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NEOPLASIA
From the Jerome Lipper Multiple Myeloma Center,
Department of Adult Oncology, Dana Farber Cancer Institute, and
Department of Medicine, Harvard Medical School, Boston, MA.
Multiple myeloma (MM) remains incurable and novel treatments are
urgently needed. Preclinical in vitro and in vivo evaluations were
performed to assess the potential therapeutic applications of human
recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) in MM. TRAIL/Apo2L potently induced apoptosis of MM cells from patients and the majority of MM cell lines,
including cells sensitive or resistant to dexamethasone (Dex),
doxorubicin (Dox), melphalan, and mitoxantrone. TRAIL/Apo2L also
overcame the survival effect of interleukin 6 on MM cells and did not
affect the survival of peripheral blood and bone marrow mononuclear
cells and purified B cells from healthy donors. The status of the TRAIL
receptors (assessed by immunoblotting and flow cytometry) could not
predict TRAIL sensitivity of MM cells. The anti-MM activity of
TRAIL/Apo2L was confirmed in nu/xid/bg mice xenografted with
human MM cells; TRAIL (500 µg intraperitoneally daily for 14 days)
was well tolerated and significantly suppressed the growth of
plasmacytomas. Dox up-regulated the expression of the TRAIL receptor
death receptor 5 (DR5) and synergistically enhanced the effect of TRAIL
not only against MM cells sensitive to, but also against those
resistant to, Dex- or Dox-induced apoptosis. Nuclear factor (NF)- The uniformly fatal outcome of multiple
myeloma (MM)1-3 warrants the development of novel
biologically based treatment strategies that selectively induce
apoptosis of malignant plasma cells. One such approach involves tumor
necrosis factor (TNF)-related apoptosis-inducing ligand or Apo2 ligand
(TRAIL/Apo2L), a member of a superfamily of cell death-inducing ligands
that also includes TNF- TRAIL/Apo2L induces apoptosis in tumor cells of diverse
origins,4,6-15 both in vitro and in various in vivo tumor
models. In contrast, TRAIL/Apo2L is not toxic to most normal human
cells in vitro,8-10 or to TRAIL-treated
animals,4,7 even though the messenger RNAs for TRAIL
receptors are expressed in a wide range of normal
tissues.16 This favorable profile of TRAIL in various
tumor models prompted us to investigate whether this death ligand is
active against MM cells.17
In this study, we show that TRAIL/Apo2L selectively induces
apoptosis of human MM cells, including MM cell lines, both sensitive and resistant to dexamethasone (Dex) and chemotherapy, as well as
patient MM cells, and exhibits in vivo anti-MM activity in mice
xenografted with human plasmacytomas. Moreover, doxorubicin (Dox) and
agents that inhibit NF- MM cell lines and MM patient cells
Reagents
Determination of TRAIL receptor status by immunoblotting Cell extracts from 10 MM cell lines (ARH-77, OCI-My-5, RPMI-8226/S, S6B45, U266, IM-9, HS-Sultan, MM-1S, MM-AS, and MM-SV) were examined by Western blot analysis for the expression of the DR4, DR5, DcR1, and DcR2 receptors for TRAIL/Apo2L. The Ewing sarcoma cell line SK-N-MC and the DHL-4 and DHL-10 cells served as positive controls for TRAIL/Apo2L receptor expression, as previously documented.15 Immunoblotting analysis was performed as previously described,19 and equal protein loading was confirmed by tubulin detection.Determination of TRAIL receptor status by flow cytometric analysis The MM cells were characterized for their surface expression of TRAIL receptors by flow cytometry. HeLa cells served as positive control for DR4/DR5 expression and as negative controls for DcR1 and DcR2 expression. SK-N-MC and CHP100S Ewing sarcoma cells served as negative controls for surface expression of DR4 and DR5, respectively. DHL-10 cells served as positive control for DcR1 and DcR2 expression. Staining was performed as previously described.20,21 Briefly, for each cell line, 106 cells were incubated with the appropriate anti-TRAIL receptor antibody or a respective control (5.0 µg) for 45 minutes. Specifically, DR4 and DR5 expression was assessed with anti-DR4 and anti-DR5 mAbs (mouse IgG1 and IgG2b as respective controls) and confirmed with goat antihuman DR4 and DR5 polyclonal antibodies, using goat IgG for control staining. DcR1 and DcR2 expression was assessed with mouse anti-DcR1 and DcR2 mAbs and goat anti-DcR1 (or rabbit anti-DcR1) and goat anti-DcR2 polyclonal antibodies. Cells were then washed with phosphate-buffered saline (PBS) and incubated for 45 minutes with 2.0 µg goat antimouse IgG FITC-conjugated F(ab')2 fragment for anti-DR4 and anti-DR5 mAb phenotypic analyses or with a donkey antigoat IgG FITC-conjugated F(ab')2 fragment for the DcR1, DcR2, DR4, and DR5 analyses with the goat polyclonal antibodies. Cells were then washed, fixed with 1% formaldehyde PBS, and analyzed on a EPICS-XL-MCL flow cytometer (Coulter).Survival, death, and apoptosis assays The effect of TRAIL/Apo2L on the survival of MM cells was examined by cell cycle analyses, using propidium iodine (PI) staining to detect cells in sub-G1 gate, as previously reported22 and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assays, as previously described.14 Induction of apoptosis was confirmed and quantitatively assessed by annexin V/PI staining and Apo2.7 staining.PI staining. For cell cycle analysis, 1 × 106 MM cells were incubated with 0.001 to 1000 ng/mL LZ-TRAIL for 24 to 48 hours. The cells were then washed twice with PBS, permeabilized with 70% ethanol in PBS for 30 minutes at 4°C, incubated with 0.5 mL of a 50-µg/mL PI solution containing 20 U/mL RNaseA (Boehringer Mannheim, Indianapolis, IN) for 30 minutes, and analyzed by flow cytometry. MTT colorimetric assay.
Cells were plated in 48-well plates to 70% to 80% confluence and then
incubated for 18 hours at 37°C with LZ-TRAIL (10-1000 ng/mL) in 2.5%
or 10% bovine serum-supplemented RPMI medium. In some experiments, MM
cells were preincubated with doxorubicin (250 or 500 ng/mL for 4 hours), the NF- Annexin V/PI staining.
Detection of early apoptotic cells was performed with the annexin V-PI
detection kit (Immunotech/Beckman Coulter). Briefly, 106 MM
cells were exposed for 4 hours to TRAIL or media, washed with Dulbecco
modified Eagle medium (DMEM), incubated in the dark at 4°C with
annexin V-FITC and PI for 15 minutes, and then analyzed by dual-color
flow cytometry. Cells that were annexin V-FITC+ (with
translocation of phosphatidylserine from the inner to the outer leaflet
of the plasma membrane) and PI Apo2.7 staining. Quantification of apoptosis induction was also performed by Apo2.7 immunostaining, which specifically detects the 38-kd mitochondrial membrane antigen 7A6 that is exposed on the mitochondrial membrane of apoptotic cells only and can be used as a late apoptotic marker in nonpermeabilized cells.23,24 MM cells cultured for 18 hours with TRAIL or media were labeled with the Apo2.7-PE conjugated mAb or mouse IgG1 isotype control, and subsequently analyzed by flow cytometry. Effect of IL-6 on TRAIL-induced apoptosis The MM-1S cells, which are rescued by IL-6 from Dex-induced apoptosis,25,26 along with S6B45 and RPMI-8226/S cells, were incubated for 24 hours with TRAIL (in concentrations up to 1000 ng/mL) in the presence or absence of IL-6 (100 ng/mL). Survival of MM cells was then assessed by MTT assay and PI.Sensitization to TRAIL-induced apoptosis by Dox,
NF-  B inhibitory peptide SN-50 or its mutant control peptide
SN-50M. MM-1S cells were also preincubated with 0.1 µM of the
proteasome inhibitor PS-341 for 4 hours. Following each of these
pretreatments, TRAIL (50 or 100 ng/mL) was added for 18 hours, and the
samples were analyzed by MTT assay.
Effect of TRAIL on healthy donor B cells Peripheral blood B cells were obtained from 5 healthy donors by Ficoll-Hypaque (Pharmacia) density centrifugation of peripheral blood mononuclear cells (PBMCs), depletion of monocytes by overnight adhesion on plastic, and enrichment for B cells either by removal of T cells by sheep red blood cell rosetting or by positive selection for CD19+ cells by fluorescence-activated cell sorting. B cells (> 85% CD19+) or unpurified PBMCs or BMMCs were exposed to TRAIL (10-1000 ng/mL) for 18 to 24 hours. Normal PBMCs or B cells were also pretreated with Dox, PS-341, or SN50 before exposure to TRAIL (50-100 ng/mL).In vivo administration of TRAIL to nu/xid/bg mice xenografted with human plasmacytomas Six- to 8-week-old male nu/xid/bg mice obtained from Jackson Laboratories (Wilmington, DE) were cared for in the animal research facility of the Dana-Farber Cancer Institute in accordance with National Institutes of Health (NIH) guidelines and those of the Animal Care and Use Committee at our institution. Mice were engrafted with 107 S6B45 human MM cells by subcutaneous injection in the right flank. On formation of a palpable tumor, mice were randomly placed into 2 cohorts of 8 mice and received either PBS or recombinant human TRAIL at 500 µg daily by intraperitoneal administration for 14 consecutive days. Tumor volumes and weights for the treated mice were obtained every other day.Statistical analysis The potential correlation of TRAIL receptor status profile with the sensitivity or resistance of each cell line to TRAIL was evaluated with the use of the McNemar paired 2 test.
The tumor volumes of human plasmacytoma xenografts (at days 1, 5, 8, 11, 14, and 18 after initiation of TRAIL administration) were compared
with the PBS-treated controls by the Mann-Whitney U test.
One-way analysis of variance and the Duncan post hoc test was performed
to compare, within the TRAIL-treated cohort (or the control group), the
tumor volumes at different time points of the study. Interactions
between TRAIL and Dox, NF-B inhibitory peptide, or PS-341 were
classified by the fractional inhibition method, as previously
described,27 and also examined by a 2-way analysis of
variance, followed by the Duncan post hoc test. A P value
less than .05 was considered statistically significant.
TRAIL/Apo2L induces apoptosis of MM cell lines and MM patient cells We first determined the effect of TRAIL/Apo2L on chemotherapy-sensitive and chemotherapy-resistant MM cell lines, as well as patient MM cells. In 10 of 16 lines tested (ARP-1, MM-1S, MM-1R, RPMI-8226/S, Dox6, Dox40, LR5, MR20, U266, and S6B45), TRAIL/Apo2L induced significant reductions in cell survival (with median effective dose values of < 300 ng/mL), assessed by the MTT assay (Figure 1A). Five MM lines, ARH-77, HS Sultan, IM-9 (Figure 1B), MM-AS, and MM-SV cells (data not shown) had more than 70% survival after exposure to doses of TRAIL/Apo2L as high as 1000 ng/mL and were considered TRAIL resistant. The OCI-My5 cells had an intermediate pattern of TRAIL-induced cell death, with about 50% survival at a TRAIL dose of 1000 ng/mL (Figure 1A), indicating moderate TRAIL sensitivity. The TRAIL sensitivity or resistance of MM cells was confirmed by annexin V-FITC/PI staining (for detection of early apoptotic annexin V+ PI
cells) (Figure 2A-C), cell cycle analysis
following PI staining (Figure 2D,E), and staining with the Apo2.7 mAb
for detection of late apoptotic cells (Figure 2F).
We also evaluated the effect of TRAIL/Apo2L on freshly isolated MM
cells from 5 patients. MM (CD38+/CD45RA
Effect of TRAIL/Apo2L on healthy donor B cells and BMMCs We next investigated whether the proapoptotic effect of TRAIL/Apo2L is selective against MM cells or whether it may also affect normal hematopoietic cells. Peripheral blood normal B cells from 7 healthy donors, as well as BMMCs from another 3 donors, were incubated with LZ-TRAIL at concentrations (10-1000 ng/mL) that induce MM cell apoptosis. The percentage of dead/apoptotic (sub-G1 region of the cell cycle profile) normal B cells after exposure to TRAIL/Apo2L did not differ from untreated controls (Figure 4A). MTT assays of normal donor PBMCs revealed no TRAIL-induced reduction in survival, whereas Apo2.7 staining of normal donor PBMCs with counterstaining for CD19, CD3, or CD14 revealed no reduction in the survival of B lymphocytes, T lymphocytes, and monocytes/macrophages, respectively (data not shown). Normal donor BMMCs were also treated with TRAIL (100-1000 ng/mL) for 18 hours and then analyzed by dual-color flow cytometry for CD38-FITC/Apo2.7-PE (to detect late apoptotic Apo2.7+ cells). TRAIL induced apoptosis of neither CD38+ or CD38 cells, suggesting that
it does not affect the survival of normal plasma cells or other
populations of normal BMMCs (Figure 4B,C).
IL-6 does not confer resistance to TRAIL-induced apoptosis Interleukin 6 is a potent growth and survival factor for MM cells and is known to inhibit apoptosis induced by Dex25 and TRAIL-related FasL.26,28 We therefore examined whether IL-6 blocks TRAIL-induced apoptosis of MM cells. MM-1S, S6B45, and RPMI-8226/S cells were cultured with TRAIL (0.001-1000 ng/mL) in the presence or absence of IL-6 (10-100 ng/mL). IL-6 did not abrogate TRAIL-induced apoptosis of S6B45, RPMI-8226/S cells, or MM-1S cells (Figure 5), even at IL-6 concentrations 2 logs higher than those shown to inhibit apoptosis in these MM cells. Moreover, TRAIL induced apoptosis of S6B45 cells, which constitutively produce IL-6 in picogram concentrations (< 10 pg/mL).29 These findings indicate that IL-6 is not a pathophysiologically significant modulator of TRAIL-induced apoptosis, in contrast to its documented role in protecting MM cells against Dex-induced apoptosis.26,28
TRAIL receptor expression in MM cell lines We investigated whether differences in MM cell sensitivity to TRAIL correlate with variations in expression of TRAIL receptors by performing immunoblotting of MM cell lysates (Figure 6) and flow cytometric analysis to detect surface expression of receptors (Figure 7). Immunoblotting analysis of 10 MM cell lines (MM-AS, MM-SV, MM-1S, U266, RPMI-8226/S, S6B45, OCI My-5, ARH-77, HS Sultan, and IM9) demonstrated expression of all 4 receptors in all MM lines (including high levels of DR5 and DcR2 in all lines and variable DR4 and DcR1 expression), regardless of their TRAIL sensitivity status. Some TRAIL-resistant lines (eg, ARH-77, HS Sultan, and IM-9) appeared to have high expression of DcR1 by immunoblotting. However, several TRAIL-sensitive lines (eg, MM-1S, U266, and OCI-My5) also had high levels of DcR1 expression. Therefore, the DcR1 status cannot serve to predict TRAIL sensitivity or resistance of MM cells. Furthermore, whereas surface expression (by flow cytometry) was also positive in all lines for DR5 and DcR2, it was negative for DcR1 (for all 3 different antihuman DcR1 antibodies tested), excluding any correlation of these parameters with TRAIL sensitivity. Although 2 TRAIL-resistant lines (ARH-77 and IM-9) had absent or dimly positive surface DR4 expression (despite high levels of expression in Western blots), other TRAIL-resistant cells (eg, HS Sultan; Figure 7) had strong surface expression of DR4 receptors, whereas no correlation was noted between lack of surface DR4 expression and TRAIL resistance in our panel of MM cell lines (McNemar paired2 test,
P = .25). Although some TRAIL-sensitive MM cells (eg,
RPMI-8226/S) had higher levels of surface DR5 expression than the
TRAIL-resistant ARH-77 or IM-9 cells, our panel of cell lines included
both strongly surface DR5+ TRAIL-resistant cells (eg, HS
Sultan cells) and weakly DR5+ TRAIL-sensitive cells. This
indicates lack of correlation between the levels of DR5 expression with
TRAIL sensitivity. Therefore, the status of signaling or "decoy"
TRAIL receptors, assessed using either immunoblotting analysis or flow
cytometry, cannot serve to reliably predict the TRAIL sensitivity (or
resistance) of MM cells.
Dox enhances the in vitro proapoptotic effect of TRAIL on MM cells We next determined whether the cytotoxic agent Dox enhanced the proapoptotic effect of TRAIL in TRAIL-sensitive and TRAIL-resistant MM cells, because Dox has been reported to enhance the apoptotic activity of TRAIL and up-regulate the DR5 receptor in MCF-7 breast cancer cells.30 MM-1S, MM-1R, RPMI-8226/S, and RPMI-8226/Dox40 cells were pretreated with Dox (250 or 500 ng/mL) for 4 hours, and then exposed to LZ-TRAIL (50 ng/mL) for 18 hours. MTT assays (Figure 8) revealed that Dox significantly enhanced the proapoptotic effect of TRAIL in these cells, reducing their survival to levels lower than expected if Dox and TRAIL had an additive interaction (P < .01, for each cell line). Western blot analysis and flow cytometry revealed that a 24-hour exposure of MM-1S cells to Dox (250 and 500 ng/mL) induced a significant dose-dependent up-regulation in the expression of DR5 and to a lesser extent of DcR1, but not of DR4 TRAIL receptor, whereas a modest decrease of DcR2 expression was also noted (Figure 9).
NF- B may play a role in the regulation of MM cell
survival,31 we investigated whether inhibition of NF-B
transcriptional activity could modulate the response of MM cells to
TRAIL. MM-1S and RPMI-8226/S cells, as well as the TRAIL-resistant
ARH-77 and IM-9 cells, were pretreated for 4 hours with a nontoxic
concentration (30 ng/mL) of the cell-permeable peptide SN50 or with its
mutant control peptide SN50M. SN50 binds to the nuclear localization sequence of NF-B and blocks its nuclear translocation, thus
inhibiting its transcriptional activity.32 As seen in
Figure 10, SN50 pretreatment enhanced
the sensitivity of MM-1S cells (< 5% survival) to TRAIL (50 ng/mL),
in contrast to pretreatment of MM-1S with the mutant control peptide
SN50M (which led to > 50% survival of MM-1S cells). Importantly,
SN50 also reversed the TRAIL resistance of ARH-77 and IM-9 cells
(Figure 10C,D); SN-50 pretreatment and TRAIL (50 ng/mL) led to less
than 60% survival of these cells, whereas these cells were resistant
even to 1000 ng/mL TRAIL without SN50 pretreatment. We also determined
whether the proteasome inhibitor PS-341, which is known to inhibit the
transcriptional activity of NF-B by blocking the degradation of the
IB inhibitory protein,33 sensitized MM cells to
TRAIL-induced apoptosis. MM-1S cells were preincubated with 0.1 µM
PS-341 for 3 hours and then exposed to TRAIL (50 or 100 ng/mL) for 18 hours. These studies demonstrated that PS-341 preincubation augmented
the sensitivity of MM-1S cells to TRAIL (Figure
11).
Normal B cells are not sensitized to TRAIL by either Dox, PS-341,
or NF- B did not sensitize normal B cells or PBMCs (data not
shown) to TRAIL. Importantly, in the context of these pretreatments, B
cells remained refractory to TRAIL at doses up to 300 ng/mL, in
contrast to MM cells, which were sensitized by these pretreatments at
doses of TRAIL as low as 50 ng/mL.
Effect of TRAIL on established human plasmacytomas in xenografted nu/xid/bg mice We next examined whether TRAIL was active against MM in vivo by treating established human plasmacytomas in nu/xid/bg mice with either TRAIL (n = 8) or PBS (n = 8). Mean plasmacytoma volumes were not significantly different at initiation of therapy on day 1 (Figure 12, P = .328 by Mann-Whitney test). Following TRAIL administration, the volume of established xenografts did not show a significant increase from baseline (P = .851, Kruskal-Wallis nonparametric one-way analysis of variance), whereas PBS-treated mice showed increasing mean tumor volumes, which became significantly greater than baseline beyond day 8 (P < .05 by Kruskall-Wallis test). Following 11 days of TRAIL administration, the mean tumor volumes for TRAIL-treated mice were significantly less than the mean tumor volumes for mice treated with PBS (P = .009 by Mann-Whitney test). Moreover, complete plasmacytoma eradication was observed in 1 of 8 TRAIL-treated animals on day 11. Significantly lower mean tumor volumes for TRAIL-treated versus PBS-treated mice were again observed on day 14 (P = .032) and on day 18 (P = .046). However, on day 18 (4 days following termination of TRAIL administration), the mean plasmacytoma volume in TRAIL-treated animals increased compared to the baseline mean tumor volume for these animals (P = .006), yet remained significantly less than that in PBS-treated mice. On day 18, the PBS-treated animals were moribund and all animals from both cohorts were euthanized in accordance with NIH and our institutional guidelines. To determine if xenografted plasmacytoma cells remained sensitive to TRAIL despite the apparent increase in tumor volume following discontinuation of TRAIL therapy, tumors from 2 animals were excised, mechanically dissociated, and cultured with LZ-human TRAIL (1000 ng/mL) for 24 hours. These studies demonstrated that the excised human plasmacytomas from 2 TRAIL-treated mice underwent apoptosis following culture with TRAIL, as assessed by PI and annexin V staining. Overall, mice treated with TRAIL tolerated therapy well, with continued display of weight gain throughout therapy (data not shown). One TRAIL-treated mouse died on day 11 of toxicity not related to TRAIL (intestinal puncture), although this mouse also exhibited a tumor response to TRAIL therapy.
In a preliminary report, we demonstrated that TRAIL/Apo2L induced apoptosis of most MM cell lines and MM patient tumor cells,17 a finding subsequently confirmed by other groups.34-37 In this report, we demonstrate that most MM cell lines, including those that are resistant to Dex and chemotherapeutic agents, are sensitive to TRAIL/Apo2L. Moreover, TRAIL induced apoptosis of MM cells from 5 of 5 patients and did not affect non-MM BMMCs, normal B cells, and hematopoietic progenitor cells. Importantly, IL-6, a major growth and survival factor of MM cells, blocks apoptosis induced by a variety of proapoptotic agents, including Dex25 and FasL,26,38 but does not abrogate TRAIL-induced apoptosis. The differential survival effect of IL-6 in protecting from FasL-induced, but not TRAIL-induced, apoptosis may reflect differences in downstream signaling of these tumoricidal TNF-related cytokines. Detailed analyses of our panel of MM cell lines for TRAIL receptor
expression by both Western blot and flow cytometry were undertaken to
discern differences that might confer TRAIL sensitivity versus
resistance. The death signaling receptors DR4 and DR5 were expressed in
all MM cell lines, evidenced by both Western blot and flow cytometric
analyses, except for the TRAIL-resistant ARH-77 and IM-9 cell lines,
which lack surface DR4 (despite strong expression by immunoblotting
analysis). However, the level of surface expression of neither DR4 nor
DR5 correlates with TRAIL-resistance in our panel of MM lines; some
TRAIL-resistant cells (eg, HS Sultan) had very strong expression of
both receptors, in comparison to some TRAIL-sensitive cells (eg,
MM-1S). Mutations at the death domain of the DR5 receptor have been
described in other neoplasias39,40 and could also account
for TRAIL resistance in cells that lack surface DR4 expression, such as
ARH-77 and IM-9 cells. However, we were able to sensitize these cells
to TRAIL by NF- The potent and selective proapoptotic effect of TRAIL/Apo2L against MM patient cells and most MM cell lines in vitro prompted us to evaluate its in vivo anti-MM effect in nu/bg/xid mice bearing established human plasmacytoma xenografts. Importantly, TRAIL inhibited the growth of human plasmacytomas and induced complete tumor eradication in 1 of 8 TRAIL-treated animals at the dose regimen (ie, 500 µg daily for 14 days) evaluated. Following discontinuation of TRAIL, increases in the mean tumor volumes were observed in TRAIL-treated mice. However, it is unlikely that selection of TRAIL-resistant MM cells contributed to these findings because plasmacytoma cells taken from 2 mice remained sensitive to TRAIL. It is possible that the use of higher TRAIL/Apo2L doses may be more effective in further shrinking or eradicating established plasmacytomas; studies evaluating higher doses of TRAIL/Apo2L, which have been successfully used in in vivo models of other neoplasias,4,7 are currently under way in our MM murine model. Importantly, TRAIL/Apo2L appeared to be well tolerated by the mice. The observed responses and lack of toxicity of LZ-TRAIL in this human plasmacytoma model are not attributable solely to differences in cross-species activity of human LZ-TRAIL, because both human and murine TRAIL are equipotent against murine cell lines in vitro.4 However, recent reports of potential toxicity of the LZ-TRAIL to human hepatocytes46 and neuronal tissues47 suggest that other forms of TRAIL, without these adverse effects, may be preferable for future clinical use. Concerns regarding emergence of TRAIL resistance, as well as potential TRAIL-related side effects in vivo, prompted us to investigate mechanisms to enhance the tumoricidal activity and therapeutic index of TRAIL/Apo2L-based therapies. We therefore examined whether Dox, which up-regulates the DR5 death signaling receptor48-50 and is commonly used to treat MM, could sensitize MM cells to TRAIL. We demonstrated that pretreatment of several MM cell lines with Dox, at clinically relevant concentrations, significantly enhanced the TRAIL sensitivity of MM cells. Specifically, Dox induced significant up-regulation of the DR5 receptor expression (and a much lesser increase in DcR1, as well as a small decrease in DcR2 expression) and, importantly, had a synergistic interaction with TRAIL/Apo2L in inducing apoptosis of MM-1S cells. This finding is consistent with previous reports in other malignancies.49-51 We showed that, within our panel of MM cell lines, the status of functional or "decoy" TRAIL receptors at baseline cannot per se explain why a particular cell line is TRAIL sensitive or resistant (possibly due to downstream intracellular modulators of apoptosis). However, this does not preclude the possibility that changes of surface expression of TRAIL receptor(s) in each particular cell line (eg, in the setting of Dox stimulation) may modulate its TRAIL sensitivity. Interestingly, the synergy of Dox with TRAIL was also documented against MM cells resistant to Dex- or Dox-induced apoptosis, suggesting that the molecular pathway(s) underlying this synergy are independent of classical mechanisms of drug resistance in MM cells. In particular, the Dox-induced sensitization of "Dox-resistant" MM cells to TRAIL/Apo2L suggests that Dox-induced apoptosis and sensitization to TRAIL/Apo2L constitute distinct biologic end points and are likely mediated by distinct mechanisms; therefore, intracellular Dox concentrations that cannot themselves induce apoptosis may be sufficient to sensitize MM cells to TRAIL/Apo2L. Ongoing efforts are delineating the mechanism underlying TRAIL/Apo2L sensitization and DR5 up-regulation by Dox. We also investigated whether agents that inhibit NF- In anticipation of future clinical trials of TRAIL/Apo2L alone and in
combination with TRAIL/Apo2L-sensitizing agents, we determined whether
TRAIL-resistant normal hematopoietic cells are also sensitized to
TRAIL/Apo2L by pretreatment with Dox or NF- In summary, TRAIL/Apo2L is a potent and selective inducer of apoptosis
in drug-sensitive and drug-resistant MM cell lines, as well as in
patient MM cells. TRAIL/Apo2L-induced apoptosis of MM cells is not
abrogated by IL-6, a major growth and survival factor for MM cells.
Factors other than TRAIL receptor status likely account for patterns of
TRAIL sensitivity and resistance in MM cells and are currently being
evaluated in our laboratory. TRAIL exhibited anti-MM activity in vivo
in mice xenografted with human plasmacytomas. Lastly, Dox and agents
inhibiting NF-
Submitted October 16, 2000; accepted March 18, 2001.
Supported by the Laurie Strauss Leukemia Foundation (S.P.T. and N.M.), the International Myeloma Foundation (S.P.T.), the American Society of Clinical Oncology Young Investigator Award (S.P.T.), the Multiple Myeloma Research Foundation (S.P.T.), and the Doris Duke Distinguished Clinical Research Scientist Award (K.C.A.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Kenneth C. Anderson, Dept of Adult Oncology, Dana Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: kenneth_anderson{at}dfci.harvard.edu.
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 N. Parquet, R. Nimmanapalli, C. Anasetti, M. Alsina, W. Dalton, and L. E. Perez Bortezomib Partially Overcomes TNF-Related Apoptosis Inducing ligand/Apo-2L (TRAIL/Apo-2L) Environment Mediated-Drug Resistance (EM-DR). Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 2459 - 2459. [Abstract] [Full Text]
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G. Zauli, E. Rimondi, V. Nicolin, E. Melloni, C. Celeghini, and P. Secchiero TNF-related apoptosis-inducing ligand (TRAIL) blocks osteoclastic differentiation induced by RANKL plus M-CSF Blood, October 1, 2004; 104(7): 2044 - 2050. [Abstract] [Full Text] [PDF]
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T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF]
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H. Jin, R. Yang, S. Fong, K. Totpal, D. Lawrence, Z. Zheng, J. Ross, H. Koeppen, R. Schwall, and A. Ashkenazi Apo2 Ligand/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Cooperates with Chemotherapy to Inhibit Orthotopic Lung Tumor Growth and Improve Survival Cancer Res., July 15, 2004; 64(14): 4900 - 4905. [Abstract] [Full Text] [PDF]
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W. Matsuyama, M. Yamamoto, I. Higashimoto, K.-i. Oonakahara, M. Watanabe, K. Machida, T. Yoshimura, N. Eiraku, M. Kawabata, M. Osame, et al. TNF-related apoptosis-inducing ligand is involved in neutropenia of systemic lupus erythematosus Blood, July 1, 2004; 104(1): 184 - 191. [Abstract] [Full Text] [PDF]
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 D. C. Spierings, E. G. de Vries, E. Vellenga, F. A. van den Heuvel, J. J. Koornstra, J. Wesseling, H. Hollema, and S. de Jong Tissue Distribution of the Death Ligand TRAIL and Its Receptors J. Histochem. Cytochem., June 1, 2004; 52(6): 821 - 831. [Abstract] [Full Text] [PDF]
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Y.-T. Tai, L. P. Catley, C. S. Mitsiades, R. Burger, K. Podar, R. Shringpaure, T. Hideshima, D. Chauhan, M. Hamasaki, K. Ishitsuka, et al. Mechanisms by which SGN-40, a Humanized Anti-CD40 Antibody, Induces Cytotoxicity in Human Multiple Myeloma Cells: Clinical Implications Cancer Res., April 15, 2004; 64(8): 2846 - 2852. [Abstract] [Full Text] [PDF]
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A. M. Evens, S. Prachand, B. Shi, M. Paniaqua, L. I. Gordon, and R. B. Gartenhaus Imexon-Induced Apoptosis in Multiple Myeloma Tumor Cells Is Caspase-8 Dependent Clin. Cancer Res., February 15, 2004; 10(4): 1481 - 1491. [Abstract] [Full Text] [PDF]
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P. Secchiero, E. Melloni, M. Heikinheimo, S. Mannisto, R. Di Pietro, A. Iacone, and G. Zauli TRAIL regulates normal erythroid maturation through an ERK-dependent pathway Blood, January 15, 2004; 103(2): 517 - 522. [Abstract] [Full Text] [PDF]
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V. Poulaki, C. S. Mitsiades, C. McMullan, D. Sykoutri, G. Fanourakis, V. Kotoula, S. Tseleni-Balafouta, D. A. Koutras, and N. Mitsiades Regulation of Vascular Endothelial Growth Factor Expression by Insulin-Like Growth Factor I in Thyroid Carcinomas J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5392 - 5398. [Abstract] [Full Text] [PDF]
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C. S. Mitsiades, N. S. Mitsiades, R. T. Bronson, D. Chauhan, N. Munshi, S. P. Treon, C. A. Maxwell, L. Pilarski, T. Hideshima, R. M. Hoffman, et al. Fluorescence Imaging of Multiple Myeloma Cells in a Clinically Relevant SCID/NOD in Vivo Model: Biologic and Clinical Implications Cancer Res., October 15, 2003; 63(20): 6689 - 6696. [Abstract] [Full Text] [PDF]
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A. Younes and M. E. Kadin Emerging Applications of the Tumor Necrosis Factor Family of Ligands and Receptors in Cancer Therapy J. Clin. Oncol., September 15, 2003; 21(18): 3526 - 3534. [Abstract] [Full Text] [PDF]
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 R. Greil, G. Anether, K. Johrer, and I. Tinhofer Tracking death dealing by Fas and TRAIL in lymphatic neoplastic disorders: pathways, targets, and therapeutic tools J. Leukoc. Biol., September 1, 2003; 74(3): 311 - 330. [Abstract] [Full Text] [PDF]
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S. Ray and A. Almasan Apoptosis Induction in Prostate Cancer Cells and Xenografts by Combined Treatment with Apo2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand and CPT-11 Cancer Res., August 1, 2003; 63(15): 4713 - 4723. [Abstract] [Full Text] [PDF]
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P. Secchiero, D. Milani, A. Gonelli, E. Melloni, D. Campioni, D. Gibellini, S. Capitani, and G. Zauli Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF-{alpha} promote the NF-{kappa}B-dependent maturation of normal and leukemic myeloid cells J. Leukoc. Biol., August 1, 2003; 74(2): 223 - 232. [Abstract] [Full Text] [PDF]
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D. C. J. Spierings, E. G. E. de Vries, W. Timens, H. J. M. Groen, H. M. Boezen, and S. de Jong Expression of TRAIL and TRAIL Death Receptors in Stage III Non-Small Cell Lung Cancer Tumors Clin. Cancer Res., August 1, 2003; 9(9): 3397 - 3405. [Abstract] [Full Text] [PDF]
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T. J. Sayers, A. D. Brooks, C. Y. Koh, W. Ma, N. Seki, A. Raziuddin, B. R. Blazar, X. Zhang, P. J. Elliott, and W. J. Murphy The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP Blood, July 1, 2003; 102(1): 303 - 310. [Abstract] [Full Text] [PDF]
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 P. G. Richardson, B. Barlogie, J. Berenson, S. Singhal, S. Jagannath, D. Irwin, S. V. Rajkumar, G. Srkalovic, M. Alsina, R. Alexanian, et al. A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma N. Engl. J. Med., June 26, 2003; 348(26): 2609 - 2617. [Abstract] [Full Text] [PDF]
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N. Mitsiades, C. S. Mitsiades, P. G. Richardson, C. McMullan, V. Poulaki, G. Fanourakis, R. Schlossman, D. Chauhan, N. C. Munshi, T. Hideshima, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells Blood, May 15, 2003; 101(10): 4055 - 4062. [Abstract] [Full Text] [PDF]
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K. Uno, T. Inukai, N. Kayagaki, K. Goi, H. Sato, A. Nemoto, K. Takahashi, K. Kagami, N. Yamaguchi, H. Yagita, et al. TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells Blood, May 1, 2003; 101(9): 3658 - 3667. [Abstract] [Full Text] [PDF]
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N. Mitsiades, C. S. Mitsiades, P. G. Richardson, V. Poulaki, Y.-T. Tai, D. Chauhan, G. Fanourakis, X. Gu, C. Bailey, M. Joseph, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications Blood, March 15, 2003; 101(6): 2377 - 2380. [Abstract] [Full Text] [PDF]
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C. M. Shipman and P. I. Croucher Osteoprotegerin Is a Soluble Decoy Receptor for Tumor Necrosis Factor-related Apoptosis-inducing Ligand/Apo2 Ligand and Can Function as a Paracrine Survival Factor for Human Myeloma Cells Cancer Res., March 1, 2003; 63(5): 912 - 916. [Abstract] [Full Text] [PDF]
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T. Hideshima, C. Mitsiades, M. Akiyama, T. Hayashi, D. Chauhan, P. Richardson, R. Schlossman, K. Podar, N. C. Munshi, N. Mitsiades, et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341 Blood, February 15, 2003; 101(4): 1530 - 1534. [Abstract] [Full Text] [PDF]
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D. Deeb, Y. X. Xu, H. Jiang, X. Gao, N. Janakiraman, R. A. Chapman, and S. C. Gautam Curcumin (Diferuloyl-Methane) Enhances Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in LNCaP Prostate Cancer Cells Mol. Cancer Ther., January 1, 2003; 2(1): 95 - 103. [Abstract] [Full Text] [PDF]
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 V. Poulaki, C. S. Mitsiades, A. M. Joussen, A. Lappas, B. Kirchhof, and N. Mitsiades Constitutive Nuclear Factor-{kappa}B Activity Is Crucial for Human Retinoblastoma Cell Viability Am. J. Pathol., December 1, 2002; 161(6): 2229 - 2240. [Abstract] [Full Text] [PDF]
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J. Ursini-Siegel, W. Zhang, A. Altmeyer, E. N. Hatada, R. K. G. Do, H. Yagita, and S. Chen-Kiang TRAIL/Apo-2 Ligand Induces Primary Plasma Cell Apoptosis J. Immunol., November 15, 2002; 169(10): 5505 - 5513. [Abstract] [Full Text] [PDF]
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P. Secchiero, A. Gonelli, G. Ciabattoni, E. Melloni, V. Grill, B. Rocca, G. Delbello, and G. Zauli TNF-related apoptosis-inducing ligand (TRAIL) up-regulates cyclooxygenase (COX)-1 activity and PGE2 production in cells of the myeloid lineage J. Leukoc. Biol., November 1, 2002; 72(5): 986 - 994. [Abstract] [Full Text] [PDF]
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 N. Mitsiades, C. S. Mitsiades, V. Poulaki, D. Chauhan, G. Fanourakis, X. Gu, C. Bailey, M. Joseph, T. A. Libermann, S. P. Treon, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells PNAS, October 29, 2002; 99(22): 14374 - 14379. [Abstract] [Full Text] [PDF]
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Y. Dai, T. H. Landowski, S. T. Rosen, P. Dent, and S. Grant Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6-independent mechanism Blood, October 16, 2002; 100(9): 3333 - 3343. [Abstract] [Full Text] [PDF]
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A. Spencer, S.-L. Yeh, K. Koutrevelis, C. Baulch-Brown ;, N. Mitsiades, C. Mitsiades, K. C. Anderson, and S. P. Treon TRAIL-induced apoptosis of authentic myeloma cells does not correlate with the procaspase-8/cFLIP ratio Blood, September 26, 2002; 100(8): 3049 - 3050. [Full Text] [PDF]
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P. Secchiero, A. Gonelli, P. Mirandola, E. Melloni, L. Zamai, C. Celeghini, D. Milani, and G. Zauli Tumor necrosis factor-related apoptosis-inducing ligand induces monocytic maturation of leukemic and normal myeloid precursors through a caspase-dependent pathway Blood, September 18, 2002; 100(7): 2421 - 2429. [Abstract] [Full Text] [PDF]
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V. Poulaki, C. S. Mitsiades, V. Kotoula, S. Tseleni-Balafouta, A. Ashkenazi, D. A. Koutras, and N. Mitsiades Regulation of Apo2L/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Thyroid Carcinoma Cells Am. J. Pathol., August 1, 2002; 161(2): 643 - 654. [Abstract] [Full Text] [PDF]
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N. Mitsiades, C. S. Mitsiades, V. Poulaki, D. Chauhan, P. G. Richardson, T. Hideshima, N. C. Munshi, S. P. Treon, and K. C. Anderson Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications Blood, May 29, 2002; 99(12): 4525 - 4530. [Abstract] [Full Text] [PDF]
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N. Mitsiades, C. S. Mitsiades, V. Poulaki, D. Chauhan, P. G. Richardson, T. Hideshima, N. Munshi, S. P. Treon, and K. C. Anderson Biologic sequelae of nuclear factor-kappa B blockade in multiple myeloma: therapeutic applications Blood, May 13, 2002; 99(11): 4079 - 4086. [Abstract] [Full Text] [PDF]
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N. Mitsiades, C. S. Mitsiades, V. Poulaki, K. C. Anderson, and S. P. Treon Intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human multiple myeloma cells Blood, March 15, 2002; 99(6): 2162 - 2171. [Abstract] [Full Text] [PDF]
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 K. C. Anderson, J. D. Shaughnessy Jr., B. Barlogie, J.-L. Harousseau, and G. D. Roodman Multiple Myeloma Hematology, January 1, 2002; 2002(1): 214 - 240. [Abstract] [Full Text]
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A. R. Jazirehi, C.-P. Ng, X.-H. Gan, G. Schiller, and B. Bonavida Adriamycin Sensitizes the Adriamycin-resistant 8226/Dox40 Human Multiple Myeloma Cells to Apo2L/Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated (TRAIL) Apoptosis Clin. Cancer Res., December 1, 2001; 7(12): 3874 - 3883. [Abstract] [Full Text] [PDF]
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W. S. Dalton, P. L. Bergsagel, W. M. Kuehl, K. C. Anderson, and J. L. Harousseau Multiple Myeloma Hematology, January 1, 2001; 2001(1): 157 - 177. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
and Fas ligand (FasL or
CD95L).
100 ng/mL) had significant increases, compared to control, in the fraction of sub-G1 cells
(Figure 
