Clinical Cancer Research Versailles No Abst AACR Membership
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
Clinical Cancer Research 13, 5528s, September 15, 2007. doi: 10.1158/1078-0432.CCR-07-0982
© 2007 American Association for Cancer Research
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Smith, M. R.
Right arrow Articles by Joshi, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Smith, M. R.
Right arrow Articles by Joshi, I.

Cancer Therapy with Antibodies and Immunoconjugates

Bortezomib Sensitizes Non–Hodgkin's Lymphoma Cells to Apoptosis Induced by Antibodies to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) Receptors TRAIL-R1 and TRAIL-R2

Mitchell R. Smith, Fang Jin and Indira Joshi

Authors' Affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Requests for reprints: Mitchell R. Smith, Lymphoma Service, Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. Phone: 215-728-2674; Fax: 215-728-3639; E-mail: M_smith{at}fccc.edu.


   Abstract
Top
 Abstract
Materials and Methods
 Results and Discussion
 Translational Research Relevance...
 Conclusions
 References
 
Non–Hodgkin's lymphoma (NHL) is an increasingly common disease that, despite advances in antibody-targeted therapy, still requires novel therapeutic approaches. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) activates a major nonmitochondrial pathway for tumor cell killing through binding to a receptor family, some activating and some decoy. Agonistic antibodies to the receptors TRAIL-R1 and TRAIL-R2 can mimic many of the effects of TRAIL. We are investigating the effects of such agonistic antibodies, mapatumumab directed at TRAIL-R1 and lexatumumab directed at TRAIL-R2, on NHL cell lines. These antibodies induce apoptosis through caspase-8 but also activate BID to involve the mitochondrial pathway and activate caspase-9. In addition, we find signaling through both the nuclear factor-{kappa}B and c-Jun NH2-terminal kinase pathways. Because the proteasome inhibitor bortezomib also affects these pathways, we have investigated the combination of TRAIL-R antibodies and bortezomib and show enhanced apoptosis and signaling as well as enhanced killing of NHL cells in a severe combined immunodeficient mouse/human NHL cell line xenograft system. The combination of bortezomib and TRAIL signaling warrants further investigation as a therapeutic regimen. Understanding the multiple intracellular pathways of TRAIL activation may lead to rationally designed therapeutic trials.

Non–Hodgkin's lymphoma and need for new therapeutic approaches. The incidence of non–Hodgkin's lymphoma (NHL) is increasing (1). Follicular NHLs are not curable (2) even with high-dose chemotherapy with autologous stem cell support (3, 4). Biological approaches to therapy may lead to improved outcomes. Monoclonal antibodies, such as the chimeric anti-CD20 rituximab, target B cells for killing by several mechanisms. These include direct signaling of apoptosis, activation of complement, and antibody-directed cytotoxicity (5). Rituximab alone (6) or combined with chemotherapy (7) has significant clinical activity in indolent NHL. Novel antibodies targeting other B-cell–specific surface antigens, or binding CD20 but with altered characteristics such as enhanced Fc receptor affinity or humanized sequences, are under clinical investigation. Nonetheless, improved therapy remains an elusive goal.

Tumor necrosis factor–related apoptosis-inducing ligand as potential NHL therapy. The major nonmitochondrial pathway of killing involves the CD95/Fas pathway (8), which can be activated by several ligand-receptor interactions, via FADD, ultimately activating caspase-8 and then caspase-3. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) promotes apoptosis selectively in cancer cells expressing death receptors with little or no effect on normal cells (9, 10) and can potentiate the effects of radiation and chemotherapy (11–15).

TRAIL induces apoptosis directly via the FADD/caspase-8–dependent signaling pathway independent of the mitochondrial pathway (16). In addition, in some cells, caspase-8–dependent cleavage of BID leads to activation of BAX (17–19), connecting the TRAIL-induced cell death pathway to the mitochondrial apoptosis pathway. TRAIL itself has clinical potential, but toxicity concerns have slowed its development (20). Agonistic antibodies, instead of the ligand, have been developed to activate TRAIL signaling. Mapatumumab (HGS-ETR1) is an agonistic antibody to TRAIL-R1 and lexatumumab (HGS-ETR2) is an agonistic antibody to TRAIL-R2.

There is a family of TRAIL receptors (reviewed in refs. 21–23), with the death receptor 4 (DR4/TRAIL-R1) and DR5 (TRAIL-R2), containing an intracellular domain that allows signaling and apoptosis induction. Two decoy receptors do not contain intracellular death domain signals. The soluble receptor osteoprotegerin may act by binding circulating TRAIL. These decoy and soluble receptors complicate design and interpretation of trials using the small-molecule TRAIL. However, the relative sensitivity of tumor cells as opposed to normal cells to the apoptosis-inducing effects of TRAIL and of mapatumumab and lexatumumab seems to be related to intracellular factors, other than receptor expression and distribution (reviewed in refs. 24, 25), which are triggered on binding of the TRAIL-R1 and/or TRAIL-R2 receptors. Understanding the signaling and apoptosis-inducing effects of TRAIL-R activation should permit rational development of combination therapy.

TRAIL-R binding, downstream signaling, and induction of apoptosis. TRAIL (Fig. 1 ) signals formation of a death-inducing signaling complex, which may contain FADD, TRADD, TRAF, and RIP. Death-inducing signaling complex activates caspase-8, and this may be controlled by c-FLIP (reviewed in refs. 23, 26–30). Death-inducing signaling complex formation leads to procaspase-8 cleavage to active caspase-8 in so-called "type I" cells. Accumulating data now show that activated caspase-8, through cleavage of BID to tBID, can also activate the mitochondrial pathway of apoptosis in cells called "type II" (23, 26–28). This leads to caspase-9 (31) and then caspase-3 activation.


Figure 1
View larger version (23K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Diagram of TRAIL-induced apoptosis pathways in NHL cells. Direct activation occurs through FADD of caspase-8 and then caspase-3. In addition, cleavage of BID to tBID activates mitochondrial pathway of apoptosis through caspase-9 to caspase-3. TRAIL receptor signaling also activates the NF-{kappa}B and c-Jun/JNK pathways.

 
Additional downstream intracellular effects of TRAIL signaling reportedly involve nuclear factor-{kappa}B (NF-{kappa}B) and c-Jun NH2-terminal kinase (JNK) to help control the apoptotic threshold (24, 32–34). NF-{kappa}B is constitutively active in many human tumors and, by influencing transcription of multiple gene targets, supports proliferation and suppresses apoptosis. Therefore, NF-{kappa}B provides an attractive target for antitumor therapies.

Signaling by TRAIL through other members of the mitogen-activated protein kinase pathway phosphorylates JNK. Besides leading to c-Jun activation and transcriptional control by the AP1 transcription factor, JNK can stimulate apoptosis through the mitochondrial pathway (34–36). Antiapoptotic signaling through JNK can be mediated through phosphorylation of JunD, which can function to promote antiapoptotic gene expression coordinately with NF-{kappa}B (37).

The proteosome inhibitor bortezomib has pleiotropic cellular effects, many of which overlap with TRAIL signaling. Bortezomib can enhance TRAIL signaling by up-regulating TRAIL receptor expression, down-regulating c-FLIP, altering NF-{kappa}B activation, and lowering the apoptotic threshold through effects on BCL-2 family proteins, X-linked inhibitor of apoptosis protein, and caspase-3 activation.

Thus, complex interactions, which are likely cell type specific, of NF-{kappa}B and JNK (38, 39) and effects downstream of caspase-8 will determine the survival or apoptotic fate of a cell after TRAIL signaling. Although the precise mechanisms of bortezomib action and its relative tumor specificity remain to be fully elucidated, bortezomib can interact with many of the same pathways. Thus, there is interest in combining bortezomib with TRAIL signaling (40–42). Here, we describe in t(14;18)-positive lymphoma cells the effects of TRAIL signaling and alterations induced by bortezomib.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results and Discussion
 Translational Research Relevance...
 Conclusions
 References
 
Cell lines and reagents
The DoHH2 and WSU-FSCCL cell lines were maintained in log-phase growth in RPMI 1640 + 10% heat-inactivated fetal bovine serum, 2 mmol/L glutamine, 100 units/mL penicillin, and 100 g/mL streptomycin, as before (43).

Mapatumumab (previously HGS-ETR1, agonistic antibody to TRAIL-R1) and lexatumumab (previously HGS-ETR2, agonistic antibody to TRAIL-R2) were a generous gift from Human Genome Sciences.

Flow cytometry assays for apoptosis and caspase activity
Apoptosis. Cells were seeded at 1 x 105/mL without antibodies or with mapatumumab or lexatumumab antibody, incubated at 37°C for 24 h, and then harvested and washed with PBS. Cells were stained with FITC-conjugated Annexin V and propidium iodide using Annexin V kit (PharMingen, BD Biosciences). Samples were analyzed by FACScan (Becton Dickinson).

DR4 and DR5 receptors. Cells (0.5 x 106) were incubated with or without bortezomib at 5 nmol/L for WSU-FSCCL cells or 15 nmol/L for DoHH2 cells for 18 h. For DR4, 50 µL (0.5 µg) of FITC-conjugated DR4 antibody (Alexis Biochemicals) were added to the pellet and incubated in the dark on ice for 30 min. After two washes with PBS, cells were resuspended in PBS and analyzed by FACScan. Control antibody was nonspecific IgG (PharMingen, BD Biosciences). For DR5, 50 µL of primary antibody (0.25 µg of anti-DR5; Biosource) were added to the pellet, incubated for 1 h on ice, washed twice in PBS, and incubated in secondary antibody (1:100 dilution of FITC-conjugated donkey anti-mouse IgG; Jackson ImmunoResearch Laboratories, Inc.) in the dark on ice for 1 h. After two washes with PBS, cells were resuspended in PBS and analyzed by FACScan.

Caspase-3 activity. Cells (0.5 x 106) were incubated with or without mapatumumab (1 µg/mL) or lexatumumab (0.5 µg/mL) for 6 or 21 h and washed with cold PBS, and then Cytofix/Cytoperm solution was added and incubated on ice for 20 min. After two washes with permeabilized/wash buffer, cells were stained with phycoerythrin-conjugated active caspase-3 antibody as described in the BD PharMingen protocol. After another two washes with permeabilized/wash buffer, cells were resuspended in this buffer and analyzed by FACScan.

Active caspase-8 and caspase-9. Cells (0.5 x 106) were incubated in the presence of mapatumumab (1 µg/mL) or lexatumumab (0.5 µg/mL) for 6 or 21 h. Fluorochrome inhibitors of caspases (FLICA) apoptosis detection kits were used to detect active caspase-8 and caspase-9 (Immunochemistry Technologies, LLC). Kits used carboxyfluorescein-labeled fluoromethyl ketone peptide specific for caspase-8 FLICA (FAM-LETD-FMK) and caspase-9 FLICA (FAM-LEHD-FMK) that bind covalently to the active caspase. These inhibitors are nontoxic and cell permeable. As per manufacturer's directions, 10 µL of 30x FLICA solution were added to cells (0.5 x 106/300 µL culture medium), incubated at 37°C and 5% CO2 for 1 h, washed twice, and resuspended in wash buffer and counterstained with propidium iodide for FACScan analysis.

Western blot
Cells (0.5 x 106) were cultured in the presence or absence of 5 nmol/L bortezomib for 18 h and then for 15 min, 1 h, or 6 h in the presence or absence of mapatumumab or lexatumumab or isotype control. Cells were then pelleted, washed thrice in PBS, and lysed in ice-cold radioimmunoprecipitation assay buffer containing 100 µg/mL phenylmethylsulfonyl fluoride and 1 µg/mL aprotinin on ice for 30 min. Lysate was centrifuged at 1,200 x g for 15 min at 4°C, and supernatant was removed and separated on 10% to 20% SDS-PAGE (Tris-HCl Ready Gel; Bio-Rad) and transferred to Immobilon-P membrane (Millipore). Membrane was blocked with 5% nonfat dry milk-0.05% Tween 20 (Sigma) in PBS for 1 h and then incubated overnight in the presence of antibody at 4°C. Primary antibodies (and dilution used) were as follows: from Trevigen, Inc., anti-cleaved caspase-3 (1:1,000), anti-caspase-8 (1 µg/mL), anti-caspase-9 (1:1,000), and anti-glyceraldehyde-3-phosphate dehydrogenase (1:3,000) and from Cell Signaling Technology, antibodies to c-Jun (1:1,000), phosphorylated JNK (1:1,000), phosphorylated NF-{kappa}B (1:1,000), and phosphorylated I{kappa}B{alpha} (1:1,000). The blot was then incubated in secondary antibody conjugated to horseradish peroxidase (Amersham) for 1 h followed by chemiluminescent detection (enhanced chemiluminescence; Amersham).

Severe combined immunodeficient/human xenograft
Clearance of lymphoma cells from ascites was assessed as before (44). Briefly, female CB17 scid mice were bred, housed, and treated in the Fox Chase Cancer Center Laboratory Animal Facility under an approved protocol. Mice, 4 to 8 weeks old, were injected i.p. with 1 x 107 WSU-FSCCL cells. Mice bearing WSU-FSCCL received 1.0 mg/kg body weight bortezomib (i.v.) on day 6 and 200 µg of the indicated antibody i.p. on day 7 after lymphoma cell injection. Cells were collected sequentially from ascites by peritoneal washings on days 18, 39, and 54, stained for anti-human CD45 with phycoerythrin-labeled antibody, and analyzed by flow cytometry.


   Results and Discussion
Top
 Abstract
 Materials and Methods
 Results and Discussion
Translational Research Relevance...
 Conclusions
 References
 
We have investigated the effect of activating the TRAIL pathway with agonistic monoclonal antibodies to TRAIL receptors TRAIL-R1 (mapatumumab) and TRAIL-R2 (lexatumumab) in t(14;18)-positive, EBV-negative NHL cell lines. WSU-FSCCL is a cell line that represents perhaps the closest model to follicular lymphoma yet published (45). Although it does contain c-myc alteration in addition to t(14;18), it grows slowly in mice, leading to death in 2 to 3 months. DoHH2 is a commonly used transformed NHL line.

Receptor levels. Receptor levels were assessed by flow cytometry (Fig. 2 ). WSU-FSCCL cells express higher levels of DR5 (TRAIL-R2) than do DoHH2 cells. Both cell lines express DR4 (TRAIL-R1) at low levels. Bortezomib increases receptor levels, with a more pronounced effect on DR5 (Fig. 2). Despite the relatively low DR4 levels, both the mapatumumab (TRAIL-R1) and lexatumumab (TRAIL-R2) antibodies similarly inhibit growth of both cell lines. Apparently, low-density antibody binding is sufficient to signal through this pathway. Higher concentration of antibody is required, however, to achieve similar effect in DoHH2 cells. Further, DoHH2 cells require longer incubation time to achieve maximum effect of the antibodies, 24 h compared with 6 h for WSU-FSCCL cells. Bortezomib effects on growth inhibition seem to be additive (data not shown).


Figure 2
View larger version (22K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. DR4 and DR5 expression. Levels of surface DR4 (top row) and DR5 (bottom row) in DoHH2 (left column) and WSU-FSCCL (right column) cells after 24 h of incubation with or without bortezomib.

 
Induction of apoptosis. Mapatumumab (TRAIL-R1) and lexatumumab (TRAIL-R2) antibodies induce apoptosis in both cell lines (Table 1 ). Bortezomib has modest effects as a single agent in inducing apoptosis but significantly increases apoptosis when combined with either TRAIL-R agonist antibody (Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1. Effects on apoptosis of mapatumumab or lexatumumab ± bortezomib

 
As expected (Fig. 3 ), mapatumumab (TRAIL-R1) and lexatumumab (TRAIL-R2) antibodies induce caspase-3 and caspase-8 activity in FSCCL cells within 6 h. Again, however, DoHH2 cells require longer exposure. Activation of caspase-8 is due to direct signaling through the TRAIL receptors to the death-inducing signaling complex. Caspase-9, however, is also activated in both cell lines (Fig. 3), indicating "cross-talk" with the mitochondrial apoptosis pathway. This is typical of TRAIL signaling in so-called type II cells. To confirm the activation of both caspase-8 and caspase-9 pathways in NHL, immunoblots of lysates from FSCCL cells (Fig. 4 ) exposed to mapatumumab (TRAIL-R1) and lexatumumab (TRAIL-R2) antibodies were analyzed. These data confirmed that both antibodies induce cleavage of caspase-8, indicated by lower levels of the intact precursor (Fig. 4) and degradation of procaspase-8 with formation of the cleaved product (Fig. 4). In addition, BID is also cleaved, showing that the cross-talk of death receptor and mitochondrial pathways involves tBID. Thus, these lymphoma cell lines have signaling of both type I and type II cells. Furthermore, bortezomib in combination with TRAIL signals enhances both of these pathways, the direct activation of caspase-8 as well as the cleavage of BID and subsequent mitochondrial apoptotic pathway with cleavage of caspase-9 (Fig. 4).


Figure 3
View larger version (10K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 3. Levels of caspase activity. Caspase-3, caspase-8, and caspase-9 activity, assayed by flow cytometry after staining with FITC-caspase-3, caspase-8 FLICA, or caspase-9 FLICA, was assessed after incubation of WSU-FSCCL cells for 6 h or DoHH2 cells for 24 h with 1 µg of the indicated antibody.

 

Figure 4
View larger version (27K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 4. Levels of caspases and BID. Western blot analysis of caspase-8 and caspase-9 and BID in WSU-FSCCL cells treated with or without 5 nmol/L bortezomib (Bort) for 18 h followed by mapatumumab (Map) or lexatumumab (Lex) or isotype control for 6 h. G3PDH, glyceraldehyde-3-phosphate dehydrogenase.

 
TRAIL receptor signaling, besides activating caspases, can activate the NF-{kappa}B and c-Jun pathways (46). We have begun to examine these additional signaling pathways. The I{kappa}B kinase IKK is phosphorylated after mapatumumab (Fig. 5 ) and lexatumumab (data not shown), leading to phosphorylation of NF-{kappa}B. Bortezomib also activates this pathway in the lymphoma cells we tested, with the combination being supra-additive (Fig. 5). Whereas TRAIL receptor signals also lead to activation of JNK (Fig. 6 ) and phosphorylation of c-Jun, bortezomib has modest effects alone or in combination with TRAIL signals on the JNK pathway (Fig. 6).


Figure 5
View larger version (18K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 5. Levels of phosphorylated NF-{kappa}B (Phospho-NF-{kappa}B) and I{kappa}B{alpha} (Phospho-I{kappa}B{alpha}). Western blot analysis of WSU-FSCCL cells treated with or without 5 nmol/L bortezomib for 18 h followed by mapatumumab (mapa) or isotype control for 15 min or 1 h.

 

Figure 6
View larger version (14K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 6. Levels of phosphorylated JNK1 (Phospho JNK1) and JNK2 (Phospho JNK2). Western blot analysis of WSU-FSCCL cells treated with or without 5 nmol/L bortezomib for 18 h followed by mapatumumab, lexatumumab, or isotype control for 15 min or 1 h.

 
As a preliminary screen for in vivo activity, we have analyzed the number of lymphoma cells in ascites of lymphoma-bearing severe combined immunodeficient mouse xenografts (44). Both mapatumumab and lexatumumab can temporarily clear lymphoma cells from ascites fluid. Bortezomib alone has no effect in this assay. With the combination of bortezomib and either TRAIL-R agonist antibody, there is a trend to prolonged time until recurrence of lymphoma cells, indicating greater cell kill with the combination therapy (Table 2 ). This is statistically significant for lexatumumab, but not for mapatumumab, probably due to the small numbers of mice. Survival experiments are in progress to confirm these data.


View this table:
[in this window]
[in a new window]

  		Table 2. Clearance of FSCCL cells from ascites

 

   Translational Research Relevance and Opportunities
Top
 Abstract
 Materials and Methods
 Results and Discussion
 Translational Research Relevance...
Conclusions
 References
 
Both mapatumumab and lexatumumab are in clinical trials in a variety of malignancies, including non–Hodgkin‘s’ lymphoma, myeloma, and carcinomas. The complexities of TRAIL signaling present both problems and possibilities for optimizing clinical utility of this signaling pathway. An understanding of the variables that define sensitivity or resistance of cancer subtypes and for individual patients would permit focusing use of these agents in appropriate patients and groups. It is becoming clear that this will need to be done in each tumor type as differences in signaling make suspect extrapolation of findings from one system to another. Knowledge of the factors that define resistance or sensitivity, along with investigation of the intracellular signals induced by these agents in preclinical models, should permit selection of combinations for clinical trials based on rational design rather than empiricism. One such ongoing trial is of bortezomib plus mapatumumab in myeloma. Ultimately, monitoring of intracellular signals in clinical samples from patients treated with these agents and combinations will allow confirmation of the preclinical data and adjustments to be made or additional agents added to the combination based on what actually occurs in the patient.


   Conclusions
Top
 Abstract
 Materials and Methods
 Results and Discussion
 Translational Research Relevance...
 Conclusions
References
 
Agonistic antibodies to TRAIL receptors induce apoptosis in NHL cells through the expected caspase-8–dependent pathway. Agonistic antibodies to TRAIL receptors also induce apoptosis of NHL by recruiting mitochondrial pathways, and this is dependent on activation of caspase-8. Active caspase-8 cleaves BID, a proapoptotic BCL-2 family protein. Truncated BID is translocated to mitochondria where it activates BAX and BAK, leading to release of cytochrome c from mitochondria. Released cytochrome c activates caspase-9. This suggests that the combination may act by down-regulating proliferative pathways while up-regulating proapoptotic cascades. Bortezomib sensitizes NHL cells to the action of mapatumumab and lexatumumab. There is evidence for alterations in receptor levels, but also for altered signaling, as possible mechanisms for the bortezomib-positive interaction. Agonistic antibodies to TRAIL receptors may be of therapeutic benefit in NHL, alone or in combination with other apoptosis-inducing agents. Use of combination therapy is being explored further in preclinical experiments in our laboratory. Use of agonistic antibodies to the TRAIL receptors TRAIL-R1 and TRAIL-R2 in patients is currently being tested in clinical trials in solid tumors and hematologic malignancies.


   Footnotes
 
Presented at the Eleventh Conference on Cancer Therapy with Antibodies and Immunoconjugates, Parsippany, New Jersey, USA, October 12-14, 2006.

Received 4/26/07; accepted 5/16/07.


   References
Top
 Abstract
 Materials and Methods
 Results and Discussion
 Translational Research Relevance...
 Conclusions
 References
 

  1. Groves FD, Linet MS, Travis LB, Devesa SS. Cancer surveillance series: non-Hodgkin's lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst 2000;92:1240–51.[Abstract/Free Full Text]
  2. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the international lymphoma study group. Blood 1994;84:1361–92.[Free Full Text]
  3. Freedman AS, Gribben JG, Neuberg D, et al. High-dose therapy and autologous bone marrow transplantation in patients with follicular lymphoma during first remission. Blood 1996;88:2780–6.[Abstract/Free Full Text]
  4. Horning SJ, Negrin RS, Hoppe RT, et al. High-dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial remission: results of a phase II clinical trial. Blood 2001;97:404–9.[Abstract/Free Full Text]
  5. Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 2003;22:7359–68.[CrossRef][Medline]
  6. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16:2825–33.[Abstract]
  7. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005;105:1417–23.[Abstract/Free Full Text]
  8. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001;104:487–501.[CrossRef][Medline]
  9. Walczak H, Miller RE, Ariail K, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999;5:157–63.[CrossRef][Medline]
  10. Ashkenazi A, Pai RC, Fong S, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand in vivo. J Clin Invest 1999;104:155–62.[Medline]
  11. Shankar S, Srivastava RK. Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications. Drug Resist Updat 2004;7:139–56.[CrossRef][Medline]
  12. Nagane M, Pan G, Weddle JJ, Dixit VM, Cavenee WK, Huang HJ. Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res 2000;60:847–53.[Abstract/Free Full Text]
  13. Keane MM, Ettenberg SA, Nau MM, Russell EK, Lipkowitz S. Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res 1999;59:734–41.[Abstract/Free Full Text]
  14. Ganten TM, Haas TL, Sykora J, et al. Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs. Cell Death Differ 2004;11:S86–96.[CrossRef][Medline]
  15. Belka C, Schmid B, Marini P, et al. Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL. Oncogene 2001;20:2190–6.[CrossRef][Medline]
  16. Ashkenazi A, Dixit V. Death receptors: signaling and modulation. Science 1998;281:1305–8.[Abstract/Free Full Text]
  17. Rudner J, Jendrossek V, Lauber K, Daniel PT, Wesselborg S, Belka C. Type I and type II reactions in TRAIL-induced apoptosis—results from dose-response studies. Oncogene 2004;24:130–40.
  18. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998;94:491–501.[CrossRef][Medline]
  19. Werner A, de Vries E, Tait SWG, Bontjer I, Borst J. TRAIL receptor and CD95 signal to mitochondria via FADD, caspase-8/10, Bid, and Bax but differentially regulate events downstream from truncated Bid. J Biol Chem 2002;277:40760–7.[Abstract/Free Full Text]
  20. Lawrence D, Shahrokh Z, Marsters S, et al. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 2001;7:383–5.[CrossRef][Medline]
  21. Yagita H, Takeda K, Hayakawa Y, Smyth M, Okumura K. TRAIL and its receptors as targets for cancer therapy. Cancer Sci 2004;95:777–83.[CrossRef][Medline]
  22. Sheridan JP, Marsters SA, Pitti RM, et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997;277:818–21.[Abstract/Free Full Text]
  23. Srivastava RK. TRAIL/Apo-2L: mechanisms and clinical applications in cancer. Neoplasia 2001;3:535–46.[CrossRef][Medline]
  24. Ehrhardt H, Fulda S, Schmid I, Hiscott J, Debatin K-M, Jeremias I. TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NG-KB. Oncogene 2003;22:3842–52.[CrossRef][Medline]
  25. Griffith TS, Rauch CT, Smolak PJ, et al. Functional analysis of TRAIL receptors using monoclonal antibodies. J Immunol 1999;162:2597–605.[Abstract/Free Full Text]
  26. Zhang L, Fang B. Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther 2005;12:228–37.[CrossRef][Medline]
  27. Nika N, Korsmeyer SJ. Cell death: critical control points. Cell 2004;116:205–19.[CrossRef][Medline]
  28. Reed JC. Apoptosis mechanisms: implications for cancer drug discovery. Oncology 2004;18:11–20.
  29. Bin L, Li X, Xu LG, Shu HB. The short splice form of Casper/c-FLIP is a major cellular inhibitor of TRAIL-induced apoptosis. FEBS Lett 2002;510:37–40.[CrossRef][Medline]
  30. Kim Y, Suh N, Sporn M, Reed JC. An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis. J Biol Chem 2002;277:22320–9.[Abstract/Free Full Text]
  31. Cummins JM, Kohli M, Rago C, Kinzler KW, Vogelstein B, Bunz F. X-linked inhibitor of apoptosis protein (XIAP) is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human cancer cells. Cancer Res 2004;64:3006–8.[Abstract/Free Full Text]
  32. Zauli G, Sancilio S, Cataldi A, Sabatini N, Bosco D, Di Pietro R. PI-3K/Akt and NF-{kappa}B/I{kappa}B{alpha} pathways are activated in Jurkat T cells in response to TRAIL treatment. J Cell Physiol 2005;202:900–11.[CrossRef][Medline]
  33. Rathore N, Matta H, Chaudhary PM. An evolutionary conserved pathway of nuclear factor-{kappa}B activation involving caspase-mediated cleavage and N-end rule pathway-mediated degradation of I{kappa}B{alpha}. J Biol Chem 2004;279:39358–65.[Abstract/Free Full Text]
  34. Franzoso G, Zazzeroni F, Papa S. JNK: a killer on a transcriptional leash. Cell Death Differ 2003;10:13–5.[CrossRef][Medline]
  35. Tournier C, Hess P, Yang DD, et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 2000;288:870–4.[Abstract/Free Full Text]
  36. Lei K, Nimnual A, Zong WX, et al. The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase. Mol Cell Biol 2002;22:4929–42.[Abstract/Free Full Text]
  37. Lamb JA, Ewen ME. Cyclin D1 and molecular chaperones: implications for tumorigenesis. Cell Cycle 2003;2:525–7.[Medline]
  38. De Smaele E, Zazzeroni F, Papa S, et al. Induction of gadd45ß by NF-{kappa}B downregulates pro-apoptotic JNK signalling. Nature 2001;414:308–13.[CrossRef][Medline]
  39. Tang G, Minemoto Y, Dibling B, et al. Inhibition of JNK activation through NF-{kappa}B target genes. Nature 2001;14:313–7.
  40. Kim S, Choi K, Dwon D, Benveniste EN, Choi C. Ubiquitin-proteasome pathway as a primary defender against TRAIL-mediated cell death. Cell Mol Life Sci 2004;61:1075–81.[CrossRef][Medline]
  41. Sayers TJ, Brooks AD, Koh CY, et al. The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. Blood 2003;102:303–10.[Abstract/Free Full Text]
  42. Johnson TR, Stone K, Nikrad M, et al. The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. Oncogene 2003;22:4953–63.[CrossRef][Medline]
  43. Smith MR, Xie T, Zhao-Zong Z, Joshi I. Efficacy of treatment with antisense oligonucleotides complementary to immunoglobulin sequences of bcl-2/immunoglobulin fusion transcript in a t(14;18) human lymphoma-scid mouse model. Clin Cancer Res 2001;7:400–6.[Abstract/Free Full Text]
  44. Smith MR, Joshi I, Jin F, Obasaju C. Enhanced efficacy of gemcitabine in combination with anti-CD20 monoclonal antibody against CD20+ non-Hodgkin's lymphoma cell lines in vitro and in scid mice. BMC Cancer 2005;5:103.[CrossRef][Medline]
  45. Mohammad RM, Mohamed AN, Smith MR, Jawadi NS, Al-Katib A. A unique EBV-negative low-grade lymphoma line (WSU-FSCCL) exhibiting both t(14;18) and t(8;11). Cancer Genet Cytogenet 1993;70:62–7.[CrossRef][Medline]
  46. Wen-Hui H, Johnson H, Shu H-B. Tumor necrosis factor-related apoptosis-inducing ligand receptors signal through NF-{kappa}B and JNK activation and apoptosis through distinct pathways. J Biol Chem 1999;274:30603–10.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
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]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Smith, M. R.
Right arrow Articles by Joshi, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Smith, M. R.
Right arrow Articles by Joshi, I.

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