class I molecules. Studies of the relative contributions of these two isoforms to intracellular proteolysis in cells which contain both isoforms have not been done. Cells may also contain a hybrid proteasome with one 11S and one 19S regulatory particle around a 20S core. This figure has been modified from Voorhees et al. (36) with permission.

View larger version (64K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. Subunit specificities of proteasome inhibitors. A cross-section of one of the constitutive 26S proteasome β rings, which has seven nonidentical subunits. Three major activities have been characterized, including a chymotrypsin-like activity that cleaves after hydrophobic amino acids, a trypsin-like activity that cleaves after basic amino acids, and a post-glutamyl peptide hydrolyzing or caspase-like activity that cleaves after acidic amino acids. In addition, under some conditions, the proteasome can show activities that cleave after branched chain amino acids or small neutral amino acids (3). Together, these activities allow the proteasome to cleave proteins with various primary structures into oligopeptides. Bortezomib binds slowly and reversibly inhibits the chymotrypsin-like activity, and with lower affinity also targets the caspase-like activity. Carfilzomib irreversibly binds and inhibits predominantly the chymotrypsin-like activity, whereas NPI-0052 irreversibly binds and inhibits the chymotrypsin-like activity and, with lower affinity, also targets the trypsin-like activity. In the immunoproteasome, carfilzomib binds the β5i subunit (12), whereas bortezomib binds the β5i and β1i subunits (122), but data about the immunoproteasome specificity of salinosporamide A is not available.

View larger version (51K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Chemical structures of clinically relevant proteasome inhibitors. Structures are presented of the proteasome inhibitors that are currently either approved for clinical use or in clinical trials, including bortezomib (A), carfilzomib (B), and salinosporamide A (C).

The possibility that proteasome inhibitors could be drug candidates was considered after studies showed that they induced apoptosis in leukemic cell lines (18, 19), including chemotherapy-resistant and radiation-resistant chronic lymphocytic leukemia cells (20). This was bolstered by findings that proteasome inhibitors induced apoptosis preferentially in transformed cells (20, 21) and were active against an in vivo non–Hodgkin's lymphoma model (21). One of the early mechanisms of action attributed to proteasome inhibitors was that they repressed nuclear factor-B (NF-B) signaling by stabilizing IB, which binds NF-B and prevents its nuclear translocation (22). Given the role of NF-B in angiogenesis, cell invasion, oncogenesis, proliferation, and suppression of apoptosis, NF-B inhibition was already an attractive approach to cancer therapy. Moreover, NF-B inhibition induced chemosensitization because many chemotherapeutics activated antiapoptotic NF-B functions (23–25). An especially strong rationale for targeting NF-B had been worked out in multiple myeloma (MM). Adhesion of myeloma cells to bone marrow stroma induced NF-B–dependent production of the antiapoptotic and growth factor interleukin-6 (26). Later studies documented the efficacy of proteasome inhibition against preclinical models as a single approach (27) and in chemosensitization and overcoming resistance (27–30) with predominantly synergistic effects when bortezomib was combined with other agents.

Proteasome inhibitors are targeted because they are very potent and selective for the proteasome. Due to their effect on proteolysis of a wide array of cellular proteins, however, they share characteristics with general cytotoxic agents, such as vinflunine, satraplatin, aurora kinase inhibitors, and epothilones, as discussed in the accompanying reviews and overview (31–35). In that light, proteasome inhibitors have a number of important mechanisms of action beyond their effects on NF-B that have been validated preclinically in cell line models (36, 37). By interfering with timely degradation of cyclins and other cell cycle regulatory proteins, proteasome inhibitors induce cell cycle arrest. Through their ability to stabilize proapoptotic proteins, such as p53 and Bax, while reducing levels of some antiapoptotic proteins, such as Bcl-2, they induce a proapoptotic state. Bortezomib-mediated programmed cell death is accompanied by c-Jun-NH₂ terminal kinase induction, generation of reactive oxygen species, transmembrane mitochondrial potential gradient dissipation, release of proapoptotic mitochondrial proteins, such as cytochrome c, and activation of intrinsic, caspase-9–mediated and extrinsic, caspase-8–mediated apoptosis. Other mechanisms include induction of aggresome formation, endoplasmic reticulum stress, and the unfolded protein response (38–41), with the latter possibly having special relevance for MM cells given their large basal load of immunoglobulin protein substrates. Readers interested in more detailed coverage of the mechanisms of action of proteasome inhibitors are referred to several excellent reviews (42, 43).

Interestingly, the pleiotropic effects of proteasome inhibitors also result in activation of antiapoptotic pathways that may suppress antitumor activity and could be targets for chemosensitization to bortezomib. Heat shock response proteins have been some of the best characterized, including HSP-27 (44), HSP-70 (45, 46), and HSP-90 (47). Other examples include stress response proteins like mitogen-activated protein kinase phosphatase-1 (48–50) and protein kinase B/Akt (51).

Proteasome Inhibitors in the Clinic as Single Agents

Building on this solid preclinical rationale, a number of phase I studies have documented that bortezomib can be safely given on a variety of schedules (52–57). Early indications of activity were seen in non–small cell lung (52) and androgen-independent prostate carcinoma (54), as well as MM and mantle cell and follicular non–Hodgkin's lymphoma (53). The most dramatic findings were in myeloma, in which among nine patients all showed some clinical benefit, including one durable complete remission. Pharmacodynamic studies showed a dose-dependent 20S proteasome inhibition in peripheral blood mononuclear cells and in limited studies of tumor tissue. However, a correlation between peripheral blood mononuclear cell proteasome inhibition and response could not be established in these small trials, which were not designed with the sample size necessary for such an analysis. Pharmacokinetic studies showed rapid bortezomib plasma clearance and tissue distribution, with an initial t_1/2 of 0.22 to 0.46 hours followed by a more gradual terminal elimination half-life, with t_1/2β of >10 hours and a large volume of distribution of >500 L. Activity against MM was confirmed with a phase II trial (58) that showed a 27% overall response rate (partial response + complete remission) in heavily pretreated patients, who received what has become the most common dose and schedule, 1.3 mg/m² as an i.v. bolus on days 1, 4, 8, and 11 of every 21-day cycle. Further follow-up (59) determined that the median duration of response was 12.7 months, the median time to progression was 7 months, and the median overall survival was 17.0 months. A subsequent phase III randomized trial (60, 61) comparing dexamethasone with bortezomib showed that the latter induced a better overall response rate (43% for bortezomib versus 18% for dexamethasone), a better response quality, as well as a longer median time to progression (6.22 months versus 3.49 months, respectively) and overall survival (29.3 months versus 23.7 months, respectively). Together, these studies led to the approval of bortezomib for relapsed/refractory myeloma in patients who have progressed after at least one prior regimen.

In non–Hodgkin's lymphoma, several phase II studies (62–64) confirmed activity in follicular, mantle cell, and marginal zone lymphoma. Most recently, a multicenter pivotal trial (65) determined that the overall response rate in relapsed mantle cell lymphoma was 33%, including 8% complete remission/unconfirmed complete remission, with a median duration of response of 9.2 months and time to progression of 6.2 months, leading to approval of bortezomib for this indication. Activity has also been described in other B-cell processes, including Waldenström's macroglobulinemia (66–69) and amyloidosis (70).

When bortezomib was being developed as a drug candidate, there was great concern that, because of the proteasome's vital role in cellular homeostasis, it could not be inhibited without dire consequences. Fortunately, an acceptable therapeutic index has been documented, but patients do face the risk of some toxicities. During phase I studies, dose-limiting toxicities included diarrhea, fatigue, fluid retention, hypokalemia, hyponatremia, hypotension, malaise, nausea, orthostasis, sensory neuropathy, and thrombocytopenia. In the phase II trial of MM patients, adverse events reported in at least 10% included anemia, anorexia, constipation, dehydration, diarrhea, dizziness, fatigue, headache, limb pain, nausea, neutropenia, peripheral neuropathy, pyrexia, rash, thrombocytopenia, vomiting, and weakness. Subsequent studies have better characterized thrombocytopenia (71) and neuropathy (72), which probably must limit dosing in the clinic. These have elucidated some of the risk factors involved in these transient, reversible effects, but a better understanding of the underlying mechanisms would be of benefit, as would the identification of biomarkers to predict efficacy or toxicity.

Proteasome Inhibition as a Means to Overcome Resistance and Induce Chemosensitization

Proteasome inhibition is a rational therapeutic approach both by itself and as a means to induce chemosensitization and overcome chemoresistance. As noted earlier, many cytotoxic agents activate the antiapoptotic NF-B pathway, and blockade of this induction by proteasome inhibition enhanced their antitumor efficacy (28, 73). In addition, several strategies by which tumor cells survive the effects of chemotherapy can be similarly abrogated. Overexpression of Bcl-2 is one such mechanism, but proteasome inhibitors induce Bcl-2 phosphorylation and cleavage into proapoptotic fragments (74). Selection of cells overexpressing P-glycoprotein is another, but because proteasome function is needed for P-glycoprotein maturation when the proteasome is inhibited, inactive P-glycoprotein isoforms accumulate that cannot remove chemotherapeutic agents from cancer cells (75, 76).

Using these rationales, bortezomib has been combined with a variety of chemotherapeutics, including carboplatin (77), docetaxel (78), irinotecan (79), melphalan (80), pegylated liposomal doxorubicin (81), and thalidomide (82), among others. Bortezomib has also been incorporated into more complex regimens, such as paclitaxel and carboplatin (83) and gemcitabine and cisplatin (84). From these studies, it seems possible to conclude that bortezomib has generally been successfully combined with other agents without significantly increased toxicity, and without the need for large dose adjustments. In several cases, these combinations have shown evidence of enhanced activity, most notably with the bortezomib/pegylated liposomal doxorubicin regimen, in which myeloma patients showed a 73% overall response rate (81) and an excellent response duration and overall survival (85). These findings led to a randomized trial comparing bortezomib with bortezomib/pegylated liposomal doxorubicin in relapsed and/or refractory myeloma (86), which found the combination induced a superior time to progression compared with bortezomib (9.3 months versus 6.5 months, respectively). Also, combination therapy improved the duration of response (10.2 months versus 7.0 months, respectively) and progression-free survival (9.0 months versus 6.5 months, respectively) and showed a trend for a superior overall survival. As a result, the bortezomib/pegylated liposomal doxorubicin combination has been approved for bortezomib-naive patients who have received at least one prior regimen and is recommended by the National Comprehensive Cancer Network (87). A number of other combinations are being currently compared with single-agent bortezomib, and it seems likely that several will outperform bortezomib.

Further development of bortezomib in MM is now focusing on its incorporation into therapy of previously untreated patients. Encouraging results have been seen using bortezomib with dexamethasone (88, 89), and early results of an ongoing randomized study comparing this with infusional vincristine, doxorubicin, and dexamethasone suggest the former is superior (90). Another induction regimen combining bortezomib with melphalan and prednisone (MP; ref. 91) showed an impressive overall response rate and durability, even in patients with high-risk cytogenetics. This led to an international randomized study of MP versus bortezomib/MP, which showed a superior overall response rate (82% for bortezomib/MP versus 50% for MP) and a better response quality (35% immunofixation-negative complete remission with bortezomib/MP versus 5% for MP). Most notably, time to progression was improved from 16.6 to 24.0 months by addition of bortezomib to MP, as was overall survival at 2 years, which improved from 69% for MP to 82.6% with bortezomib/MP (92). As a result, it is likely that bortezomib/MP will become one of the standards of care for initial therapy of older patients with myeloma, as well as patients who may not be transplant candidates. Other attractive regimens include bortezomib with thalidomide and dexamethasone (93) and bortezomib with combination chemotherapy (94). Toxicities in the up-front setting have been comparable with those seen in relapsed/refractory patients, and stem cell mobilizations have been possible without significant compromise in stem cell yields.

Resistance to Proteasome Inhibitors

Bortezomib has documented activity in a number of hematologic malignancies, but despite encouraging preclinical data, studies in solid tumors have yielded disappointing results. This contrast is as yet unexplained, but a number of hypotheses can be advanced to account for the resistance of solid tumors. Most of the preclinical modeling of proteasome inhibitor–based regimens used chemotherapy-naive tumor cells or xenografts. Subsequent trials targeted chemotherapy-exposed populations, including some patients who had already received the chemotherapeutic with which bortezomib was then paired. A more fruitful approach may be to randomize chemotherapy-naive patients to an active drug or the same agent with a proteasome inhibitor. Another issue of trial design may revolve around the appropriate sequencing of bortezomib vis-à-vis the other agent(s) with which it is paired. One recent preclinical study showed that synergy between bortezomib and cytarabine was sequence-dependent (95), whereas another found that bortezomib given before docetaxel inhibited the latter's activity in a p21-dependent fashion (96), possibly because cells were arrested at G₁-S before the point at which docetaxel was maximally active. Because such considerations were not factored into the design of earlier trials, it is possible that dosing schedules prepared with such findings in mind could result in enhanced efficacy.

From a molecular perspective, it is interesting to note that mantle cell (97) and a substantial proportion of myelomas (98) are driven by overexpression of cyclin D isoforms. Because proteasome inhibitors induce p21 and p27 accumulation, which blocks the cell cycle distal to the effects of cyclin D, it may be that bortezomib works best against cyclin D–driven tumors. Whereas a fraction of some solid tumors are cyclin D–dependent, such as breast cancer (99), no clinical trials have specifically targeted patients with these molecular lesions (100). Indeed, there is preclinical evidence that bortezomib may be more active against cyclin D1–expressing breast cancer models (101). Also of interest are recent findings that activation of the noncanonical NF-B pathway (102, 103) predicted for the highest response rate to bortezomib in myeloma, providing clinical validation of the importance of NF-B in the mechanism of action of bortezomib. In that the activation status of this pathway in solid tumor patients has not been as well studied, enriching for this population could also be of benefit. Indeed, some solid tumor models have been described in which bortezomib may paradoxically activate NF-B (104), possibly abrogating one of its major mechanisms of action. Finally, proteasome activity may itself be a determinant of resistance to bortezomib and related agents. Interestingly, chronic lymphocytic leukemia cells have been found to have increased proteasome chymotrypsin-like activity (105), as is the case in a number of tumor types, and this was felt to underlie their sensitivity to proteasome inhibitors. Contrary to this hypothesis, however, chronic lymphocytic leukemia patients did not benefit from bortezomib (106), and recent studies in resistant cell lines showed that they have increased proteasome activity (107), suggesting that tumor types with compromised ubiquitin-proteasome pathway function may be most sensitive. Thus, it may be that with appropriate selection of patients with disease whose molecular determinants predict for responsiveness to bortezomib, more positive findings in solid tumor populations may be obtained.

In addition to primary resistance, secondary or acquired resistance is also emerging as an area of interest. Individual patients can achieve excellent responses on retreatment with bortezomib (108), but in larger studies its ability to reinduce a response in patients with previously sensitive disease is 31% to 60% (109, 110), with the higher rate reflecting the addition of other agents. Acquired resistance to peptide-aldehyde proteasome inhibitors has been ascribed to efflux through P-glycoprotein (111) and metabolism by an aldo-keto reductase (112). The former may have some applicability to bortezomib as P-glycoprotein blockade enhanced bortezomib sensitivity in models of leukemia (113) and Ewing's sarcoma (114). Another approach to overcome acquired resistance may be to block 3-hydroxy-3-methyl-glutaryl-CoA reductase (115), although the mechanism involved has not been defined. Further studies will be needed with in vitro preclinical models of bortezomib resistance, ideally validated with clinical samples from patients with acquired resistance, to better delineate the relevant mechanisms in vivo and test targeted approaches to abrogate these pathways.

Next Generation Proteasome Inhibitors

With the validation of the proteasome as a target for cancer therapy, interest has focused on the possibility that other inhibitors could offer some advantages. Two second-generation agents have entered phase I trials: NPI-0052 (salinosporamide A) and carfilzomib (formerly PR-171). Unlike bortezomib, which binds the proteasome in a slowly reversible manner, NPI-0052 and carfilzomib bind irreversibly, abrogating one mechanism of recovery from proteasome inhibition, namely release of the target by the drug. They both induce depolarization of the transmitochondrial membrane potential (Fig. 5 ) and activate caspase-8–mediated apoptosis, whereas carfilzomib also activates caspase-9. Preclinical studies have shown that both (12, 17) at least partially overcome bortezomib resistance in vitro. Moreover, in a number of models, including MM (12, 17) and chronic lymphocytic leukemia (116), these inhibitors have shown enhanced potency compared with bortezomib, suggesting they may have a broader spectrum of activity. Early results from phase I studies of carfilzomib indicate that it is well tolerated, even on a dose-intense schedule, and may have less neurotoxicity than bortezomib (117, 118). Evidence of antitumor activity is being seen in MM and Waldenström's macroglobulinemia, including in myeloma patients with previously bortezomib-refractory disease, and phase II studies are planned. Another interesting target may be the immunoproteasome (119), whose expression may be more tissue-restricted than the constitutive proteasome. All of the currently available inhibitors target both the constitutive and immunoproteasome isoforms, but the identification of specific immunoproteasome inhibitors (120, 121) may allow for further improvements in the therapeutic index of these drugs. In that the immunoproteasome is expressed predominantly in hematopoietic tissues, it is possible that such agents could act without incurring neurotoxicity or gastrointestinal effects, among others, because those tissues express much lower levels of immunoproteasome subunits.

View larger version (28K): [in this window] [in a new window] [Download PPT slide]   Fig. 5. Mitochondrial membrane depolarization due to carfilzomib. RPMI 8226 myeloma cells were treated with vehicle (DMSO) or carfilzomib and then stained with the cationic dye JC-1 (123). In cells with intact mitochondria, JC-1 accumulates inside the mitochondria as aggregates and exhibits a fluorescence emission shift from red (600 nm) to green (525 nm). Mitochondrial depolarization causes a collapse of the mitochondrial membrane, allowing JC-1 to diffuse throughout the cell and exhibit a green fluorescence emission. Thus, viable cells will have mitochondria that fluoresce both red and green, whereas dying or dead cells will have a higher red/green ratio. Vehicle-treated RPMI 8226 (top) show dual fluorescence, whereas carfilzomib-treated cells show loss of red fluorescence indicative of mitochondrial depolarization.

The first clinical trials evaluating the therapeutic potential of proteasome inhibition began not quite 10 years ago, and since then, remarkable progress has been made. Bortezomib, the first such inhibitor in the clinic, has been approved for relapsed/refractory myeloma and mantle cell lymphoma. Trials evaluating bortezomib-based combination therapies have supported the possibility that proteasome inhibitors can induce chemosensitization and overcome chemoresistance. Indeed, the first bortezomib-based regimen has just been approved for clinical use against myeloma, and other such combinations are likely to achieve a similar status. Studies of bortezomib's activity in the up-front setting are showing encouraging results, and it is likely that bortezomib-based therapies will gain additional approvals in these and a number of other indications. In that preclinical studies identified non–Hodgkin's lymphoma and MM as being particularly susceptible to proteasome inhibitor–based therapies, the validation of the ubiquitin-proteasome pathway as a target clinically represents a triumph of translational medicine. Additional studies are needed, however, to better understand the mechanisms of proteasome inhibitor–mediated toxicities, such as peripheral neuropathy, as well as mechanisms of primary and secondary resistance, for this agent to gain wider applicability. A new generation of proteasome inhibitors are now entering the clinic and may initially represent an effective option for patients who are bortezomib intolerant or whose disease is bortezomib refractory. It seems clear at this time that proteasome inhibitors will be part of our current and future armamentarium against a number of diseases and that we are only beginning to appreciate the full therapeutic potential of targeting this pathway.

Footnotes

Grant support: Leukemia and Lymphoma Society grant 6096-07, National Cancer Institute grant RO1 CA102278, and Multiple Myeloma Research Foundation (R.Z. Orlowski). R.Z. Orlowski is a Leukemia and Lymphoma Society Mansbach Foundation Scholar in Clinical Research.

Conflict of Interest and Financial Disclosure Statement: R.Z. Orlowski serves on advisory boards for Millennium Pharmaceuticals, Inc. and Proteolix, Inc.

Received 10/ 3/07; revised 12/13/07; accepted 12/27/07.

References

1. Ciechanover A. Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Cell Death Differ 2005;12:1178–90.[CrossRef][Medline]
2. Demartino GN, Gillette TG. Proteasomes: machines for all reasons. Cell 2007;129:659–62.[CrossRef][Medline]
3. Orlowski M, Wilk S. Catalytic activities of the 20 S proteasome, a multicatalytic proteinase complex. Arch Biochem Biophys 2000;383:1–16.[CrossRef][Medline]
4. Touitou R, Richardson J, Bose S, et al. A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 -subunit of the 20S proteasome. EMBO J 2001;20:2367–75.[CrossRef][Medline]
5. Li X, Amazit L, Long W, et al. Ubiquitin- and ATP-independent proteolytic turnover of p21 by the REG-proteasome pathway. Mol Cell 2007;26:831–42.[CrossRef][Medline]
6. Tambyrajah WS, Bowler LD, Medina-Palazon C, Sinclair AJ. Cell cycle-dependent caspase-like activity that cleaves p27(KIP1) is the β(1) subunit of the 20S proteasome. Arch Biochem Biophys 2007;466:186–93.[CrossRef][Medline]
7. Vinitsky A, Michaud C, Powers JC, Orlowski M. Inhibition of the chymotrypsin-like activity of the pituitary multicatalytic proteinase complex. Biochemistry 1992;31:9421–8.[CrossRef][Medline]
8. Vinitsky A, Cardozo C, Sepp-Lorenzino L, Michaud C, Orlowski M. Inhibition of the proteolytic activity of the multicatalytic proteinase complex (proteasome) by substrate-related peptidyl aldehydes. J Biol Chem 1994;269:29860–6.[Abstract/Free Full Text]
9. Adams J, Behnke M, Chen S, et al. Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg Med Chem Lett 1998;8:333–8.[CrossRef][Medline]
10. Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999;59:2615–22.[Abstract/Free Full Text]
11. Sin N, Kim KB, Elofsson M, et al. Total synthesis of the potent proteasome inhibitor epoxomicin: a useful tool for understanding proteasome biology. Bioorg Med Chem Lett 1999;9:2283–8.[CrossRef][Medline]
12. Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against pre-clinical models of multiple myeloma. Blood 2007;110:3281–90.[Abstract/Free Full Text]
13. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 2007;67:6383–91.[Abstract/Free Full Text]
14. Stapnes C, Doskeland AP, Hatfield K, et al. The proteasome inhibitors bortezomib and PR-171 have antiproliferative and proapoptotic effects on primary human acute myeloid leukaemia cells. Br J Haematol 2007;136:814–28.[CrossRef][Medline]
15. Fenteany G, Schreiber SL. Lactacystin, proteasome function, and cell fate. J Biol Chem 1998;273:8545–8.[Free Full Text]
16. Feling RH, Buchanan GO, Mincer TJ, et al. Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed Engl 2003;42:355–7.[CrossRef]
17. Chauhan D, Catley L, Li G, et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 2005;8:407–19.[CrossRef][Medline]
18. Imajoh-Ohmi KT, Sugiyama S, Tanaka K, Omura S, Kikuchi H. Lactacystin, a specific inhibitor of the proteasome, induces apoptosis in human monoblast U937 cells. Biochem Biophys Res Commun 1995;217:1070–7.[CrossRef][Medline]
19. Shinohara K, Tomioka M, Nakano H, et al. Apoptosis induction resulting from proteasome inhibition. Biochem J 1996;317:385–8.[Medline]
20. Delic J, Masdehors P, Omura S, et al. The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF--initiated apoptosis. Br J Cancer 1998;77:1103–7.[Medline]
21. Orlowski RZ, Eswara JR, Lafond-Walker A, et al. Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor. Cancer Res 1998;58:4342–8.[Abstract/Free Full Text]
22. Orlowski RZ, Baldwin AS. NF-B as a therapeutic target in cancer. Trends Mol Med 2002;8:385–9.[CrossRef][Medline]
23. Wang CY, Mayo MW, Baldwin AS, Jr. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-B. Science 1996;274:784–7.[Abstract/Free Full Text]
24. Wang CY, Cusack JC, Jr., Liu R, Baldwin AS, Jr. Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-B. Nat Med 1999;5:412–7.[CrossRef][Medline]
25. Cusack JC, Jr., Liu R, Houston M, et al. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-B inhibition. Cancer Res 2001;61:3535–40.[Abstract/Free Full Text]
26. Chauhan D, Uchiyama H, Akbarali Y, et al. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-B. Blood 1996;87:1104–12.[Abstract/Free Full Text]
27. 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;61:3071–6.[Abstract/Free Full Text]
28. Ma MH, Yang HH, Parker K, et al. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 2003;9:1136–44.[Abstract/Free Full Text]
29. Hideshima T, Chauhan D, Richardson P, et al. NF-B as a therapeutic target in multiple myeloma. J Biol Chem 2002;277:16639–47.[Abstract/Free Full Text]
30. Mitsiades N, Mitsiades CS, Poulaki V, et al. Biologic sequelae of nuclear factor-B blockade in multiple myeloma: therapeutic applications. Blood 2002;99:4079–86.[Abstract/Free Full Text]
31. Bennouna J, Delord JP, Campone M, Pinel M-C. Vinflunine: a new microtubule inhibitor agent. Clin Cancer Res 2008;14:1610–17.[Abstract/Free Full Text]
32. Choy H, Park C, Yao M. Current status and future prospect for satraplatin: an oral platinum analogue. Clin Cancer Res 2008;14:1618–23.[Abstract/Free Full Text]
33. Gautschi O, Heighway J, Mack PC, et al. Aurora kinases as anticancer drug targets.Clin Cancer Res 2008;14:1624–33.
34. Lee JL, Swain SM. The epothilones: translating from the laboratory to the clinic. Clin Cancer Res 2008;14:1643–9.
35. Teicher BA. Newer cytotoxic agents: attacking cancer broadly. Clin Cancer Res 2008;14:1650–7.
36. Voorhees PM, Dees EC, O'Neil B, Orlowski RZ. The proteasome as a target for cancer therapy. Clin Cancer Res 2003;9:6316–25.[Abstract/Free Full Text]
37. Rajkumar SV, Richardson PG, Hideshima T, Anderson KC. Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 2005;23:630–9.[Abstract/Free Full Text]
38. Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A 2005;102:8567–72.[Abstract/Free Full Text]
39. Nawrocki ST, Carew JS, Pino MS, et al. Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis. Cancer Res 2005;65:11658–66.[Abstract/Free Full Text]
40. Nawrocki ST, Carew JS, Dunner K, Jr., et al. Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res 2005;65:11510–9.[Abstract/Free Full Text]
41. Obeng EA, Carlson LM, Gutman DM, et al. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006;107:4907–16.[Abstract/Free Full Text]
42. Richardson PG, Mitsiades C, Hideshima T, Anderson KC. Bortezomib: proteasome inhibition as an effective anticancer therapy. Annu Rev Med 2006;57:33–47.[CrossRef][Medline]
43. Nencioni A, Grunebach F, Patrone F, Ballestrero A, Brossart P. Proteasome inhibitors: antitumor effects and beyond. Leukemia 2007;21:30–6.[CrossRef][Medline]
44. Hideshima T, Podar K, Chauhan D, et al. p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene 2004;23:8766–76.[CrossRef][Medline]
45. Robertson JD, Datta K, Biswal SS, Kehrer JP. Heat-shock protein 70 antisense oligomers enhance proteasome inhibitor-induced apoptosis. Biochem J 1999;344:477–85.[CrossRef][Medline]
46. Voorhees PM, Chen Q, Kuhn DJ, et al. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in pre-clinical models of multiple myeloma. Clin Cancer Res 2007;13:6469–78.[Abstract/Free Full Text]
47. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood 2006;107:1092–100.[Abstract/Free Full Text]
48. Orlowski RZ, Small GW, Shi YY. Evidence that inhibition of p44/42 mitogen-activated protein kinase signaling is a factor in proteasome inhibitor-mediated apoptosis. J Biol Chem 2002;277:27864–71.[Abstract/Free Full Text]
49. Small GW, Shi YY, Edmund NA, et al. Evidence that mitogen-activated protein kinase phosphatase-1 induction by proteasome inhibitors plays an antiapoptotic role. Mol Pharmacol 2004;66:1478–90.[Abstract/Free Full Text]
50. Shi YY, Small GW, Orlowski RZ. Proteasome inhibitors induce a p38 mitogen-activated protein kinase (MAPK)-dependent anti-apoptotic program involving MAPK phosphatase-1 and Akt in models of breast cancer. Breast Cancer Res Treat 2006;100:33–47.[CrossRef][Medline]
51. Hideshima T, Catley L, Yasui H, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 2006;107:4053–62.[Abstract/Free Full Text]
52. Aghajanian C, Soignet S, Dizon DS, et al. A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 2002;8:2505–11.[Abstract/Free Full Text]
53. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 2002;20:4420–7.[Abstract/Free Full Text]
54. Papandreou CN, Daliani DD, Nix D, et al. Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 2004;22:2108–21.[Abstract/Free Full Text]
55. Cortes J, Thomas D, Koller C, et al. Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res 2004;10:3371–6.[Abstract/Free Full Text]
56. Blaney SM, Bernstein M, Neville K, et al. Phase I study of the proteasome inhibitor bortezomib in pediatric patients with refractory solid tumors: a Children's Oncology Group study (ADVL0015). J Clin Oncol 2004;22:4804–9.[Abstract/Free Full Text]
57. Dy GK, Thomas JP, Wilding G, 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 2005;11:3410–6.[Abstract/Free Full Text]
58. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003;348:2609–17.[Abstract/Free Full Text]
59. Richardson PG, Barlogie B, Berenson J, et al. Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial. Cancer 2006;106:1316–9.[CrossRef][Medline]
60. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487–98.[Abstract/Free Full Text]
61. Richardson PG, 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;110:3557–60.[Abstract/Free Full Text]
62. O'Connor OA, Wright J, Moskowitz C, et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non–Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol 2005;23:676–84.[Abstract/Free Full Text]
63. Goy A, Younes A, McLaughlin P, et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol 2005;23:667–75.[Abstract/Free Full Text]
64. Belch A, Kouroukis CT, Crump M, et al. A phase II study of bortezomib in mantle cell lymphoma: the National Cancer Institute of Canada Clinical Trials Group trial IND.150. Ann Oncol 2007;18:116–21.[Abstract/Free Full Text]
65. Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006;24:4867–74.[Abstract/Free Full Text]
66. Treon SP, Hunter ZR, Matous J, et al. Multicenter clinical trial of bortezomib in relapsed/refractory Waldenstrom's macroglobulinemia: results of WMCTG Trial 03-248. Clin Cancer Res 2007;13:3320–5.[Abstract/Free Full Text]
67. Chen CI, Kouroukis CT, White D, et al. Bortezomib is active in patients with untreated or relapsed Waldenstrom's macroglobulinemia: a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1570–5.[Abstract/Free Full Text]
68. Strauss SJ, Maharaj L, Hoare S, et al. Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor response with clinical activity. J Clin Oncol 2006;24:2105–12.[Abstract/Free Full Text]
69. Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, et al. Treatment of relapsed or refractory Waldenstrom's macroglobulinemia with bortezomib. Haematologica 2005;90:1655–8.[Abstract/Free Full Text]
70. Wechalekar A, Gillmore J, Lachmann H, Offer M, Hawkins P. Efficacy and safety of bortezomib in systemic AL amyloidosis-a preliminary report [abstract 129]. Blood 2006;108:42a.
71. Lonial S, Waller EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 2005;106:3777–84.[Abstract/Free Full Text]
72. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 2006;24:3113–20.[Abstract/Free Full Text]
73. Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003;101:2377–80.[Abstract/Free Full Text]
74. Ling YH, Liebes L, Ng B, et al. PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther 2002;1:841–9.[Abstract/Free Full Text]
75. Loo TW, Clarke DM. Superfolding of the partially unfolded core-glycosylated intermediate of human P-glycoprotein into the mature enzyme is promoted by substrate-induced transmembrane domain interactions. J Biol Chem 1998;273:14671–4.[Abstract/Free Full Text]
76. Loo TW, Clarke DM. The human multidrug resistance P-glycoprotein is inactive when its maturation is inhibited: potential for a role in cancer chemotherapy. FASEB J 1999;7:1724–32.
77. Aghajanian C, Dizon DS, Sabbatini P, et al. Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer. J Clin Oncol 2005;23:5943–9.[Abstract/Free Full Text]
78. Messersmith WA, Baker SD, Lassiter L, et al. Phase I trial of bortezomib in combination with docetaxel in patients with advanced solid tumors. Clin Cancer Res 2006;12:1270–5.[Abstract/Free Full Text]
79. Ryan DP, O'Neil BH, Supko JG, et al. A phase I study of bortezomib plus irinotecan in patients with advanced solid tumors. Cancer 2006;107:2688–97.[CrossRef][Medline]
80. Berenson JR, Yang HH, Sadler K, et al. Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. J Clin Oncol 2006;24:937–44.[Abstract/Free Full Text]
81. Orlowski RZ, Voorhees PM, Garcia RA, et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 2005;105:3058–65.[Abstract/Free Full Text]
82. Barlogie B, Shaughnessy JD, Tricot G, et al. Treatment of multiple myeloma. Blood 2004;103:20–32.[Abstract/Free Full Text]
83. Ma C, Mandrekar SJ, Alberts SR, et al. A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies. Cancer Chemother Pharmacol 2007;59:207–15.[CrossRef][Medline]
84. Voortman J, Smit EF, Honeywell R, et al. A parallel dose-escalation study of weekly and twice-weekly bortezomib in combination with gemcitabine and cisplatin in the first-line treatment of patients with advanced solid tumors. Clin Cancer Res 2007;13:3642–51.[Abstract/Free Full Text]
85. Biehn SE, Moore DT, Voorhees PM, et al. Extended follow-up of outcome measures in multiple myeloma patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin. Ann Hematol 2007;86:211–6.[CrossRef][Medline]
86. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 2007;25:3892–901.[Abstract/Free Full Text]
87. Anderson KC, Alsina M, Bensinger W, et al. Multiple myeloma. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2007;5:118–47.[Medline]
88. Jagannath S, Durie BG, Wolf J, et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 2005;129:776–83.[CrossRef][Medline]
89. Harousseau JL, Attal M, Leleu X, et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica 2006;91:1498–505.[Abstract/Free Full Text]
90. Harousseau JL, Marit G, Caillot D, et al. VELCADE/dexamethasone versus VAD as induction treatment prior to autologous stem cell transplantation in newly diagnosed multiple myeloma: an interim analysis of the IFM 2005-01 randomized multicenter phase III trial [abstract 56]. Blood 2006;108:21a.
91. Mateos MV, Hernandez JM, Hernandez MT, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase I/II study. Blood 2006;108:2165–72.[Abstract/Free Full Text]
92. San Miguel JF, Schlag R, Khuageva N, et al. MMY-3002: a phase 3 study comparing bortezomib-melphalan-prednisone (VMP) with melphalan-prednisone (MP) in newly diagnosed multiple myeloma [abstract 76]. Blood 2007;110:31a.
93. Wang M, Giralt S, Delasalle K, Handy B, Alexanian R. Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma. Hematology 2007;12:235–9.[CrossRef][Medline]
94. Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol 2007;138:176–85.[CrossRef][Medline]
95. Weigert O, Pastore A, Rieken M, et al. Sequence-dependent synergy of the proteasome inhibitor bortezomib and cytarabine in mantle cell lymphoma. Leukemia 2007;21:524–8.[CrossRef][Medline]
96. Canfield SE, Zhu K, Williams SA, McConkey DJ. Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells. Mol Cancer Ther 2006;5:2043–50.[Abstract/Free Full Text]
97. Ruan J, Leonard JP. Mantle cell lymphoma: current concept in biology and treatment. Cancer Treat Res 2006;131:141–59.[Medline]
98. Bergsagel PL, Kuehl WM, Zhan F, et al. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 2005;106:296–303.[Abstract/Free Full Text]
99. Roy PG, Thompson AM. Cyclin D1 and breast cancer. Breast 2006;15:718–27.[CrossRef][Medline]
100. Yang CH, Gonzalez-Angulo AM, Reuben JM, et al. Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. Ann Oncol 2006;17:813–7.[Abstract/Free Full Text]
101. Ishii Y, Pirkmaier A, Alvarez JV, et al. Cyclin D1 overexpression and response to bortezomib treatment in a breast cancer model. J Natl Cancer Inst 2006;98:1238–47.[Abstract/Free Full Text]
102. Annunziata CM, Davis RE, Demchenko Y, et al. Frequent engagement of the classical and alternative NF-B pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 2007;12:115–30.[CrossRef][Medline]
103. Keats JJ, Fonseca R, Chesi M, et al. Promiscuous mutations activate the noncanonical NF-B pathway in multiple myeloma. Cancer Cell 2007;12:131–44.[CrossRef][Medline]
104. Dolcet X, Llobet D, Encinas M, et al. Proteasome inhibitors induce death but activate NF-B on endometrial carcinoma cell lines and primary culture explants. J Biol Chem 2006;281:22118–30.[Abstract/Free Full Text]
105. Masdehors P, Merle-Beral H, Maloum K, et al. Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes. Blood 2000;96:269–74.[Abstract/Free Full Text]
106. Faderl S, Rai K, Gribben J, et al. Phase II study of single-agent bortezomib for the treatment of patients with fludarabine-refractory B-cell chronic lymphocytic leukemia. Cancer 2006;107:916–24.[CrossRef][Medline]
107. Fuchs D, Berges C, Opelz G, Daniel V, Naujokat C. Increased expression and altered subunit composition of proteasomes induced by continuous proteasome inhibition establish apoptosis resistance and hyperproliferation of Burkitt lymphoma cells. J Cell Biochem 2008;103:270–83.[CrossRef][Medline]
108. Bhandari M, Jagannath S. Repeated complete responses with bortezomib in a heavily pretreated primary refractory patient with light chain multiple myeloma. Clin Lymphoma Myeloma 2007;7:373–5.[Medline]
109. Conner TM, Doan QCD, LeBlanc AL, Walters IB, Beveridge RA. An observational, retrospective analysis of retreatment with bortezomib of mulitple myeloma (MM) patients [abstract 3531]. Blood 2006;108:1007a.[CrossRef]
110. Wolf JL, Richardson P, Schuster M, et al. Utility of bortezomib retreatment for patients with relapsed multiple myeloma [abstract 3532]. Blood 2006;108:1008a.
111. Sharma RC, Inoue S, Roitelman J, Schimke RT, Simoni RD. Peptide transport by the multidrug resistance pump. J Biol Chem 1992;267:5731–4.[Abstract/Free Full Text]
112. Inoue S, Sharma RC, Schimke RT, Simoni RD. Cellular detoxification of tripeptidyl aldehydes by an aldo-keto reductase. J Biol Chem 1993;268:5894–8.[Abstract/Free Full Text]
113. Rumpold H, Salvador C, Wolf AM, et al. Knockdown of PgP resensitizes leukemic cells to proteasome inhibitors. Biochem Biophys Res Commun 2007;361:549–54.[CrossRef][Medline]
114. Nakamura T, Tanaka K, Matsunobu T, et al. The mechanism of cross-resistance to proteasome inhibitor bortezomib and overcoming resistance in Ewing's family tumor cells. Int J Oncol 2007;31:803–11.[Medline]
115. Schmidmaier R, Baumann P, Bumeder I, et al. First clinical experience with simvastatin to overcome drug resistance in refractory multiple myeloma. Eur J Haematol 2007;79:240–3.[CrossRef][Medline]
116. Ruiz S, Krupnik Y, Keating M, et al. 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 2006;5:1836–43.[Abstract/Free Full Text]
117. Orlowski RZ, Stewart K, Vallone M, et al. Safety and antitumor efficacy of the proteasome inhibitor carfilzomib (PR-171) dosed for five consecutive days in hematologic malignancies: phase I results [abstract 409]. Blood 2007;110:127a.
118. Alsina M, Trudel S, Vallone M, et al. Phase I single agent antitumor activity of twice weekly-consecutive day dosing of the proteasome inhibitor carfilzomib (PR-171) in hematologic malignancies [abstract 411]. Blood 2007;110:128a.
119. Rivett AJ, Hearn AR. Proteasome function in antigen presentation: immunoproteasome complexes, Peptide production, and interactions with viral proteins. Curr Protein Pept Sci 2004;5:153–61.[CrossRef][Medline]
120. Orlowski RZ, Kuhn DJ, Small GW, Michaud C, Orlowski M. Identification of novel inhibitors that specifically target the immunoproteasome, and selectively induce apoptosis in multiple myeloma and other immunoproteasome-expressing model systems [abstract 248]. Blood 2005;106:76a.
121. Ho YK, Bargagna-Mohan P, Wehenkel M, Mohan R, Kim KB. LMP2-specific inhibitors: chemical genetic tools for proteasome biology. Chem Biol 2007;14:419–30.[CrossRef][Medline]
122. Altun M, Galardy PJ, Shringarpure R, et al. Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells. Cancer Res 2005;65:7896–901.[Abstract/Free Full Text]
123. Smiley ST, Reers M, Mottola-Hartshorn C, et al. Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. Proc Natl Acad Sci U S A 1991;88:3671–5.[Abstract/Free Full Text]

This article has been cited by other articles:

				T.-M. Yang, D. Barbone, D. A. Fennell, and V. C. Broaddus Bcl-2 Family Proteins Contribute to Apoptotic Resistance in Lung Cancer Multicellular Spheroids Am. J. Respir. Cell Mol. Biol., July 1, 2009; 41(1): 14 - 23. [Abstract] [Full Text] [PDF]

				M. Nojima, R. Maruyama, H. Yasui, H. Suzuki, Y. Maruyama, I. Tarasawa, Y. Sasaki, H. Asaoku, H. Sakai, T. Hayashi, et al. Genomic Screening for Genes Silenced by DNA Methylation Revealed an Association between RASD1 Inactivation and Dexamethasone Resistance in Multiple Myeloma Clin. Cancer Res., July 1, 2009; 15(13): 4356 - 4364. [Abstract] [Full Text] [PDF]

				T. A. Soucy, P. G. Smith, and M. Rolfe Targeting NEDD8-Activated Cullin-RING Ligases for the Treatment of Cancer Clin. Cancer Res., June 15, 2009; 15(12): 3912 - 3916. [Abstract] [Full Text] [PDF]

				K. Dunleavy, S. Pittaluga, M. S. Czuczman, S. S. Dave, G. Wright, N. Grant, M. Shovlin, E. S. Jaffe, J. E. Janik, L. M. Staudt, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma Blood, June 11, 2009; 113(24): 6069 - 6076. [Abstract] [Full Text] [PDF]

				D. J. Kuhn, S. A. Hunsucker, Q. Chen, P. M. Voorhees, M. Orlowski, and R. Z. Orlowski Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors Blood, May 7, 2009; 113(19): 4667 - 4676. [Abstract] [Full Text] [PDF]

				A. Delmonte, M. Ghielmini, and C. Sessa Beyond Monoclonal Antibodies: New Therapeutic Agents in Non-Hodgkin's Lymphomas Oncologist, May 1, 2009; 14(5): 511 - 525. [Abstract] [Full Text] [PDF]

				M. IIJIMA, I. MOMOSE, and D. IKEDA TP-110, a New Proteasome Inhibitor, Down-regulates IAPs in Human Multiple Myeloma Cells Anticancer Res, April 1, 2009; 29(4): 977 - 985. [Abstract] [Full Text] [PDF]

				R. C Smallridge, L. A Marlow, and J. A Copland Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies Endocr. Relat. Cancer, March 1, 2009; 16(1): 17 - 44. [Abstract] [Full Text] [PDF]

				J. Ruan, K. Hajjar, S. Rafii, and J. P. Leonard Angiogenesis and antiangiogenic therapy in non-Hodgkin's lymphoma Ann. Onc., March 1, 2009; 20(3): 413 - 424. [Abstract] [Full Text] [PDF]

				S. Dayal, A. Sparks, J. Jacob, N. Allende-Vega, D. P. Lane, and M. K. Saville Suppression of the Deubiquitinating Enzyme USP5 Causes the Accumulation of Unanchored Polyubiquitin and the Activation of p53 J. Biol. Chem., February 20, 2009; 284(8): 5030 - 5041. [Abstract] [Full Text] [PDF]

				G. Pagnan, D. Di Paolo, R. Carosio, F. Pastorino, D. Marimpietri, C. Brignole, A. Pezzolo, M. Loi, L. J.V. Galietta, F. Piccardi, et al. The Combined Therapeutic Effects of Bortezomib and Fenretinide on Neuroblastoma Cells Involve Endoplasmic Reticulum Stress Response Clin. Cancer Res., February 15, 2009; 15(4): 1199 - 1209. [Abstract] [Full Text] [PDF]

				G. Bisping, D. Wenning, M. Kropff, D. Gustavus, C. Muller-Tidow, M. Stelljes, G. Munzert, F. Hilberg, G. J. Roth, M. Stefanic, et al. Bortezomib, Dexamethasone, and Fibroblast Growth Factor Receptor 3-Specific Tyrosine Kinase Inhibitor in t(4;14) Myeloma Clin. Cancer Res., January 15, 2009; 15(2): 520 - 531. [Abstract] [Full Text] [PDF]

				P. G. Richardson, C. Mitsiades, J. Laubach, D. Chauhan, T. Hideshima, and K. Anderson Realizing the Anticancer Potential of Proteasome Inhibition: The Clinical Development of Bortezomib and Second-generation Proteasome Inhibitors ASCO Educational Book, January 1, 2009; 2009(1): 163 - 170. [Abstract] [Full Text] [PDF]

				X. Wang, H. Xu, D. Ju, and Y. Xie Disruption of Rpn4-Induced Proteasome Expression in Saccharomyces cerevisiae Reduces Cell Viability Under Stressed Conditions Genetics, December 1, 2008; 180(4): 1945 - 1953. [Abstract] [Full Text] [PDF]

				D. Plesca, S. Mazumder, V. Gama, S. Matsuyama, and A. Almasan A C-terminal Fragment of Cyclin E, Generated by Caspase-mediated Cleavage, Is Degraded in the Absence of a Recognizable Phosphodegron J. Biol. Chem., November 7, 2008; 283(45): 30796 - 30803. [Abstract] [Full Text] [PDF]

				R. Oerlemans, N. E. Franke, Y. G. Assaraf, J. Cloos, I. van Zantwijk, C. R. Berkers, G. L. Scheffer, K. Debipersad, K. Vojtekova, C. Lemos, et al. Molecular basis of bortezomib resistance: proteasome subunit {beta}5 (PSMB5) gene mutation and overexpression of PSMB5 protein Blood, September 15, 2008; 112(6): 2489 - 2499. [Abstract] [Full Text] [PDF]

				G. C. Prendergast Refining Cytotoxic Therapy: Progress in Generalized Therapeutics for Cancer Cancer Reviews Online Content, April 1, 2008; 2008(4): 7 - 7. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Orlowski, R. Z. Articles by Kuhn, D. J. Search for Related Content PubMed PubMed Citation Articles by Orlowski, R. Z. Articles by Kuhn, D. J. Related Collections Therapeutics and Targets Therapeutics and Targets: Experimental Therapeutics– Small Molecules Clinical Research: Clinical Trials