| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics |
Department of Adult Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 [T. H., P. R., D. C., K. C. A]; and Millennium Pharmaceuticals, Inc. Cambridge, Massachusetts 02139 [V. J. P., P. J. E., J. A.]
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
B-dependent induction of interleukin-6 secretion in BMSCs, as well as inhibiting proliferation and growth signaling of residual adherent MM cells. These data, therefore, demonstrate that PS-341 both acts directly on MM cells and alters cellular interactions and cytokine secretion in the BM millieu to inhibit tumor cell growth, induce apoptosis, and overcome drug resistance. Given the acceptable animal and human toxicity profile of PS-341, these studies provide the framework for clinical evaluation of PS-341 to improve outcome for patients with this universally fatal hematological malignancy. |
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
B activation and related drug resistance by inhibiting degradation of IB and the P105 precursor of p50 subunit of NF-B (7, 8, 9, 10)
. Moreover, proteasome inhibitors are synergistic with Dex3
in an asthma model (11)
. Finally, the proteasome inhibitor PS-341 demonstrated marked in vivo activity against human prostate cancer (1)
and Burkitt’s lymphoma (12)
in a murine model; produced additive growth delays with 5-fluorouracil, cisplatin, Taxol, and Adriamycin against Lewis lung carcinoma (13)
; and demonstrated antiangiogenic activity in an orthotopic pancreatic cancer model (14)
. PS-341 is nearly completing Phase I testing in humans, with an acceptable toxicity profile, and will soon be evaluated for efficacy in Phase II clinical trials.
MM is an incurable hematological malignancy, which affected 13,700 new individuals in the United States in 2000 (15)
, and novel biologically based therapies are, therefore, urgently needed. There are several characteristics of MM that suggest that it is an ideal candidate for proteasome inhibitor therapy. First, MM cells adhere to BMSCs, which both localizes them in the BM millieu (16)
and confers resistance to apoptosis (17)
. Proteasome inhibitors have been reported to down-regulate cytokine-induced expression of VCAM-1 (18)
, a major ligand on BMSCs for VLA-4 on MM cells (19)
, and thereby might inhibit MM cell-BMSC binding and related protection against apoptosis. Second, adherence of MM cells to BMSCs triggers NF-B-dependent transcription and secretion of IL-6 (19)
, a MM cell growth and survival factor (20)
. By virtue of its inhibition of NF-B activation (7, 8, 9, 10)
, PS-341 can inhibit this synthesis of IL-6. Third, Dex is a major therapy for MM, and PS-341 synergizes with Dex (11)
. Moreover, resistance to Dex in MM cells is conferred by IL-6 (21, 22, 23)
, and PS-341 may overcome Dex resistance by virtue of its effects on IL-6. In addition, NF-B has been shown to play a role in the rescue of MM cells from Dex-induced apoptosis by Bcl-2 (24)
, and PS-341 may also overcome Dex resistance by inhibiting NF-B activation. Finally, increased angiogenesis has recently been described in MM BM (25)
, as well as significant in vitro and clinical activity of antiangiogenic agents such as thalidomide and its analogues (26
, 27)
. The antiangiogenic effect of PS-341 (14
, 28)
, therefore, represents another potential mechanism of anti-MM activity.
In this study, we examined the effects of PS-341 on human MM cell lines, freshly isolated patient MM cells, as well as MM cells adherent to BMSCs. Given that PS-341 has a favorable toxicity profile, these studies provide the framework for clinical evaluation of PS-341 in patients with MM.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
BMSC Cultures.
BM specimens were obtained from patients with MM. Mononuclear cells separated by Ficoll-Hipaque density sedimentation were used to establish long-term BM cultures, as described previously (27)
. When an adherent cell monolayer had developed, cells were harvested in HBSS containing 0.25% trypsin and 0.02% EDTA and were washed and collected by centrifugation.
Proteasome Inhibitor.
PS-3411 [pyrazylCONH(CHPhe)CONH(CHisobutyl)B(OH)2; Millennium Predictive Medicine Inc., Cambridge, MA) was dissolved in DMSO and stored at -20°C until use. PS-341 was diluted in culture medium (0.0001–10 x 10-3 M) immediately before use. PS-341 and control media contained <0.1% DMSO.
DNA Synthesis.
Proliferation was measured as described previously (27)
. MM cells (3 x 104 cells/well) were incubated in 96-well culture plates (Costar, Cambridge, MA) in the presence of media, PS-341, and/or Dex or recombinant IL-6 (Genetics Institute, Cambridge, MA) for 48 h at 37°C. DNA synthesis was measured by [3H]thymidine (NEN Products, Boston MA) uptake. Cells were pulsed with [3H]thymidine (0.5 µCi/well) during the last 8 h of 48-h cultures. All of the experiments were performed in triplicate.
Growth Inhibition Assay.
The inhibitory effect of PS-341 on MM and BMSC growth was assessed by measuring MTT dye absorbance of the cells. Cells from 48-h cultures were pulsed with 10 µl of 5 mg/ml MTT to each well for the last 4 h of 48-h cultures, followed by 100 µl of isopropanol containing 0.04 N HCl. Absorbance was measured at 570 nm using a spectrophotometer (Molecular Devices Corp., Sunnyvale CA).
Cell Cycle Analysis.
MM cells and patient MM cells cultured for 0, 4, 6, 8, 12, and 16 h in PS-341 (0.01 x 10-6 M) or control media were harvested, washed with PBS, fixed with 70% ethanol, and treated with 10 µg/ml RNase (Roche Diagnostics Corp., Indianapolis, IN). Cells were then stained with PI (Sigma; 5 µg/ml), and cell cycle profile was determined using the program M software on an Epics flow cytometer (Coulter Immunology, Hialeah, FL), as in prior studies (27)
.
Assays of Apoptosis.
MM cells were cultured for 12 h at 37°C in the presence of PS-341 (0.01 x 10-6 M). To assay for apoptosis, genomic DNA, extracted using a genomic DNA purification kit (Promega, Madison, WI) was electrophoresed on 2% agarose gel containing 5 µg/ml ethidium bromide and was analyzed under UV light for DNA fragmentation, as in prior studies (27)
. Additional assays of apoptosis included PI staining for the percentage of sub-G0/G1 phase cells and caspase-3 cleavage, as in our prior studies (27)
.
Immunoblotting.
MM cells were cultured with PS-341 and were harvested, washed, and lysed using lysis buffer [50 x 10-3 M Tris-HCl (pH 7.4), 150 x 10-3 M NaCl, 1% NP40, 5 x 10-3 M EDTA, 5 x 10-3 M NaF, 2 x 10-3 M Na3VO4, 1 x 10-3 M PMSF, 5 µg/ml leupeptine, and 5 µg/ml aprotinin]. For detection of p21, p27, Bcl-2, Bax, caspase-3, phospho-MAPK, phospho-STAT3, ERK2, or 
-tubulin, cell lysates were subjected to SDS-PAGE, transferred to PVDF membrane (Bio-Rad Laboratories, Hercules, CA), and immunoblotted with anti-p21, anti-p27, anti-Bcl-2, anti-Bax, anti-ERK2, anti-caspase-3 (Santa Cruz Biotechnology), or anti--tubulin (Sigma) Abs. To characterize the inhibition of growth signaling by PS-341, immunoblotting was also done with anti-phospho-specific MAPK or anti-phospho-specific STAT3 Abs (New England Biolabs, Beverly, MA).
Assays of NF-B Activation.
To analyze the effect of PS-341 on degradation of IB induced by TNF (R&D Systems) in MM.1S cells, MM.1S cells were pretreated with control media (0.05% DMSO) or PS-341 (5 x 10-6 M) for 2 h. TNF (5 ng/ml) was then added for the times indicated, and the cells were washed with PBS. Whole-cell extracts were prepared and analyzed by Western blotting using anti-IB Ab (Santa Cruz Biotechnology). The antigen-Ab complexes were visualized by ECL.
To assay for NF-B activation in BMSCs, BMSCs were preincubated with PS-341 (5 x 10-6 M for 1 h) before stimulation with TNF (10 ng/ml) for 10, 20, or 30 min. Cells were then pelleted, resuspended in 400 µl of hypotonic lysis buffer A [20 x 10-3 M HEPES (pH 7.9), 10 x 10-3 M KCl, 1 x 10-3 M EDTA, 0.2% Triton X-100, 1 x 10-3 M Na3VO4, 5 x 10-3 M NaF, 1 x 10-3 M PMSF, 5 µg/ml leupeptin, and 5 µg/ml aprotinin], and kept on ice for 20 min. After centrifugation (14,000 x g for 5 min) at 4°C, the nuclear pellet was extracted with 100 µl of hypertonic lysis buffer B [20 x 10-3 M HEPES (pH 7.9), 400 x 10-3 M NaCl, 1 x 10-3 M EDTA, 1 x 10-3 M Na3VO4, 5 x 10-3 M NaF, 1 x 10-3 M PMSF, 5 µg/ml leupeptin, and 5 µg/ml aprotinin) on ice for 20 min. After centrifugation (14000 x g for 5 min) at 4°C, the supernatant was diluted to 100 x 10-3 M NaCl and subjected to SDS-PAGE. Nuclear extracts were immunoblotted with anti-p65 NF-B Ab (Santa Cruz Biotechnology). The PVDF membrane was stripped and reprobed with anti-nucleolin Ab (Santa Cruz Biotechnology) to confirm equal loading of protein.
EMSA.
Nuclear extracts for EMSAs were carried out as in our previous studies (19)
. Double-stranded NF-B consensus oligonucleotide probe (5'-GGGGACTTTCCC-3', Santa Cruz Biotechnology) was end-labeled with [
-32P]ATP (50 µCi at 222 TBq/mM; NEN, Boston, MA). Binding reactions containing 1 ng of oligonucleotide and 3 µg of nuclear protein were conducted at room temperature for 20 min in total volume of 10 µl of binding buffer [10 mM Tris-HCl (pH 7.5), 50 mM NaCl, 1 mM MgCl2, 0.5 mM EDTA, 0.5 mM DTT, 4% glycerol (v/v), and 0.5 µg of poly (dI·dC) (Pharmacia, Peapack, NJ)]. For supershift analysis, 1 µg of anti-p65 NF-B Ab was added 5 min before the reaction mixtures, immediately after the addition of radiolabeled probe. The samples were loaded onto a 4% polyacrylamide gel, transferred to Whatman paper (Whatman International, Maidstone, United Kingdom), and visualized by autoradiography.
Effect of PS-341 on Paracrine MM Cell Growth and Signaling in the BM.
Adhesion assays were performed as described previously (19)
. MM.1S cells were pretreated with PS-341 for 12 h, washed, and labeled with Na251CrO4 (NEN). Cells were then added to BMSC-coated 96-well plates and incubated for 1 h. After incubation, each well was washed twice with media and lysed with 0.5% NP40, and lysate radioactivity was counted on a gamma counter.
To evaluate growth stimulation and signaling in MM cells adherent to BMSCs, 3 x 104 MM.1S cells were cultured in BMSC-coated 96-well plates for 48 h in the presence or absence of PS-341. DNA synthesis was measured as described above. To characterize the signaling in MM cells that is triggered by the adhesion to BMSCs, MM.1S cells (5 x 106) were cultured in BMSC-coated 6-well plates for 4 h in the presence or absence of PS-341 (5 x 10-6 M). MM.1S cells were harvested, washed with PBS, lysed, subjected to SDS-PAGE, transferred to PVDF membrane, and immunoblotted with anti-phospho-MAPK and anti-phospho-STAT3 Abs. The Duoset ELISA (R&D System) was used to measure IL-6 in supernatants of 48-h cultures of BMSCs with or without MM.1S cells, in the presence or absence of PS-341.
Statistical Analysis.
Statistical significance of differences observed in drug-treated versus control cultures was determined using Student’s t test. The minimal level of significance was P < 0.05.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
, the growth of these MM cell lines was completely inhibited by PS-341 (0.1 x 10-6 M). Fifty % growth inhibition (IC50) in U266, IM-9, and Hs Sultan cells was noted at concentrations of 0.003, 0.006, or 0.02 x 10-6 M, respectively. To examine whether there was cross-resistance between PS-341 and conventional therapies, RPMI8226 MM cells resistant to Dox (Dox/40 cells), Mit (MR20 cells), and Mel (LR5 cells) were similarly studied. Proliferation of Dox40, MR20, and LR5 MM cells was unaffected by culturing with 400 NM/liter Dox, 20 nM/liter Mit, and 5 x 10-6 M Mel, respectively (data not shown). Importantly, cell growth of Dox40, MR20, and LR5 MM cells was completely inhibited by PS-341 (0.1 x 10-6 M; Fig. 1B
). IC50 of PS-341 in RPMI8226, Dox40, MR20, and LR5 was 0.03, 0.04, 0.02, and 0.02 x 10-6 M, respectively. Dex-sensitive (MM.1S) and -resistant (MM.1R) MM cell lines were similarly examined. As can be seen in Fig. 1C
, growth of both cell lines was completely inhibited by PS-341 (0.01 x 10-6 M). IC50 of PS-341 in MM.1S and MM.1R cells was 0.0015 and 0.003 x 10-6 M, respectively. These data demonstrate that PS-341 effectively inhibits the growth of chemoresistant MM cells at pharmacologically achievable doses and can overcome resistance to Dox, Mit, Mel, and Dex. As was true for MM cell lines, cell growth of four patients’ MM cells (MM1–4) was also inhibited by PS-341 in a dose-dependent fashion (Fig. 1D)
, with IC50 of PS-341 at 0.0035, 0.005, 0.03, and 0.0025 x 10-6 M, respectively. PS-341 similarly inhibited the proliferation of these MM cell lines and patient MM cells, as assessed by [3H]thymidine uptake in 48-h cultures (data not shown). PBMCs from three normal volunteers were also examined for their susceptibility to PS-341. As can be seen in Fig. 1E
, IC50 of PS-341 in these PBMCs is 
0.1 x 10-6 M. These findings are consistent with the reported increased sensitivity to proteasome inhibitors of B chronic lymphocytic leukemia cells relative to normal B lymphocytes (30)
.
|
, MTT assay at 48 h revealed that PS-341 alone (0.0025 and 0.005 x 10-6 M) and Dex alone (0.001 to 0.625 x 10-6 M) each significantly inhibited MM.1S cell growth in a dose-dependent fashion and, furthermore, showed that their growth inhibitory effects are additive.
Given the additive effect of PS-341 and Dex (11)
, as well as the known role of IL-6 as a growth factor (31)
and an inhibitor of Dex-induced apoptosis (32, 33, 34)
, we next examined whether exogenous IL-6 could overcome the growth inhibitory effect that is triggered by PS-341. Although IL-6 (50 ng/ml) triggered a 1.3-fold increase in MM.1S cell growth in cultures with media alone, PS-341 inhibited this response in a dose-dependent fashion (Fig. 1G)
. This result showed that IL-6 does not overcome the inhibitory effect of PS-341 on MM cell growth.
PS-341 Induces Apoptosis and IB Degradation and Inhibits p44/42 MAPK Activation in MM Cells.
To further analyze the mechanism of PS-341-induced inhibition of DNA synthesis and to determine whether PS-341 induced apoptosis of MM cells, we examined the cell cycle profile of U266 and patient MM cells cultured with media or PS-341 (0.01 x 10-6 M) for 0, 4, 6, 8, 12, and 16 h. After incubation, cells were harvested and stained with PI. As shown in Fig. 2A
, PS-341 induced a progressive increase in sub-G0/G1 phase cells in a time-dependent manner; similar results were observed for RPMI8226 and MM.1S cells (data not shown). To confirm these results, we performed agarose gel electrophoresis using genomic DNA purified from MM cell lines and patient MM cells treated with PS-341 (0.01 x 10-6 M) for 12 h. Apoptosis, evidenced by DNA fragmentation, was induced by PS-341 (Fig. 2B)
.
|
as well as RPMI8226, MM.1S, and patient MM cells (data not shown). Apoptosis occurred despite up-regulation of p21 and p27 in U266, IM9, ARH77, and RPMI8226 cells (Fig. 2C)
. No changes in Bcl-2 or Bax expression were induced by PS-341. These cell lines contain either wild-type p53 or mutant p53 phenotype, and these results confirm prior reports that proteasome inhibitors can induce apoptosis in both settings (1
, 4
, 5)
.
To determine whether the apoptotic effect of PS-341 is reversible, RPMI8226 cells were treated with 0.01 x 10-6 M PS-341 for 0, 2, 4, 6, 8, 12, or 24 h. Cells were then washed and cultured in PS-341-free media for 24 h. Cell viability and percentage of apoptotic cells were assessed by trypan blue and PI staining, respectively. Fig. 2E
demonstrates an irreversible progressive drug exposure time-dependent effect of PS-341 on RPMI 8226 cells: >50% growth inhibition was observed in cultures with PS-341 for 6 h, with complete abrogation of growth at exposure times of >12 h.
Because PS-341 inhibits TNF-stimulated activation of NF-B in primary HUVECs by blocking the degradation of the inhibitor IB (33)
, we next examined whether PS-341 also inhibited degradation of IB in TNF-treated MM cells. Specifically, MM.1S cells were treated with 5 x 10-6 M PS-341 or control media for 1 h and were subsequently stimulated by TNF (5 ng/ml). As can be seen in Fig. 2F
, IB decreased after stimulation of TNF in DMSO control media-treated MM.1S cells, but not in PS-341-treated cells. Inhibition of NF-B activation by PS-341 was further confirmed by EMSA. As can be seen in Fig. 2G
, activation of NF-B by TNF was inhibited by pretreatment with PS-341 (5 x 10-6 M for 1 h). These data indicated that PS-341 inhibits NF-B activation in MM cells by stabilizing IB.
Because we have shown that proliferation of MM cells induced by IL-6 is mediated via the Ras-Raf MAPK cascade (31)
, we also determined whether PS-341 inhibits the activation of p42/44 MAPK that is triggered by IL-6. As can be seen Fig. 2H
, tyrosine phosphorylation of p42/44 MAPK that was triggered by IL-6 was inhibited completely by PS-341 pretreatment of MM.1S cells for 2 h, whereas the activation of STAT3 was unaffected. This result demonstrates that PS-341 selectively inhibits the tyrosine phosphorylation of MAPK that is triggered by IL-6 in MM.1S cells.
Effect of PS-341 on Paracrine MM Cell Growth and Signaling in the BM Microenvironment.
We next examined the effect of PS-341 on paracrine MM cell growth and signaling in the BM. As shown in Fig. 3A
, PS-341 inhibited the proliferation of two MM patients’ BMSCs in a dose-dependent fashion, with IC50 of 5 and 10 x 10-6 M, respectively. This IC50 was more than 170-fold higher than for MM cell lines and patient MM cells.
|
. Binding of MM cells to BMSCs triggers NF-B-dependent transcription and the secretion of IL-6 in BMSCs (19)
, which mediates paracrine growth and survival of tumor cells. As shown in Fig. 3C
, the adhesion of MM.1S cells to BMSCs induced a >3-fold increase in IL-6 secretion, which was inhibited to baseline levels by PS-341 (0.01 and 0.1 x 10-6 M). The binding of MM cells to BMSCs also triggered a 2-fold increase in DNA synthesis of MM.1S cells, which was completely abrogated by PS-341 (0.001 x 10-6 M; Fig. 3D
).
Given our prior studies, which showed that MM-cell binding to BMSCs triggers NF-B-dependent transcription and secretion of IL-6 in BMSCs, we next examined the effect of PS-341 on NF-B activation in BMSCs, assessed by p65 NF-B nuclear translocation. As can be seen in Fig. 3E
, TNF (10 ng/ml for 15 min) induced nuclear p65 NF-B in BMSCs, and PS-341 blocked this response. Finally, PS-341 also blocked the activation of MAPK, but not of STAT3, in MM cells adherent to BMSCs for 4 h (Fig. 3F)
, consistent with its effect of inhibiting tumor cell growth and proliferation.
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
In this study, we first showed that PS-341 acts directly to inhibit the growth of MM cell lines and patient MM cells, assessed both by MTT assay and DNA synthesis. Growth inhibition of MM cell lines that were sensitive and resistant to Mel, Dox, and Dex was observed at an IC50 of <0.01 x 10-6 M PS-341. These data demonstrate that PS-341 effectively inhibits the growth of chemoresistant MM cells at pharmacologically achievable doses and suggests independent mechanisms of resistance to Dox, Mel, and Dex versus PS-341. These results are also consistent with the reported increased sensitivity to proteasome inhibitors of B chronic lymphocytic leukemia cells relative to normal B lymphocytes (30) .
Given the additive effect of PS-341 and Dex (11) , as well as the known effect of IL-6 as a growth factor (31) and an inhibitor of Dex-induced apoptosis (23) , we examined whether Dex added to the anti-MM activity of PS-341; and conversely, whether exogenous IL-6 could abrogate its antitumor effects. Importantly, Dex enhanced the inhibitory effects of PS-341 on MM growth, evidenced by MTT assay; moreover, IL-6 cannot protect MM cells against PS-341. These studies suggest the potential therapeutic advantage of combined Dex and PS-341 in treatment protocols for MM.
Our studies further confirmed that PS-341 induced apoptosis of MM cells, evidenced by cell cycle analysis, DNA fragmentation, and caspase 3 cleavage. Apoptosis occurred despite the induction of p21 and p27, and without associated changes in Bcl-2 or Bax expression. Importantly, it occurred in MM cell lines containing either wild-type p53 or mutant p53, confirming prior reports that proteasome inhibitors can induce apoptosis in both settings (1 , 4 , 5) . Moreover, the apoptotic effect of PS-341 was irreversible at all of the intervals examined (2–24 h), further suggesting its potential clinical utility.
In this study, PS-341 inhibited IL-6-triggered activation of p42/44 MAPK, known to mediate proliferation (31)
, as well as TNF--induced activation of NF-B, known to mediate drug resistance (24)
. In contrast, the IL-6 induced activation of STAT3 in MM cells was unaffected by PS-341, demonstrating differential susceptibility of protein kinases in the Raf/MEK/MAPK versus JAK/STAT3 signaling pathways to PS-341.
Our study demonstrates the importance of studying the effects of novel agents such as proteasome inhibitors not only on the tumor cells directly, but also within the BM microenvironment. Importantly, these studies show that PS-341 also inhibited paracrine growth of MM cells within the BM millieu. First, adhesion of MM cells to BMSCs confers protection against apoptosis (17)
, and PS-341 inhibits tumor cell binding. Second, PS-341 inhibited MAPK growth signaling (31)
, even in those MM cells adhering to BMSCs, overcoming the growth-promoting effects of BMSC binding. Third, PS-341 abrogates the NF-B-dependent up-regulation of IL-6 triggered by tumor to BMSC binding (19)
, which is of central importance given that IL-6 is the major growth and survival factor for MM cells (20)
. In previous studies, NF-B activation conferred protection of tumor cells against apoptosis by modulating transcription targets of the Bcl-2 homologue Bfl/A1, the immediate-early response gene IEX-1 L, the inhibitors of apoptosis c-IAP1 and c-IAP2, and TNF receptor-associated factors 1 and 2 (8
, 34
, 35) . These studies, coupled with our prior studies demonstrating that IL-6 can block Dex-induced apoptosis and confer drug resistance in MM cells (21
, 23
, 32)
, further suggest that the inhibition of NF-B activation by PS-341 can overcome drug resistance.
These studies, therefore, demonstrate that the proteasome inhibitor PS-341 both directly induces apoptosis of human MM cells and abrogates paracrine growth of MM cells in the BM via altering cellular interactions and cytokine secretion in the BM millieu. They provide the framework for the clinical investigation of these novel agents to improve outcome for patients with this presently incurable disease.
|
FOOTNOTES |
|---|
1 Supported by NIH Grant PO-1 78378 and the Doris Duke Distinguished Clinical Research Scientist Award (to K. C. A.). 
2 To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-2144; Fax: (617) 632-2140; E-mail: kenneth_anderson{at}dfci.harvard.edu
3 The abbreviations used are: Dex, dexamethasone; MM, multiple myeloma; BM, bone marrow; BMSC, BM stromal cell; VCAM-1, vascular cell adhesion molecule-1; VLA-4, very late antigen-4; IL, interleukin; NF-B, nuclear factor B; Dox, doxorubicin; Mit, mitoxantrone; Mel, melphalan; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide; PI, propidium iodide; PMSF, phenylmethylsulfonyl fluoride; PVDF, polyvinylidene difluoride; Ab, antibody; MAPK, mitogen-activated protein kinase; STAT3, signal transducing and transcription 3; ERK2, extracellular signal-regulated kinase 2; TNF, tumor necrosis factor; EMSA, electrophoretic mobility shift analysis; PBMC, peripheral blood mononuclear cell; HUVEC, human umbilical vein endothelial cell.
Received 10/25/00. Accepted 2/ 1/01.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
B1 precursor protein and the activation of NF-B. Cell, 78: 773-785, 1994.[Medline]
-induced apoptosis by NF-B. Science (Washington DC), 274: 787-789, 1996.B in preventing TNF- induced cell death. Science (Washington DC), 274: 782-784, 1996. and cancer therapy-induced apoptosis: potentiation by inhibition of NF-B. Science (Washington DC), 274: 784-787, 1996.B and subsequent inhibition of vascular endothelial growth factor production. Proc. Am. Assoc. Cancer Res., 41: 71 2000.
B. Blood, 87: 1104-1112, 1996.B in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by Bcl-2. Blood, 93: 3044-3052, 1999.B control. Proc. Natl. Acad. Sci. USA, 94: 10057-10062, 1997.B antiapoptosis: induction of TRAF-1 and TRAF-2 and cIAP2 to suppress caspase-8 activation. Science (Washington DC), 281: 680-683, 1998.
This article has been cited by other articles:
|
|
 |
|
  P. G. Richardson, E. Weller, S. Jagannath, D. E. Avigan, M. Alsina, R. L. Schlossman, A. Mazumder, N. C. Munshi, I. M. Ghobrial, D. Doss, et al. Multicenter, Phase I, Dose-Escalation Trial of Lenalidomide Plus Bortezomib for Relapsed and Relapsed/Refractory Multiple Myeloma J. Clin. Oncol., December 1, 2009; 27(34): 5713 - 5719. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Ooi, P. J. Hayden, V. Kotoula, D. W. McMillin, E. Charalambous, E. Daskalaki, N. S. Raje, N. C. Munshi, D. Chauhan, T. Hideshima, et al. Interactions of the Hdm2/p53 and Proteasome Pathways May Enhance the Antitumor Activity of Bortezomib Clin. Cancer Res., December 1, 2009; 15(23): 7153 - 7160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Koreth, K. E. Stevenson, H. T. Kim, M. Garcia, V. T. Ho, P. Armand, C. Cutler, J. Ritz, J. H. Antin, R. J. Soiffer, et al. Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors Blood, October 29, 2009; 114(18): 3956 - 3959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Parlati, S. J. Lee, M. Aujay, E. Suzuki, K. Levitsky, J. B. Lorens, D. R. Micklem, P. Ruurs, C. Sylvain, Y. Lu, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome Blood, October 15, 2009; 114(16): 3439 - 3447. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Blotta, P. Tassone, R. H. Prabhala, P. Tagliaferri, D. Cervi, S. Amin, J. Jakubikova, Y.-T. Tai, K. Podar, C. S. Mitsiades, et al. Identification of novel antigens with induced immune response in monoclonal gammopathy of undetermined significance Blood, October 8, 2009; 114(15): 3276 - 3284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Shanmugam, S. K. McBrayer, J. Qian, K. Raikoff, M. J. Avram, S. Singhal, V. Gandhi, P. T. Schumacker, N. L. Krett, and S. T. Rosen Targeting Glucose Consumption and Autophagy in Myeloma with the Novel Nucleoside Analogue 8-Aminoadenosine J. Biol. Chem., September 25, 2009; 284(39): 26816 - 26830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Reece, V. Sanchorawala, U. Hegenbart, G. Merlini, G. Palladini, J.-P. Fermand, R. A. Vescio, X. Liu, Y. A. Elsayed, A. Cakana, et al. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study Blood, August 20, 2009; 114(8): 1489 - 1497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Treon, L. Ioakimidis, J. D. Soumerai, C. J. Patterson, P. Sheehy, M. Nelson, M. Willen, J. Matous, J. Mattern II, J. G. Diener, et al. Primary Therapy of Waldenstrom Macroglobulinemia With Bortezomib, Dexamethasone, and Rituximab: WMCTG Clinical Trial 05-180 J. Clin. Oncol., August 10, 2009; 27(23): 3830 - 3835. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Huber, A. Tagwerker, D. Heininger, G. Mayer, A. R. Rosenkranz, and K. Eller The proteasome inhibitor Bortezomib aggravates renal ischemia-reperfusion injury Am J Physiol Renal Physiol, August 1, 2009; 297(2): F451 - F460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hideshima, H. Ikeda, D. Chauhan, Y. Okawa, N. Raje, K. Podar, C. Mitsiades, N. C. Munshi, P. G. Richardson, R. D. Carrasco, et al. Bortezomib induces canonical nuclear factor-{kappa}B activation in multiple myeloma cells Blood, July 30, 2009; 114(5): 1046 - 1052. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fulciniti, P. Tassone, T. Hideshima, S. Vallet, P. Nanjappa, S. A. Ettenberg, Z. Shen, N. Patel, Y.-t. Tai, D. Chauhan, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma Blood, July 9, 2009; 114(2): 371 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-S. Eom, C.-K. Min, B.-S. Cho, S. Lee, J.-W. Lee, W.-S. Min, C.-C. Kim, M. Kim, and Y. Kim Retrospective Comparison of Bortezomib-containing Regimens with Vincristine-Doxorubicin-Dexamethasone (VAD) as Induction Treatment Prior to Autologous Stem Cell Transplantation for Multiple Myeloma Jpn. J. Clin. Oncol., July 1, 2009; 39(7): 449 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Deleu, M. Lemaire, J. Arts, E. Menu, E. Van Valckenborgh, I. Vande Broek, H. De Raeve, L. Coulton, B. Van Camp, P. Croucher, et al. Bortezomib Alone or in Combination with the Histone Deacetylase Inhibitor JNJ-26481585: Effect on Myeloma Bone Disease in the 5T2MM Murine Model of Myeloma Cancer Res., July 1, 2009; 69(13): 5307 - 5311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Hoang, A. Benavides, Y. Shi, P. Frost, and A. Lichtenstein Effect of autophagy on multiple myeloma cell viability Mol. Cancer Ther., July 1, 2009; 8(7): 1974 - 1984. [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. Hideshima, D. Chauhan, T. Kiziltepe, H. Ikeda, Y. Okawa, K. Podar, N. Raje, A. Protopopov, N. C. Munshi, P. G. Richardson, et al. Biologic sequelae of I{kappa}B kinase (IKK) inhibition in multiple myeloma: therapeutic implications Blood, May 21, 2009; 113(21): 5228 - 5236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-F. Chen, P.-Y. Yeh, C. Hsu, C.-H. Hsu, Y.-S. Lu, H.-P. Hsieh, P.-J. Chen, and A.-L. Cheng Bortezomib Overcomes Tumor Necrosis Factor-related Apoptosis-inducing Ligand Resistance in Hepatocellular Carcinoma Cells in Part through the Inhibition of the Phosphatidylinositol 3-Kinase/Akt Pathway J. Biol. Chem., April 24, 2009; 284(17): 11121 - 11133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Sung, A. B. Kunnumakkara, G. Sethi, P. Anand, S. Guha, and B. B. Aggarwal Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model Mol. Cancer Ther., April 1, 2009; 8(4): 959 - 970. [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]
|
|
|
|
|
|
U. VALENTINER, C. HAANE, N. NEHMANN, and U. SCHUMACHER Effects of Bortezomib on Human Neuroblastoma Cells In Vitro and in a Metastatic Xenograft Model Anticancer Res, April 1, 2009; 29(4): 1219 - 1225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. B. Aggarwal, R.V. Vijayalekshmi, and B. Sung Targeting Inflammatory Pathways for Prevention and Therapy of Cancer: Short-Term Friend, Long-Term Foe Clin. Cancer Res., January 15, 2009; 15(2): 425 - 430. [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]
|
|
|
|
|
|
Z. Lin, M. Bazzaro, M.-C. Wang, K. C. Chan, S. Peng, and R. B.S. Roden Combination of Proteasome and HDAC Inhibitors for Uterine Cervical Cancer Treatment Clin. Cancer Res., January 15, 2009; 15(2): 570 - 577. [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]
|
|
|
|
 |
|
 R. Sarkozi, P. Perco, K. Hochegger, J. Enrich, M. Wiesinger, M. Pirklbauer, S. Eder, M. Rudnicki, A. R. Rosenkranz, B. Mayer, et al. Bortezomib-Induced Survival Signals and Genes in Human Proximal Tubular Cells J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 645 - 656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Fels, J. Ye, A. T. Segan, S. J. Kridel, M. Spiotto, M. Olson, A. C. Koong, and C. Koumenis Preferential Cytotoxicity of Bortezomib toward Hypoxic Tumor Cells via Overactivation of Endoplasmic Reticulum Stress Pathways Cancer Res., November 15, 2008; 68(22): 9323 - 9330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
G. B. Lesinski, E. T. Raig, K. Guenterberg, L. Brown, M. R. Go, N. N. Shah, A. Lewis, M. Quimper, E. Hade, G. Young, et al. IFN-{alpha} and Bortezomib Overcome Bcl-2 and Mcl-1 Overexpression in Melanoma Cells by Stimulating the Extrinsic Pathway of Apoptosis Cancer Res., October 15, 2008; 68(20): 8351 - 8360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Chanan-Khan, P. Sonneveld, M. W. Schuster, E. A. Stadtmauer, T. Facon, J.-L. Harousseau, D. Ben-Yehuda, S. Lonial, H. Goldschmidt, D. Reece, et al. Analysis of Herpes Zoster Events Among Bortezomib-Treated Patients in the Phase III APEX Study J. Clin. Oncol., October 10, 2008; 26(29): 4784 - 4790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lioni, K. Noma, A. Snyder, A. Klein-Szanto, J. A. Diehl, A. K. Rustgi, M. Herlyn, and K. S.M. Smalley Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway Mol. Cancer Ther., September 1, 2008; 7(9): 2866 - 2875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-F. Chen, P.-Y. Yeh, K.-H. Yeh, Y.-S. Lu, S.-Y. Huang, and A.-L. Cheng Down-regulation of Phospho-Akt Is a Major Molecular Determinant of Bortezomib-Induced Apoptosis in Hepatocellular Carcinoma Cells Cancer Res., August 15, 2008; 68(16): 6698 - 6707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Koldehoff, D. W. Beelen, and A. H. Elmaagacli Small-molecule inhibition of proteasome and silencing by vascular endothelial cell growth factor-specific siRNA induce additive antitumor activity in multiple myeloma J. Leukoc. Biol., August 1, 2008; 84(2): 561 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lu, J. Yang, X. Song, S. Gong, H. Zhou, L. Guo, N. Song, X. Bao, P. Chen, and J. Wang Point Mutation of the Proteasome {beta}5 Subunit Gene Is an Important Mechanism of Bortezomib Resistance in Bortezomib-Selected Variants of Jurkat T Cell Lymphoblastic Lymphoma/Leukemia Line J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 423 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Gu, X. Chen, G. Gao, and H. Dong Caspase-2 functions upstream of mitochondria in endoplasmic reticulum stress-induced apoptosis by bortezomib in human myeloma cells Mol. Cancer Ther., August 1, 2008; 7(8): 2298 - 2307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. N. Utecht and J. Kolesar Bortezomib: A novel chemotherapeutic agent for hematologic malignancies Am. J. Health Syst. Pharm., July 1, 2008; 65(13): 1221 - 1231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Mitsiades, E. M. Ocio, A. Pandiella, P. Maiso, C. Gajate, M. Garayoa, D. Vilanova, J. C. Montero, N. Mitsiades, C. J. McMullan, et al. Aplidin, a Marine Organism-Derived Compound with Potent Antimyeloma Activity In vitro and In vivo Cancer Res., July 1, 2008; 68(13): 5216 - 5225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Carew, S. T. Nawrocki, V. K. Reddy, D. Bush, J. E. Rehg, A. Goodwin, J. A. Houghton, R. A. Casero Jr, L. J. Marton, and J. L. Cleveland The Novel Polyamine Analogue CGC-11093 Enhances the Antimyeloma Activity of Bortezomib Cancer Res., June 15, 2008; 68(12): 4783 - 4790. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. W. H. van Hees, Y.-P. Li, C. A. C. Ottenheijm, B. Jin, C. J. C. Pigmans, M. Linkels, P. N. R. Dekhuijzen, and L. M. A. Heunks Proteasome inhibition improves diaphragm function in congestive heart failure rats Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1260 - L1268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Sakasai and R. Tibbetts RNF8-dependent and RNF8-independent Regulation of 53BP1 in Response to DNA Damage J. Biol. Chem., May 16, 2008; 283(20): 13549 - 13555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Leleu, J. Eeckhoute, X. Jia, A. M. Roccaro, A.-S. Moreau, M. Farag, A. Sacco, H. T. Ngo, J. Runnels, M. R. Melhem, et al. Targeting NF-{kappa}B in Waldenstrom macroglobulinemia Blood, May 15, 2008; 111(10): 5068 - 5077. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Shanker, A. D. Brooks, C. A. Tristan, J. W. Wine, P. J. Elliott, H. Yagita, K. Takeda, M. J. Smyth, W. J. Murphy, and T. J. Sayers Treating Metastatic Solid Tumors With Bortezomib and a Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor Agonist Antibody J Natl Cancer Inst, May 7, 2008; 100(9): 649 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Uddin, M. Ahmed, P. Bavi, R. El-Sayed, N. Al-Sanea, A. AbdulJabbar, L. H. Ashari, S. Alhomoud, F. Al-Dayel, A. R. Hussain, et al. Bortezomib (Velcade) Induces p27Kip1 Expression through S-Phase Kinase Protein 2 Degradation in Colorectal Cancer Cancer Res., May 1, 2008; 68(9): 3379 - 3388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Baritaki, E. Suzuki, K. Umezawa, D. A. Spandidos, J. Berenson, T. R. Daniels, M. L. Penichet, A. R. Jazirehi, M. Palladino, and B. Bonavida Inhibition of Yin Yang 1-Dependent Repressor Activity of DR5 Transcription and Expression by the Novel Proteasome Inhibitor NPI-0052 Contributes to its TRAIL-Enhanced Apoptosis in Cancer Cells J. Immunol., May 1, 2008; 180(9): 6199 - 6210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M Voorhees, E C. Dees, B. O'Neil, and R. Z Orlowski The Proteasome as a Target for Cancer Therapy Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 153 - 170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Z. Orlowski and D. J. Kuhn Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade Clin. Cancer Res., March 15, 2008; 14(6): 1649 - 1657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Kyle and S. V. Rajkumar Multiple myeloma Blood, March 15, 2008; 111(6): 2962 - 2972. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Fojo Commentary: Novel Therapies for Cancer: Why Dirty Might Be Better Oncologist, March 1, 2008; 13(3): 277 - 283. [Full Text] [PDF]
|
|
|
|
|
|
R. Piva, B. Ruggeri, M. Williams, G. Costa, I. Tamagno, D. Ferrero, V. Giai, M. Coscia, S. Peola, M. Massaia, et al. CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib Blood, March 1, 2008; 111(5): 2765 - 2775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Liu, Z. Liu, Z. Xie, J. Pang, J. Yu, E. Lehmann, L. Huynh, T. Vukosavljevic, M. Takeki, R. B. Klisovic, et al. Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-{kappa}B-dependent DNA methyltransferase activity in acute myeloid leukemia Blood, February 15, 2008; 111(4): 2364 - 2373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Perez, N. Parquet, K. Shain, R. Nimmanapalli, M. Alsina, C. Anasetti, and W. Dalton Bone Marrow Stroma Confers Resistance to Apo2 Ligand/TRAIL in Multiple Myeloma in Part by Regulating c-FLIP J. Immunol., February 1, 2008; 180(3): 1545 - 1555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Chauhan, A. Singh, M. Brahmandam, K. Podar, T. Hideshima, P. Richardson, N. Munshi, M. A. Palladino, and K. C. Anderson Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma Blood, February 1, 2008; 111(3): 1654 - 1664. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Colado, S. Alvarez-Fernandez, P. Maiso, J. Martin-Sanchez, M. B. Vidriales, M. Garayoa, E. M. Ocio, J. C. Montero, A. Pandiella, and J. F. San Miguel The effect of the proteasome inhibitor bortezomib on acute myeloid leukemia cells and drug resistance associated with the CD34+ immature phenotype Haematologica, January 1, 2008; 93(1): 57 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-K. Min, M.-J. Lee, K.-S. Eom, S. Lee, J.-W. Lee, W.-S. Min, C.-C. Kim, M. Kim, J. Lim, Y. Kim, et al. Bortezomib in Combination with Conventional Chemotherapeutic Agents for Multiple Myeloma Compared with Bortezomib Alone Jpn. J. Clin. Oncol., December 21, 2007; (2007) hym126v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Zhang, A. J. Paterson, P. Huang, K. Wang, and J. E. Kudlow Metabolic Control of Proteasome Function Physiology, December 1, 2007; 22(6): 373 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Voorhees, Q. Chen, D. J. Kuhn, G. W. Small, S. A. Hunsucker, J. S. Strader, R. E. Corringham, M. H. Zaki, J. A. Nemeth, and R. Z. Orlowski Inhibition of Interleukin-6 Signaling with CNTO 328 Enhances the Activity of Bortezomib in Preclinical Models of Multiple Myeloma Clin. Cancer Res., November 1, 2007; 13(21): 6469 - 6478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Kuhn, Q. Chen, P. M. Voorhees, J. S. Strader, K. D. Shenk, C. M. Sun, S. D. Demo, M. K. Bennett, F. W. B. van Leeuwen, A. A. Chanan-Khan, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma Blood, November 1, 2007; 110(9): 3281 - 3290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Poulaki, C. S. Mitsiades, V. Kotoula, J. Negri, D. McMillin, J. W. Miller, and N. Mitsiades The Proteasome Inhibitor Bortezomib Induces Apoptosis in Human Retinoblastoma Cell Lines In Vitro Invest. Ophthalmol. Vis. Sci., October 1, 2007; 48(10): 4706 - 4719. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Rosinol, A. Oriol, M. V. Mateos, A. Sureda, P. Garcia-Sanchez, N. Gutierrez, A. Alegre, J. J. Lahuerta, J. de la Rubia, C. Herrero, et al. Phase II Pethema Trial of Alternating Bortezomib and Dexamethasone As Induction Regimen Before Autologous Stem-Cell Transplantation in Younger Patients With Multiple Myeloma: Efficacy and Clinical Implications of Tumor Response Kinetics J. Clin. Oncol., October 1, 2007; 25(28): 4452 - 4458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Neri, S. Kumar, M. T. Fulciniti, S. Vallet, S. Chhetri, S. Mukherjee, Y. Tai, D. Chauhan, P. Tassone, S. Venuta, et al. Neutralizing B-Cell Activating Factor Antibody Improves Survival and Inhibits Osteoclastogenesis in a Severe Combined Immunodeficient Human Multiple Myeloma Model Clin. Cancer Res., October 1, 2007; 13(19): 5903 - 5909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Davenport, H. E. Moore, A. S. Dunlop, S. Y. Sharp, P. Workman, G. J. Morgan, and F. E. Davies Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells Blood, October 1, 2007; 110(7): 2641 - 2649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Zou, J. Kawada, L. Pesnicak, and J. I. Cohen Bortezomib Induces Apoptosis of Epstein-Barr Virus (EBV)-Transformed B Cells and Prolongs Survival of Mice Inoculated with EBV-Transformed B Cells J. Virol., September 15, 2007; 81(18): 10029 - 10036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Z. Orlowski, A. Nagler, P. Sonneveld, J. Blade, R. Hajek, A. Spencer, J. San Miguel, T. Robak, A. Dmoszynska, N. Horvath, 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., September 1, 2007; 25(25): 3892 - 3901. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-T. Tai, M. Fulciniti, T. Hideshima, W. Song, M. Leiba, X.-F. Li, M. Rumizen, P. Burger, A. Morrison, K. Podar, et al. Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis Blood, September 1, 2007; 110(5): 1656 - 1663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. E. Davies, P. Wu, M. Jenner, M. Srikanth, R. Saso, and G. J. Morgan The combination of cyclophosphamide, velcade and dexamethasone (CVD) induces high response rates with comparable toxicity to velcade alone (V) and velcade plus dexamethasone (VD) Haematologica, August 1, 2007; 92(8): 1149 - 1150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Manochakian, K. C. Miller, and A. A. Chanan-Khan Clinical Impact of Bortezomib in Frontline Regimens for Patients with Multiple Myeloma Oncologist, August 1, 2007; 12(8): 978 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kiziltepe, T. Hideshima, K. Ishitsuka, E. M. Ocio, N. Raje, L. Catley, C.-Q. Li, L. J. Trudel, H. Yasui, S. Vallet, et al. JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells Blood, July 15, 2007; 110(2): 709 - 718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Demo, C. J. Kirk, M. A. Aujay, T. J. Buchholz, M. Dajee, M. N. Ho, J. Jiang, G. J. Laidig, E. R. Lewis, F. Parlati, et al. Antitumor Activity of PR-171, a Novel Irreversible Inhibitor of the Proteasome Cancer Res., July 1, 2007; 67(13): 6383 - 6391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Giuliani, F. Morandi, S. Tagliaferri, M. Lazzaretti, S. Bonomini, M. Crugnola, C. Mancini, E. Martella, L. Ferrari, A. Tabilio, et al. The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients Blood, July 1, 2007; 110(1): 334 - 338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kiziltepe, T. Hideshima, L. Catley, N. Raje, H. Yasui, N. Shiraishi, Y. Okawa, H. Ikeda, S. Vallet, S. Pozzi, et al. 5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells Mol. Cancer Ther., June 1, 2007; 6(6): 1718 - 1727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Richardson, C. Mitsiades, R. Schlossman, N. Munshi, and K. Anderson New Drugs for Myeloma Oncologist, June 1, 2007; 12(6): 664 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Spisek, A. Charalambous, A. Mazumder, D. H. Vesole, S. Jagannath, and M. V. Dhodapkar Bortezomib enhances dendritic cell (DC) mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications Blood, June 1, 2007; 109(11): 4839 - 4845. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sukhdeo, M. Mani, Y. Zhang, J. Dutta, H. Yasui, M. D. Rooney, D. E. Carrasco, M. Zheng, H. He, Y.-T. Tai, et al. Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma PNAS, May 1, 2007; 104(18): 7516 - 7521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Strauss, K. Higginbottom, S. Juliger, L. Maharaj, P. Allen, D. Schenkein, T. A. Lister, and S. P. Joel The Proteasome Inhibitor Bortezomib Acts Independently of p53 and Induces Cell Death via Apoptosis and Mitotic Catastrophe in B-Cell Lymphoma Cell Lines Cancer Res., March 15, 2007; 67(6): 2783 - 2790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Berenson, J. Matous, R. A. Swift, R. Mapes, B. Morrison, and H. S. Yeh A Phase I/II Study of Arsenic Trioxide/Bortezomib/Ascorbic Acid Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma Clin. Cancer Res., March 15, 2007; 13(6): 1762 - 1768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Veschini, D. Belloni, C. Foglieni, M. G. Cangi, M. Ferrarini, F. Caligaris-Cappio, and E. Ferrero Hypoxia-inducible transcription factor-1 alpha determines sensitivity of endothelial cells to the proteosome inhibitor bortezomib Blood, March 15, 2007; 109(6): 2565 - 2570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Voortman, A. Checinska, G. Giaccone, J. A. Rodriguez, and F. A.E. Kruyt Bortezomib, but not cisplatin, induces mitochondria-dependent apoptosis accompanied by up-regulation of noxa in the non-small cell lung cancer cell line NCI-H460 Mol. Cancer Ther., March 1, 2007; 6(3): 1046 - 1053. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Horton, D. Pati, S. E. Plon, P. A. Thompson, L. R. Bomgaars, P. C. Adamson, A. M. Ingle, J. Wright, A. H. Brockman, M. Paton, et al. A Phase 1 Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients with Refractory Leukemia: a Children's Oncology Group Study Clin. Cancer Res., March 1, 2007; 13(5): 1516 - 1522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-P. Armand, A. K. Burnett, J. Drach, J.-L. Harousseau, B. Lowenberg, and J. San Miguel The Emerging Role of Targeted Therapy for Hematologic Malignancies: Update on Bortezomib and Tipifarnib Oncologist, March 1, 2007; 12(3): 281 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Jakob, K. Egerer, P. Liebisch, S. Turkmen, I. Zavrski, U. Kuckelkorn, U. Heider, M. Kaiser, C. Fleissner, J. Sterz, et al. Circulating proteasome levels are an independent prognostic factor for survival in multiple myeloma Blood, March 1, 2007; 109(5): 2100 - 2105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Meister, U. Schubert, K. Neubert, K. Herrmann, R. Burger, M. Gramatzki, S. Hahn, S. Schreiber, S. Wilhelm, M. Herrmann, et al. Extensive Immunoglobulin Production Sensitizes Myeloma Cells for Proteasome Inhibition Cancer Res., February 15, 2007; 67(4): 1783 - 1792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Trudel, A. K. Stewart, Z. Li, Y. Shu, S.-B. Liang, Y. Trieu, D. Reece, J. Paterson, D. Wang, and X.-Y. Wen The Bcl-2 Family Protein Inhibitor, ABT-737, Has Substantial Antimyeloma Activity and Shows Synergistic Effect with Dexamethasone and Melphalan Clin. Cancer Res., January 15, 2007; 13(2): 621 - 629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. An and M. B. Rettig Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib Mol. Cancer Ther., January 1, 2007; 6(1): 61 - 69. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-Z. Ying, H.-G. Zhang, and P. W. Sanders EGF Receptor Activity Modulates Apoptosis Induced by Inhibition of the Proteasome of Vascular Smooth Muscle Cells J. Am. Soc. Nephrol., January 1, 2007; 18(1): 131 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Podar, G. Tonon, M. Sattler, Y.-T. Tai, S. LeGouill, H. Yasui, K. Ishitsuka, S. Kumar, R. Kumar, L. N. Pandite, et al. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma PNAS, December 19, 2006; 103(51): 19478 - 19483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Williamson, J. L. Blank, F. J. Bruzzese, Y. Cao, J. S. Daniels, L. R. Dick, J. Labutti, A. M. Mazzola, A. D. Patil, C. L. Reimer, et al. Comparison of biochemical and biological effects of ML858 (salinosporamide A) and bortezomib Mol. Cancer Ther., December 1, 2006; 5(12): 3052 - 3061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Fribley, B. Evenchik, Q. Zeng, B. K. Park, J. Y. Guan, H. Zhang, T. J. Hale, M. S. Soengas, R. J. Kaufman, and C.-Y. Wang Proteasome Inhibitor PS-341 Induces Apoptosis in Cisplatin-resistant Squamous Cell Carcinoma Cells by Induction of Noxa J. Biol. Chem., October 20, 2006; 281(42): 31440 - 31447. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Marciniak and D. Ron Endoplasmic reticulum stress signaling in disease. Physiol Rev, October 1, 2006; 86(4): 1133 - 1149. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hideshima, P. Neri, P. Tassone, H. Yasui, K. Ishitsuka, N. Raje, D. Chauhan, K. Podar, C. Mitsiades, L. Dang, et al. MLN120B, a Novel I{kappa}B Kinase {beta} Inhibitor, Blocks Multiple Myeloma Cell Growth In vitro and In vivo. Clin. Cancer Res., October 1, 2006; 12(19): 5887 - 5894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Li, S. Cortez, T. Nakamachi, V. Batuman, and A. Arimura Pituitary Adenylate Cyclase-Activating Polypeptide Is a Potent Inhibitor of the Growth of Light Chain-Secreting Human Multiple Myeloma Cells. Cancer Res., September 1, 2006; 66(17): 8796 - 8803. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Yu, B. B. Friday, J.-P. Lai, L. Yang, J. Sarkaria, N. E. Kay, C. A. Carter, L. R. Roberts, S. H. Kaufmann, and A. A. Adjei Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol. Cancer Ther., September 1, 2006; 5(9): 2378 - 2387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Dolcet, D. Llobet, M. Encinas, J. Pallares, A. Cabero, J. A. Schoenenberger, J. X. Comella, and X. Matias-Guiu Proteasome Inhibitors Induce Death but Activate NF-{kappa}B on Endometrial Carcinoma Cell Lines and Primary Culture Explants J. Biol. Chem., August 4, 2006; 281(31): 22118 - 22130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Leiba, L. Cahalon, A. Shimoni, O. Lider, A. Zanin-Zhorov, I. Hecht, U. Sela, I. Vlodavsky, and A. Nagler Halofuginone inhibits NF-{kappa}B and p38 MAPK in activated T cells J. Leukoc. Biol., August 1, 2006; 80(2): 399 - 406. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Achanta, A. Modzelewska, L. Feng, S. R. Khan, and P. Huang A Boronic-Chalcone Derivative Exhibits Potent Anticancer Activity through Inhibition of the Proteasome Mol. Pharmacol., July 1, 2006; 70(1): 426 - 433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Obeng, L. M. Carlson, D. M. Gutman, W. J. Harrington Jr, K. P. Lee, and L. H. Boise Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells Blood, June 15, 2006; 107(12): 4907 - 4916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Maiso, X. Carvajal-Vergara, E. M. Ocio, R. Lopez-Perez, G. Mateo, N. Gutierrez, P. Atadja, A. Pandiella, and J. F. San Miguel The Histone Deacetylase Inhibitor LBH589 Is a Potent Antimyeloma Agent that Overcomes Drug Resistance Cancer Res., June 1, 2006; 66(11): 5781 - 5789. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Khan, J. K. Stauffer, R. Williams, J. A. Hixon, R. Salcedo, E. Lincoln, T. C. Back, D. Powell, S. Lockett, A. C. Arnold, et al. Proteasome Inhibition to Maximize the Apoptotic Potential of Cytokine Therapy for Murine Neuroblastoma Tumors J. Immunol., May 15, 2006; 176(10): 6302 - 6312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hideshima, L. Catley, H. Yasui, K. Ishitsuka, N. Raje, C. Mitsiades, K. Podar, N. C. Munshi, D. Chauhan, P. G. Richardson, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells Blood, May 15, 2006; 107(10): 4053 - 4062. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
), Hs Sultan (
), and IM-9 (•) MM cells; B, drug-sensitive RPMI (
), Dox-resistant (Dox40; •), Mit-resistant (MR20; 
) and with PS-341 0.0025 (
) or 0.005 (
), and 24 (
) h. Cells were washed, resuspended in PS-341-free media, and then stained with trypan blue and PI to assess cell viability and apoptosis. F, MM.1S cells were pretreated with either DMSO control or PS-341 (5 x 10-6 M for 1 h) prior to stimulation with TNF
), or MM.1S cells alone (