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NEOPLASIA
From the Institut National de la Santé et de la
Recherche Médicale Unité 463 Institut de Biologie, Nantes,
France; Service d'Hématologie Clinique, Nantes, France; and the
Department of Molecular Pharmacology, ISIS Pharmaceuticals,
Carlsbad, CA.
Multiple myeloma (MM) is a plasma cell malignancy that occurs
mainly in bone marrow. As MM cells proliferate slowly, it would seem
essential to find means of preventing their growth and accumulation inside bone marrow. The present study used an antisense strategy to
elucidate the respective roles of Bcl-2, Bcl-xL, and Mcl-1 proteins in myeloma cell survival. Each antisense oligonucleotide (ASO;
Bcl-2, Bcl-xL, or Mcl-1 ASO) introduced into human myeloma cell lines by electroporation induced a marked reduction in the level
of the corresponding protein. Mcl-1 ASO triggers an important decrease
of viability in all myeloma cell lines tested and in 2 primary myeloma
cells, whereas neither Bcl-2 nor Bcl-xL ASO affected the
viability of myeloma cells. The decrease of cell viability induced by
Mcl-1 ASO treatment was associated with an induction of apoptosis that
occurred through the disruption of mitochondrial membrane potential
Multiple myeloma (MM) is a disorder in which
malignant plasma cells accumulate within bone marrow where they
proliferate slowly and display a weak apoptotic index in
vivo.1 This situation suggests that their accumulation
could be due to a defect related to the apoptotic process. Proteins of
the Bcl-2 family play a key role in apoptosis and are classified as
antiapoptotic (eg, Bcl-xL, Bcl-2, Mcl-1, A1) or
proapoptotic (eg, Bcl-xS, Bax, Bad, Bag,
Bak).2 Bcl-2 protein is known to confer resistance to apoptosis. The role of this protein is still unclear in MM, but our
previous results suggest that Bcl-2 could be involved in regulation of
the cell cycle.3 Data in the literature indicate that
Bcl-2 contributes to an antiapoptotic effect by reducing cell
proliferation.4,5 Bcl-xL is also known to
promote cell survival, and a report suggests that expression of this
protein in MM may reflect disease severity and serve as an indicator of
patient chemoresistance.6 The role of Mcl-1 in supporting
cell survival was demonstrated initially in Chinese hamster ovary
cells, and studies suggest that this protein plays an important role in
B cells, particularly during the late stages of
differentiation.7 Moreover, our work showed that Mcl-1 and
Bcl-xL are coregulated by interleukin 6 (IL-6) in human
myeloma cells.8 The signal transduction pathway leading to
Bcl-xL and Mcl-1 up-regulation seems to depend on a common mechanism involving the janus kinase (JAK)-signal transducers and
activators of transcription (STAT) pathway.9,10 In fact, a
JAK2 inhibitor and subsequently a dominant-negative STAT3 protein inhibited Bcl-xL expression in U266 myeloma cells and
induced apoptosis.10 A previous study by our group showed
that a JAK2 inhibitor is able to abolish the effect of IL-6 on Mcl-1
up-regulation in myeloma cells.9 On the whole, these
results indicate that Bcl-2, Bcl-xL, and Mcl-1 are
important antiapoptotic proteins. The role of Bcl-2, on one hand, and
of Bcl-xL and Mcl-1, on the other hand, are complementary
in controlling apoptosis in MM.
In the present study, antisense oligonucleotides (ASOs) designed to
inhibit the expression of Bcl-2, Bcl-xL, or Mcl-1 were used
to show that each of these proteins has a definitive and specific
antiapoptotic role in myeloma cells. The behavior of human myeloma cell
lines was analyzed as well as that of malignant plasma cells from
patients with MM after inhibition of Bcl-2, Bcl-xL, or
Mcl-1 by a specific ASO.
Human myeloma cell lines and culture conditions
Patients
Monoclonal antibodies and reagents Dexamethasone (Dex) was obtained from Alexis (San Diego, CA), z-VAD-fmk from Calbiochem (La Jolla, CA), and anti-IL-6 blocking monoclonal antibody (mAb) B-E8 from Diaclone Research (Besançon, France). Anti-Bcl-x and anti-Mcl-1 rabbit affinity-purified polyclonal antibodies were purchased, respectively, from Transduction Laboratories (Interchim, Montluçon, France) and DAKO (Glostrup, Denmark). Anti-Bcl-2 mAb was obtained from DAKO, Bad mAb from Transduction Laboratories, and Bax mAb from Beckman Coulter (Roissy CDG, France).ASO synthesis The 2'-O-methoxyethyl-deoxynucleotide ASOs used in all experiments had a uniform phosphorothioate backbone.11 ASOs were synthesized by using an Applied Biosystems 380B automated DNA synthesizer (Foster City, CA) and purified as previously described.11 These ASOs were selected to obtain the most efficient down-regulation of the related protein. The Bcl-2 or Bcl-xL control ASOs were mismatched on some bases (their sequences are shown in Table 1). The Mcl-1 control ASO, ISIS 29848, was synthesized as a mixture of A (adenine), G (guanosine), T (thymine), and C (cytosine) bases to provide a preparation containing an equimolar mix of all possible 4th to 19th oligonucleotides. The oligochemistry of the control was the same as that of the other oligonucleotides (Table 1). Bcl-xL and Mcl-1 ASOs were previously described in other cellular models.12,13
Electroporation After overnight incubation in 2% FCS, myeloma cell lines (2 × 107) were suspended in 1 mL RPMI-1640 medium. Cells (360 µL) were mixed with a mismatched control (40 µL) or ASOs at the concentration of interest. The mix was then placed directly into 0.4-cm gap electroporation chambers and electroporated with an EasyJect Plus (Eurogentec, Seraing, Belgium) at 250 V and 1050 microfarad (µF). Cells were then resuspended in fresh medium supplemented with 2% FCS. Myeloma cells from patients and XG-6 HMCL were electroporated at 210 V, 900 µF, and resuspended in fresh medium supplemented with 10% FCS.Cell viability Cell viability was determined by vital dye (0.4% eosin) exclusion and assessed by visual inspection in a hemocytometer.Western blot Cells (4 × 106) were resuspended in 150 µL lysis buffer (10 mM Tris, pH 7.6, 150 mM NaCl, 5 mM EDTA, and 1% Triton X-100) containing 2 mM phenylmethylsulfonyl fluoride and 2 mg/mL aprotinin. After 40 minutes on ice, lysates were cleared by centrifugation at 12 000g for 30 minutes at 4°C. The protein concentration of lysates was determined by using bicinchoninic acid (BCA protein assay; Pierce, Rockford, IL). Equal amounts of protein (Bcl-2, Bcl-xL, or Mcl-1) were separated by 10% sodium dodecyl sulfate-polyacrylamide gel and then electrotransferred to polyvinylidene fluoride membranes. Western blot analysis was performed by standard techniques with enhanced chemiluminescence detection (Pierce). The blot was quantified by using 1D Image Analysis Software (Eastman Kodak, Rochester, NY).Apoptosis detection The percentage of apoptotic cells was determined by flow cytometry with the use of APO 2.7 mAb coupled to phycoerythrin (Beckman Coulter). Cells (2.5 × 105) were sampled in each condition and washed with phosphate-buffered saline before incubation with APO 2.7 mAb (2.5 µL) for 20 minutes. In these conditions, APO 2.7 staining detected delayed apoptosis. Alternately, cell cycle distribution was analyzed, in which case 2 × 105 cells were incubated for 40 minutes at 37°C in a solution of Triton X-100 0.1%, sodium citrate 0.1%, and 5 IU RNAse before staining with propidium iodide 50 mg/L. Flow cytometry analysis was performed on a FACSCalibur with the use of the CELLQuest program (Becton Dickinson). Data were gated on the FL2-area versus FL2-width cytogram to exclude doublets and aggregates, and a minimum of 2 × 104 gated cells was collected per sample. The cell cycle was analyzed by using the Modfit LT program V2.01 for Mac (Verity Software House). Early apoptotic cells were detected as a subdiploid peak, as described previously.14Measurement of mitochondrial membrane potential   m) when sequestered in the
mitochondrial membrane of healthy cells. Mitochondrial membrane
depolarization is associated with a large shift in emission at 590 nm
(red fluorescence).15
Caspase-3 activity Caspase-3 activity was measured with a caspase-3 colorimetric assay (R&D Systems, Abingdon, United Kingdom). Cells (3 × 106) were collected for each lysate. Caspase activity was determined as indicated by the manufacturer.
ASOs inhibit the protein of interest specifically Five HMCLs (U266, L363, LP-1, OPM-2, and XG-6) were chosen for their different endogenous levels of the 3 antiapoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1) and their growth status. XG-6 is an IL-6-dependent HMCL; U266 is a well-characterized IL-6 autocrine HMCL; and L363, LP-1, and OPM-2 are independent of IL-6 for their growth. XG-6, U266, and L363 exhibited both high Bcl-xL and Mcl-1 endogenous levels, whereas LP-1 and OPM-2 displayed a lower level of both Bcl-xL and Mcl-1. Bcl-2 was highly expressed in all 5 HMCLs.8 Because HMCLs are difficult to transfect, electroporation was used to introduce ASOs. Cells were electroporated in the presence of ASO or the related mismatched control, and the expression of the corresponding protein was then analyzed by Western blot at different times after electroporation. Each ASO (Bcl-2, Bcl-x, and Mcl-1) induced dose- and time-dependent depletion of the corresponding protein, whereas the mismatched control had no effect, indicating the specificity of the ASO (Figure 1). Because of the variable endogenous levels of each protein of interest, the ASO concentration used differed and was calculated to obtain maximal inhibition of the protein with the lowest nonspecific effects. Bcl-2 ASO was used at a concentration of 10 µM, and maximum protein inhibition was observed at 72 hours. Bcl-2 ASO induced a depletion of more than 90% in L363 and OPM-2 cells and of 75% and 65% in U266 and LP-1, respectively (Figure 1 and data not shown). With Bcl-xL ASO, the strongest effect was observed at 40 hours with 20 µM ASO. In these conditions, Bcl-x ASO was responsible for an 80% down-regulation of Bcl-xL protein in L363 and LP-1 and a 50% down-regulation in U266 (Figure 1). On the basis of the endogenous levels of Mcl-1, Mcl-1 ASO was used at a concentration of 20 µM in LP-1, OPM-2, and XG-6 and 30 µM in U266 and L363 HMCLs. The down-regulation of Mcl-1 in the presence of ASO was observed as early as 6 hours, becoming maximal between 12 and 18 hours. This difference in kinetics seems attributable to the presence of 2 regions enriched in proline, glutamate, serine, and threonine (PEST sequences) in the Mcl-1 sequence, which could target Mcl-1 for rapid turnover via proteasome-mediated degradation.16 Mcl-1 ASO induced major down-regulation of Mcl-1 protein level, ie, a depletion of at least 70% in U266, LP-1, and OPM-2 and a lesser depletion in L363 (53%) and XG-6 (50%) (Figure 1 and data not shown). As shown in Figure 1, depletion of each protein by the related ASO did not alter the level of any of the other antiapoptotic proteins evaluated by Western blot, except Bcl-xL, which slightly decreased in the presence of Mcl-1 ASO. It is noteworthy that the levels of some proapoptotic (Bad and Bax) proteins were not modified, regardless of the ASO used (data not shown).
Mcl-1 but not Bcl-2 or Bcl-xL down-regulation induces rapid and strong apoptosis of human myeloma cells To analyze the biologic effects of ASO-induced depletion of Bcl-2, Bcl-xL, or Mcl-1, cell viability and apoptosis were determined at different times after electroporation in U266, L363, and LP1 HMCLs. Apoptosis was estimated by using either APO 2.7 staining or cell cycle analysis. Treatment by Bcl-2 ASO or Bcl-xL had no effect on cell viability in any of the 3 HMCLs studied (Figure 2A). In contrast, Mcl-1 ASO triggered a decrease of cell viability in all 3 HCMLs tested (Figure 2A) and induced a significant apoptosis in U266 and LP1 cells (Figure 2B). Of note, LP-1 displayed the most dramatic induction of apoptosis (a 3-fold increase) when Mcl-1 protein level was decreased. Apoptosis was detected as early as day 2 after introduction of the ASO, with a maximum effect at days 4 and 6 (Figure 2B). This rapid apoptosis was also revealed by the occurrence of a subdiploid peak (50%) as early as 18 hours after introduction of Mcl-1 ASO in U266 (Figure 2C). Down-regulation of Mcl-1 was lowest for L363. Nonetheless, Mcl-1 ASO induced a small but significant apoptosis as shown by the appearance of a subdiploid peak of 35% in L363 cells treated by Mcl-1 ASO versus 12.5% in control cells at day 1 (Figure 2C). Finally, in a fourth cell line tested OPM-2, Mcl-1 ASO triggers apoptosis (2-fold increase) (data not shown). Altogether, these results show that specific disruption of Mcl-1 expression results in a rapid entry into apoptosis in myeloma cells, whereas the specific disruption of Bcl-xL or Bcl-2 expression has no effect on cell viability or apoptosis.
Down-regulation of either Bcl-xL or Bcl-2 proteins does not sensitize myeloma cells to apoptosis induced by Mcl-1 ASO We compared the efficiency of Mcl-1 ASO in combination or not with either Bcl-2 or Bcl-xL ASO on the induction of apoptosis in U266 and L363 cells. We demonstrated that the down-regulation of either Bcl-xL or Bcl-2 proteins does not sensitize U266 and L363 cells to apoptosis induced by Mcl-1 ASO (Figure 3). These results may be explained by the strong efficiency of Mcl-1 ASO and above all by the rapid induction of apoptosis that characterized Mcl-1-induced apoptosis.
Bcl-2 or Mcl-1 down-regulation sensitizes myeloma cells to Dex-induced apoptosis Dex is known to be effective in the treatment of MM, and our work and that of other groups have shown that IL-6 protects myeloma cells from Dex-induced apoptosis in vitro.17,18 In this context, further investigations were performed to determine whether Bcl-2, Bcl-xL, or Mcl-1 depletion sensitizes HMCLs to glucocorticoids. In U266 cells, which are primarily resistant to Dex, the addition of Bcl-2 ASO to Dex triggered a decrease of cell viability and an increase of apoptosis (80% increase at days 6 and 8) (Figure 4A,B). Bcl-2 ASO also sensitized L363 cells to Dex, producing 80% and 120% increases of apoptosis at days 3 and 6, respectively, (Figure 4B). However, treatment of LP-1 cells by Dex in the presence of Bcl-2 ASO did not sensitize cells to glucocorticoids (Figure 4A,B). The same observation was made with OPM-2 (data not shown). On the whole, these results indicate the efficiency of Bcl-2 down-regulation in sensitizing some myeloma cells to apoptosis in the presence of Dex. In contrast to Bcl-2 ASO, addition of Bcl-x ASO did not sensitize myeloma cells to Dex-induced apoptosis in any of the 3 cell lines tested (Figure 4B). The combination of Dex and Mcl-1 ASO induced only a small increase of apoptosis in cell lines (LP1 and U266) in which Mcl-1 ASO alone induced already an important apoptosis. However, in L363 cells in which Mcl-1 ASO alone is poorly efficient the combination of Dex and Mcl-1 ASO triggered a dramatic decrease of viable cells and an important increase of apoptosis (Figure 4A,B).
Effect of IL-6 on apoptosis induced by Mcl-1 ASO Because IL-6 is the major growth factor of myeloma cells, we tested the effect of IL-6 on apoptosis induced by ASO either by neutralizing autocrine IL-6 in U266 or by testing the effect of Mcl-1 ASO in XG-6, an IL-6-dependent cell line. When IL-6 was neutralized by the addition of B-E8 mAb in U266, Bcl-2 ASO induced a weak but significant increase of apoptosis (50% increase at day 8) (Figure 5A). Furthermore, the inhibition of IL-6 by B-E8 intensified the apoptosis induced by Dex (75%, 100%, and 60% increase at day, 6, 8, and 10, respectively) (Figure 5A). The inhibition of IL-6 autocrine did not allow us to detect any effect of Bcl-x ASO and did not significantly modify the apoptosis induced by Mcl-1 ASO (Figure 5A). Mcl-1 ASO triggered an important decrease of cell viability in XG-6 HCMLs cultured with 6 ng/mL IL-6 and 10% FCS, showing that IL-6 is unable to prevent apoptosis following Mcl-1 depletion (Figure 5B). Altogether, these results indicate that Mcl-1 depletion results in entry into apoptosis in myeloma cells even in the presence of IL-6.
Characterization of the Mcl-1 ASO-induced apoptosis To unravel the mechanisms by which Mcl-1 depletion induced apoptosis, we examined the involvement of caspase pathway either using a broad-spectrum irreversible caspase inhibitor (z-VAD-fmk) or measuring caspase-3 activity. The addition of 100 µM z-VAD-fmk in LP-1 totally blocks the apoptosis induced by Mcl-1 ASO, indicating a caspase-dependent process (Figure 6A). This finding was also confirmed by the increase of caspase-3 activity induced by Mcl-1 treatment as shown in Figure 6B. Finally, LP-1 cells were probed with JC-1 to visualize disruption of mitochondrial membrane potential. When cells were treated with Mcl-1 ASO, an important shift in red fluorescence was observed, indicating loss of mitochondrial membrane potential (Figure 6C).
Mcl-1 down-regulation induces apoptosis in freshly expanded myeloma cells Studies were then conducted to determine the effect of Mcl-1 ASO in primary myeloma cells. The reduction of Mcl-1 levels after electroporation by Mcl-1 ASO in primary myeloma cells from 2 patients showed a decrease in the Mcl-1 level of 70% and 50%, respectively, for patients 1 and 2 (Figure 7A). Further studies of cell survival after Mcl-1 delivery indicated that Mcl-1 down-regulation triggered an induction of apoptosis in both patients. The increase of apoptosis at day 4 after ASO treatment was greater in patient 1 (200%) than in patient 2 (169%), which is consistent with the most marked depletion of Mcl-1 level in patient 1 (Figure 7B). Of note, although Bcl-2 ASO treatment had induced a significant down-regulation of Bcl-2 protein in patient 1, this depletion had no effect on cell viability (result not shown).
This study used antisense strategy to define the specific role of
3 major antiapoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1) in the survival of human myeloma cells. Mcl-1 proved to be a key determinant in ensuring the survival of myeloma cells. Furthermore, we
demonstrated that apoptosis triggered by Mcl-1 depletion occurred through the disruption of mitochondrial membrane potential Our investigations and those of other groups indicate that Mcl-1 and Bcl-xL, unlike Bcl-2, are regulated by survival and apoptotic stimuli such as IL-6, which accounts for their role in the regulation of myeloma cell survival.7,9,10 Moreover, our earlier work showed that Mcl-1 and Bcl-xL are coexpressed in myeloma cells.8 On the whole, these data suggest that Bcl-xL and Mcl-1, but not Bcl-2, regulate apoptosis in a similar way. Nonetheless, our study clearly demonstrates that Mcl-1 rather than Bcl-xL is an essential survival protein in MM. We show here that specific disruption of Mcl-1 expression either in HMCLs or primary myeloma cells results in a rapid entry into apoptosis. Moreover, we demonstrated that the combination of IL-6 and high concentration of serum does not prevent this apoptosis. Surprisingly, the depletion of Bcl-xL did not induce apoptosis in any of the conditions tested, although it cannot be excluded that the residual Bcl-xL level (< 20%) interfered with our observations. Moreover, the combination of Mcl-1 and Bcl-xL ASOs does not potentiate the effect of Mcl-1 ASO. The explanation for the differential behavior of these 2 proteins is currently unknown, and further investigations of their interactions with proapoptotic proteins would seem of particular interest. Finally, our study is the first to demonstrate that the maintenance of Mcl-1 expression in cells exhibiting it physiologically is the essential mechanism for preventing apoptosis. Moreover, the level of Bcl-2 remained stable after Mcl-1 treatment but provided no protection from apoptosis, indicating that Mcl-1 and Bcl-2 play distinct roles in apoptosis regulation. Finally, the strong and rapid apoptosis induced by Mcl-1 ASO cannot be maximized by Bcl-2 ASO. Apoptosis induction by Mcl-1 ASO triggered a weak down-regulation of Bcl-xL expression that is prevented by the addition of z-VAD-fmk caspase inhibitor. This finding is in agreement with the negative coregulation of Mcl-1 and Bcl-xL induced by withdrawal of survival factors.8 It is noteworthy that an increasing number of studies have dealt with the importance of the protection afforded by Mcl-1. In particular, it has been shown that Mcl-1 induction is required to prevent apoptosis during the differentiation of U937.19 The importance of Mcl-1 in B-cell chronic lymphocytic leukemia has also been stressed in the study of Kitada et al,20 showing that protein kinase inhibitors induce apoptosis by down-regulating Mcl-1 levels. Finally, up-regulation of Mcl-1 was found to prevent apoptosis of hepatoma cells by IL-6.21 The functional effect of Bcl-2 in MM remains unclear. Some studies suggest that chemotherapeutic agents enhance Bcl-2 levels and contribute to chemoresistance,22 whereas others claim that Bcl-2 expression has no relation to short-term survival in MM, implying that Bcl-2 does not play a major role in influencing response to treatment.23 Our study and others found an inverse correlation between Bcl-2 expression and the proliferation rate of both normal and malignant plasma cells, thus indicating that Bcl-2 could also play a role in regulating the cell cycle.3,24 Our current data show that down-regulation of Bcl-2 cannot induce apoptosis in myeloma cells, even in combination with Bcl-xL ASO (data not shown), although it sensitizes these cells to Dex-induced apoptosis. These results are consistent with our previous data, indicating that the Bcl-2-dependent cell cycle position controls the regulation of chemosensitivity and with the notion that G1-phase-dependent expression of Bcl-2 messenger RNA and protein correlates with the chemoresistance of human cancer cells.25 MM remains an incurable disease, despite intensive chemotherapy. Although Bcl-2 antisense therapeutic strategy is feasible without toxicity26,27 and has already been proposed for MM patients,28 our results suggest that an approach involving Mcl-1 deserves more thorough testing. This approach is of special interest because the presence of IL-6 cannot prevent the Mcl-1 ASO-induced apoptosis.
Submitted June 28, 2001; accepted February 2, 2002.
Supported by grants from the Ligue contre le Cancer de Loire-Atlantique. S.D. is supported by the Association pour la Recherche sur le Cancer.
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: Martine Amiot, U463, Institut de Biologie, 9, quai Moncousu 44 093 Nantes cedex 01, France; e-mail: mamiot{at}nantes.inserm.fr.
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© 2002 by The American Society of Hematology.
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 J. K. Brunelle, J. Ryan, D. Yecies, J. T. Opferman, and A. Letai MCL-1-dependent leukemia cells are more sensitive to chemotherapy than BCL-2-dependent counterparts J. Cell Biol., November 2, 2009; 187(3): 429 - 442. [Abstract] [Full Text] [PDF]
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P. Lunghi, N. Giuliani, L. Mazzera, G. Lombardi, M. Ricca, A. Corradi, A. M. Cantoni, L. Salvatore, R. Riccioni, A. Costanzo, et al. Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways Blood, September 15, 2008; 112(6): 2450 - 2462. [Abstract] [Full Text] [PDF]
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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]
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M. Romagnoli, G. Desplanques, S. Maiga, S. Legouill, M. Dreano, R. Bataille, and S. Barille-Nion Canonical Nuclear Factor {kappa}B Pathway Inhibition Blocks Myeloma Cell Growth and Induces Apoptosis in Strong Synergy with TRAIL Clin. Cancer Res., October 15, 2007; 13(20): 6010 - 6018. [Abstract] [Full Text] [PDF]
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M. Rahmani, E. M. Davis, T. R. Crabtree, J. R. Habibi, T. K. Nguyen, P. Dent, and S. Grant The Kinase Inhibitor Sorafenib Induces Cell Death through a Process Involving Induction of Endoplasmic Reticulum Stress Mol. Cell. Biol., August 1, 2007; 27(15): 5499 - 5513. [Abstract] [Full Text] [PDF]
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S. Trudel, Z. H. Li, J. Rauw, R. E. Tiedemann, X. Y. Wen, and A. K. Stewart Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma Blood, June 15, 2007; 109(12): 5430 - 5438. [Abstract] [Full Text] [PDF]
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R. Nimmanapalli, M.-A. Lyu, M. Du, M. J. Keating, M. G. Rosenblum, and V. Gandhi The growth factor fusion construct containing B-lymphocyte stimulator (BLyS) and the toxin rGel induces apoptosis specifically in BAFF-R-positive CLL cells Blood, March 15, 2007; 109(6): 2557 - 2564. [Abstract] [Full Text] [PDF]
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R. Tang, A.-M. Faussat, P. Majdak, C. Marzac, S. Dubrulle, Z. Marjanovic, O. Legrand, and J.-P. Marie Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells. Mol. Cancer Ther., March 1, 2006; 5(3): 723 - 731. [Abstract] [Full Text] [PDF]
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K. J. Aichberger, M. Mayerhofer, M.-T. Krauth, H. Skvara, S. Florian, K. Sonneck, C. Akgul, S. Derdak, W. F. Pickl, V. Wacheck, et al. Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides Blood, April 15, 2005; 105(8): 3303 - 3311. [Abstract] [Full Text] [PDF]
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J. Gauduchon, F. Gouilleux, S. Maillard, V. Marsaud, J.-M. Renoir, and B. Sola 4-Hydroxytamoxifen Inhibits Proliferation of Multiple Myeloma Cells In vitro through Down-Regulation of c-Myc, Up-Regulation of p27Kip1, and Modulation of Bcl-2 Family Members Clin. Cancer Res., March 15, 2005; 11(6): 2345 - 2354. [Abstract] [Full Text] [PDF]
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J.-P. Piret, E. Minet, J.-P. Cosse, N. Ninane, C. Debacq, M. Raes, and C. Michiels Hypoxia-inducible Factor-1-dependent Overexpression of Myeloid Cell Factor-1 Protects Hypoxic Cells against tert-Butyl Hydroperoxide-induced Apoptosis J. Biol. Chem., March 11, 2005; 280(10): 9336 - 9344. [Abstract] [Full Text] [PDF]
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M. Derouet, L. Thomas, A. Cross, R. J. Moots, and S. W. Edwards Granulocyte Macrophage Colony-stimulating Factor Signaling and Proteasome Inhibition Delay Neutrophil Apoptosis by Increasing the Stability of Mcl-1 J. Biol. Chem., June 25, 2004; 279(26): 26915 - 26921. [Abstract] [Full Text] [PDF]
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J. Moreaux, E. Legouffe, E. Jourdan, P. Quittet, T. Reme, C. Lugagne, P. Moine, J.-F. Rossi, B. Klein, and K. Tarte BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone Blood, April 15, 2004; 103(8): 3148 - 3157. [Abstract] [Full Text] [PDF]
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T. Ikezoe, T. Saito, K. Bandobashi, Y. Yang, H. P. Koeffler, and H. Taguchi HIV-1 protease inhibitor induces growth arrest and apoptosis of human multiple myeloma cells via inactivation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 Mol. Cancer Ther., April 1, 2004; 3(4): 473 - 479. [Abstract] [Full Text] [PDF]
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Y. Dai, X.-Y. Pei, M. Rahmani, D. H. Conrad, P. Dent, and S. Grant Interruption of the NF-{kappa}B pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells Blood, April 1, 2004; 103(7): 2761 - 2770. [Abstract] [Full Text] [PDF]
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M. Linden, N. Kirchhof, C. Carlson, and B. Van Ness Targeted overexpression of Bcl-XL in B-lymphoid cells results in lymphoproliferative disease and plasma cell malignancies Blood, April 1, 2004; 103(7): 2779 - 2786. [Abstract] [Full Text] [PDF]
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N. C. Munshi, T. Hideshima, D. Carrasco, M. Shammas, D. Auclair, F. Davies, N. Mitsiades, C. Mitsiades, R. S. Kim, C. Li, et al. Identification of genes modulated in multiple myeloma using genetically identical twin samples Blood, March 1, 2004; 103(5): 1799 - 1806. [Abstract] [Full Text] [PDF]
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A. R. Jazirehi and B. Bonavida Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin's lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis Mol. Cancer Ther., January 1, 2004; 3(1): 71 - 84. [Abstract] [Full Text]
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K. Brocke-Heidrich, A. K. Kretzschmar, G. Pfeifer, C. Henze, D. Loffler, D. Koczan, H.-J. Thiesen, R. Burger, M. Gramatzki, and F. Horn Interleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family-independent survival pathway closely associated with Stat3 activation Blood, January 1, 2004; 103(1): 242 - 251. [Abstract] [Full Text] [PDF]
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N. W. C. J. van de Donk, M. M. J. Kamphuis, B. van Kessel, H. M. Lokhorst, and A. C. Bloem Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels Blood, November 1, 2003; 102(9): 3354 - 3362. [Abstract] [Full Text] [PDF]
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M. Trikha, R. Corringham, B. Klein, and J.-F. Rossi Targeted Anti-Interleukin-6 Monoclonal Antibody Therapy for Cancer: A Review of the Rationale and Clinical Evidence Clin. Cancer Res., October 15, 2003; 9(13): 4653 - 4665. [Abstract] [Full Text] [PDF]
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F. Magrangeas, V. Nasser, H. Avet-Loiseau, B. Loriod, O. Decaux, S. Granjeaud, F. Bertucci, D. Birnbaum, C. Nguyen, J.-L. Harousseau, et al. Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease Blood, June 15, 2003; 101(12): 4998 - 5006. [Abstract] [Full Text] [PDF]
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Q. Liu and Y. Gazitt Potentiation of dexamethasone-, paclitaxel-, and Ad-p53-induced apoptosis by Bcl-2 antisense oligodeoxynucleotides in drug-resistant multiple myeloma cells Blood, May 15, 2003; 101(10): 4105 - 4114. [Abstract] [Full Text] [PDF]
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 S. Barille-Nion, B. Barlogie, R. Bataille, P. L. Bergsagel, J. Epstein, R. G. Fenton, J. Jacobson, W. M. Kuehl, J. Shaughnessy, and G. Tricot Advances in Biology and Therapy of Multiple Myeloma Hematology, January 1, 2003; 2003(1): 248 - 278. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
-mercapto-ethanol.
m
6 M). A control involving cells electroporated without
ASO was performed. (A) Cell viability was determined as indicated in
Figure 
