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Antitumor Effects of Bortezomib (PS-341) on Primary Effusion Lymphomas

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Antitumor Effects of Bortezomib (PS-341) on Primary Effusion Lymphomas Leukemia (2004) 18, 1699–1704 & 2004 Nature Publishing Group All rights reserved 0887-6924/04 $30.00 www.nature.com/leu Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas JAn1, Y Sun1, M Fisher1 and MB Rettig1,2 1VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA; and 2Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Primary effusion lymphomas (PELs) are a rare type of non- treatment of refractory multiple myeloma, where it has an Hodgkin’s lymphoma that are resistant to cytotoxic chemother- acceptable toxicity profile.4–6 By inhibiting the proteasome, apy. PELs manifest constitutive activation of nuclear factor kappa B (NF-jB), and inhibition of NF-jB induces apoptosis of which degrades proteins that are marked by ubiquitination, PELs and sensitizes to tumor necrosis factor-related apoptosis- bortezomib modulates the cellular concentrations of hundreds inducing ligand (TRAIL)-induced death. Bortezomib (PS-341), a of proteins that are involved in a wide variety of functions, peptidyl boronic acid inhibitor of the proteasome, is a potent including cell cycle progression, signal transduction, and agent against a wide range of hematologic malignancies and apoptosis.7,8 For example, the proteasome regulates the activity has been shown to inhibit NF-jB. Thus, we examined the of the NF-kB pathway, in that the degradation of I kappa B (IkB), cytotoxic effects of bortezomib alone and in combination with the NF-kB inhibitory protein, is dependent upon the ubiquitin– various drugs. Bortezomib potently inhibited NF-jB in PEL cells 9 in a dose-dependent manner. In addition, bortezomib inhibited proteasome pathway. Given the important role or heightened 2 growth and induced apoptosis of PEL cell lines (IC50 values of NF-kB activity in promoting the survival of PEL cells, we 3.4–5.0 nM). Results of drug interactions between bortezomib postulated that bortezomib has potent cytotoxic effects on PELs. and chemotherapy (doxorubicin and Taxol) were schedule- Thus, we studied the cytotoxic effects of bortezomib alone and dependent: synergistic interactions were generally observed in combination with TRAIL as well as chemotherapy and when PEL cells were pretreated with bortezomib prior to chemotherapy, whereas additive or even antagonistic interac- dexamethasone on PELs. tions occurred with chemotherapy pretreatment or simulta- neous treatment with bortezomib and chemotherapy. Most schedules of bortezomib and dexamethasone were synergistic, Materials and methods although pretreatment with dexamethasone resulted in additive interactions. Effects of combinations of bortezomib and TRAIL Cells and reagents were generally additive. Thus, bortezomib represents a promis- ing potential therapy for the treatment of PEL. Leukemia (2004) 18, 1699–1704. doi:10.1038/sj.leu.2403460 The KS-1, BCBL-1, and BCP-1 PEL cell lines, which are infected Published online 2 September 2004 with KSHV but not other herpesviruses, were maintained in Keywords: proteasome inhibition; PS-341; primary effusion RPMI plus 20% FBS and antibiotics. Bortezomib (Millennium lymphoma; chemotherapy; TRAIL; NF-kB Pharmaceuticals, Cambridge, MA, USA) and recombinant, human TRAIL (Calbiochem, San Diego CA, USA) were dissolved in dimethyl sulfoxide (DMSO) and phosphate-buffered saline (PBS), respectively. Bay 11-7082 (Calbiochem, San Diego, CA, USA), a chemical inhibitor of the NF-kB pathway, Introduction was dissolved in DMSO. Doxorubicin and paclitaxel (Taxol) were purchased from Sigma (St Louis, MO, USA) and dissolved PELs, which occur in both human immunodeficiency virus- in water and methanol, respectively. The corticosteroid, dex- positive and -negative patients, represent a rare subtype of non- amethasone (Sigma) was dissolved in ethanol. For all experiments, Hodgkin’s lymphoma that is uniformly infected with the the final concentration of solvents was maintained at 0.1%. Kaposi’s sarcoma-associated herpesvirus, also known as human A kB responsive plasmid (p4x-kB-luc), in which four copies of herpesvirus 8. Unlike most non-Hodgkin’s lymphomas, PELs are the kB-response element (kB-RE) drives expression of firefly relatively resistant to standard cytotoxic chemotherapy, and luciferase, was purchased from Invitrogen (Carlsbad, CA, USA). virtually all patients succumb to the disease with a median The pRL-SV40 plasmid, in which Renilla luciferase is constitu- survival of approximately 60 days.1 One of the biochemical tively expressed under the regulation of the SV40 promoter/ hallmarks of PELs is constitutive NF-kB activation, which results enhancer, was purchased from Promega Corporation (Madison, in heightened expression of antiapoptotic genes and is critical WI, USA) and was used for normalization of firefly luciferase for PEL cell survival.2 In fact, drugs that inhibit NF-kB activation activity. have exhibited considerable activity against PELs both in vitro and in vivo.1–3 In addition, inhibition of NF-kB sensitizes PEL cells to tumor necrosis factor-related apoptosis-inducing ligand Transient transfections and reporter gene assays (TRAIL)-induced apoptosis.3 Recently, the proteasome inhibitor bortezomib (formerly PS- Cells were plated in 24-well plates the day prior to transfection. 341) has demonstrated potent cytotoxicity across a wide variety The plasmids were transfected with Lipofectamine Plus (Life of hematologic malignancies and solid tumors and received Technologies, Gaithersburg, MD, USA), according to the approval by the Food and Drug Administration (FDA) for the manufacturer’s instructions. Protein was extracted 48 h after transfection, and firefly and Renilla luciferase were measured on Correspondence: Dr MB Rettig, VAGLAHS-West LA, 11301 Wilshire a TD20/20 tube luminometer (Turner Designs, Sunnyvale, CA, Blvd, Building 304, Room E1-113, Los Angeles, CA 90073, USA; Fax: þ 1 310 268 4508; E-mail: [email protected] USA) using a Dual Luciferase Assay kit (Promega Corporation), Received 19 February 2004; accepted 10 June 2004; Published online according to the manufacturer’s instructions. Firefly luciferase 2 September 2004 activity was normalized to Renilla luciferase expression. Antitumor effects of bortezomib on PELs JAnet al 1700 Electrophoretic mobility shift assay (EMSA) and Western a BCBL-1 blotting 1.2 10 1 The EMSAs and Western blots were performed, as described. 0.8 0.6 Assessment of cytotoxicity RLU 0.4 0.2 0 Cells were seeded in 96-well plates the day prior to chemical DMSO 0.625 1.25 2.5 5 10 treatment. Various drug combinations were added to cells, and Bortezomib (nM) 48 h later, cell viability was assessed by the MTT (3,[4,5- dimethylthiazol-2-yl-] diphenyltetrazolium bromide) assay. In TNF b + total, 25 ml of MTT (5 mg/ml) was added to each well for 3 h at TNF Bortezomib (nM) cold comp. 371C. Subsequently, 120 ml of 10% sodium dodecyl sulfate/ − + 2.5 5 7.5 10 wt mut 0.01 N HCl was added overnight at 371C. Absorbance was measured at 570 nm on a microplate reader. All experiments NF-κB were performed in triplicate. Assessment of apoptosis Cells were plated in 10 cm2 dishes. The next day, cells were treated with various concentrations of bortezomib or vehicle c control for 48 h. Cells were harvested and then stained with an Bortezomib (nM) 0 2.5 5 7.5 10 annexin V-FITC kit (BD Biosciences, Palo Alto, CA, USA), κ α according to the manufacturer’s instructions. Cells were I B analyzed on a Becton Dickenson FACS Caliber flow cytometer Actin with CellQuest software (BD Biosciences). Figure 1 Bortezomib inhibits constitutive NF-kB activation in Median effect/combination index (CI) isobologram PELs. (a) Bortezomib blocks NF-kB-driven reporter gene expression. method for multiple drug effect analysis The pNF-kB-luc (1 mg) and pRL-SV40 (1 ng) reporter plasmids were transfected into 1 Â 105 BCBL-1 cells in 24-well plates. At 5 h after transfection, bortezomib was added at the indicated concentrations for The effect of drug combinations on cytotoxicity was performed an additional 48 h. Firefly luciferase is reported and was normalized to by the median effect/combination index (CI) method using Renilla luciferase activity. Results represent median of three experi- Calcusyn software, version 1.1.1 (Biosoft, Ferguson, MO, USA) ments and are reported as relative luminescence units (RLU)7s.d. 11 as were the IC50 values, as previously described. CI and IC50 Similar results were obtained for the BCP-1 and KS-1 cell lines (data values were calculated from median results of the MTT not shown). (b) Bortezomib inhibits NF-kB nuclear localization. BCBL- 1 cells (1 Â 107 cells) were plated in 10 cm2 dishes and treated with assays. Fixed drug ratios were maintained for CI analysis. CI bortezomib for 60 min or TNFa (20 ng/ml) for 20 min. Nuclear protein values significantly greater than 1 indicate drug antagonism, was extracted for EMSA. Cold competition with excess wild-type CI values significantly less than 1 are indicative of synergy, and probe abrogated the gel shifted bands, whereas cold mutant probe had CI values not significantly different than 1 indicate an additive no effect (rightmost two lanes). (c) Bortezomib blocks the degradation 5 drug effect. Linear regression correlation coefficients of the of IkBa. BCBL-1 cells (5 Â 10 cells/well) were plated in six-well plates median effects plots were required to be 40.90 to demonstrate and treated with bortezomib for 90 min. In total, 10 mg of cellular protein was subjected to immunoblotting for IkBa (top panel). Bottom that the effects of the drugs follow
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