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Proteasome Inhibitor PS-341, a Potential Therapeutic Agent for Adult T-Cell Leukemia

Metabolism Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1374

	ABSTRACT

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Nuclear factor B (NF-B) plays a major role in the pathogenesis of human T-cell lymphotrophic virus I-associated malignancy. Proteasome inhibitors provide a rational approach to control constitutively activated NF-B in human T-cell lymphotrophic virus I-infected T cells. We report that the proteasome inhibitor PS-341 decreased NF-B DNA binding activity by preventing degradation of IB. In our murine model of adult T-cell leukemia, PS-341 used alone did not yield prolongation of the survival of tumor-bearing mice. However, when combined with the current clinically approved drug humanized anti-Tac, therapy with PS-341 was associated with a complete remission in a proportion of treated animals, whereas only a partial response was observed in animals treated with humanized anti-Tac alone.

	INTRODUCTION

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The nuclear transcription factor NF-B² plays a central role in oncogenesis induced by HTLV-I, the etiological agent of an aggressive and fatal disease termed ATL (1) . The viral transcriptional activator protein Tax plays a crucial role in T-cell immortalization and factor-independent growth by activating the NF-B pathway through its activation of IB kinase (2 , 3) . The inactivation of tumor suppressor p53 in HTLV-I-positive cells is also dependent on activation of the NF-B pathway (4) . The observation that NF-B, rather than Tax, is indispensable for the maintenance of the malignant phenotype of HTLV-I provides a molecular target for the therapy of ATL (5) .

NF-B is a family of proteins consisting of NF-B1 (p50/p105), NF-B2 (p52/p100), p65 (RelA), RelB, and c-Rel. Whereas almost all combinations of homo- and heterodimers can exist, the dominant form that is activated in response to extracellular signals is the heterodimer of p65 and p50. In unstimulated cells, NF-B is held in the cytoplasm by binding to IBs (IB, IBß, and IB). On stimulation, IB becomes rapidly phosphorylated and polyubiquitinated and consequently targets itself to the 26S proteasome for degradation. NF-B is then released and translocates into the nucleus, where it activates transcription of responsive genes (6) . In HTLV-I-infected T cells, the constitutive activation of NF-B is associated with phosphorylation and rapid proteolytic degradation of IB (7) and chronic down-regulation and inactivation of IBß expression (8 , 9) due to the interaction of HTLV-I-encoded Tax protein with IB kinase. Therefore, the 26S proteasome inhibitor represents a rational target for the interruption of the NF-B pathway for ATL therapy.

PS-341, a dipeptidyl boronic acid analogue, is a selective inhibitor of the proteasome with only modest activity toward serine and thiol proteases (10) . PS-341 has potent and reversible inhibitory activity against the hydrolysis of polypeptide substrates by the 20S proteasome and hydrolysis of ubiquitinated proteins by the 26S proteasome (11) . By stabilizing cytoplasmic IB, PS-341 has shown its inhibitory effect on transactivation of NF-B in vitro and in vivo (12) . PS-341 has an inhibitory potency (K_i) of 0.6 nM against the chymotryptic activity of the 20S proteasome with an average inhibition of cell growth (GI₅₀) across the entire NCI cell panel at 7 nM. In the Lewis lung carcinoma mouse model, oral (p.o.) administration of PS-341 (0.1–1 mg/kg) delays tumor growth and the development of metastasis in the lung (13) .

In this study, we investigated the efficacy of PS-341 in ATL cells and in a murine model of ATL. We were particularly interested in the combination therapy involving PS-341 and HAT (humanized anti-IL-2R antibody, daclizumab, Zenapax^®), which is available clinically for the treatment of ATL. The scientific basis for the use of HAT to treat ATL is based on a striking surface feature of HTLV-I-infected leukemic T cells that overexpress IL-2R in contrast with the lack of expression by normal resting cells (14) . In a model of ATL in NOD/SCID mice, we demonstrated previously that HAT acts via an antibody-dependent cellular cytotoxicity (ADCC) mechanism involving FcR binding of the monoclonal antibody by monocyte and polymorphonuclear leukocyte effector cells (15) . The discovery that a NF-B response element exists in the IL-2R promoter region (16) suggests the possible additive or synergistic efficacy of this combination through an action interfering with the interleukin 2 signaling pathway.

	MATERIALS AND METHODS

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PS-341 and HAT.
PS-341 was obtained from the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute. HAT was acquired from Hoffmann-La Roche Inc. (Nutley, NJ).

Source of ATL Cells.
ATL cells (MET-1 cells) were maintained in NOD/SCID mice (Jackson Laboratories, Bar Harbor, ME), which were originally injected with purified ATL cells of a patient with acute ATL (15) . The injected mice at the late stage of the disease usually had enlarged spleens, from which MET-1 cells were harvested for in vitro study or further transfer to naïve NOD/SCID mice.

Whole Cell and Nuclear Extraction of ATL Cells.
MET-1 cells (10⁶ cells/ml) were cultured at 37°C in the presence of 5% CO₂ in 10 ml of RPMI 1640 medium (10% fetal bovine serum) with 1 µM PS-341. Whole cell extracts and nuclear extracts were prepared from washed cells by using RIPA solution and nuclear extraction reagents (Pierce, Rockford, IL).

Western Blot Analysis.
Whole cell extracts were resolved on 10% bis-Tris SDS-PAGE gels (Invitrogen, San Diego, CA) with standard procedures. Western blotting was performed using anti-IB antibody (1:1000; Santa Cruz Biotechnology, Santa Cruz, CA), anti-ubiquitin antibody (1:1000; Santa Cruz Biotechnology), and anti-vinculin antibody (1:1000; Sigma Chemical Co.) in PBS with 1% Tween 20. Proteins were visualized by the enhanced chemiluminescence reaction with horseradish-peroxidase-conjugated goat antibody against mouse or rabbit IgG (Santa Cruz Biotechnology) using enhanced chemiluminescence films (Amersham Pharmacia Biotech, Buckinghamshire, United Kingdom) and reagents (Pierce).

EMSA and Supershift.
Analysis of NF-B DNA binding activities by EMSA was carried out as described by McKinsey et al. (9) . For the supershift assay with specific antibodies against NF-B, nuclear extracts were preincubated with 1 µg of each antibody for 45 min at 4°C before the addition of the end-labeled double-stranded oligonucleotide probe. The antibodies used were anti-p50 antibody, anti-p52 antibody, anti-c-Rel antibody, and anti-p65 antibody (Santa Cruz Biotechnology). DNA-protein complexes were resolved on 6% polyacrylamide DNA retardation gels detected by autoradiography.

Therapeutic Efficacy of PS-341 in an ATL Murine Model.
MET-1 cells (10⁷) separated from enlarged spleens of leukemic NOD/SCID mice were i.p. injected into each naïve NOD/SCID mouse (body weight, 20–22 g; age, 8 weeks old). The progression of ATL in injected mice was monitored by measuring serum levels of sIL-2R using an ELISA (R&D Systems, Minneapolis, MN) 1 week after injection. The mice with sIL-2R levels of 1,000–10,000 pg/ml were entered into the study. Groups (8 mice/group) and treatments were as follows: (a) daily i.p. administration of PBS; (b) weekly i.v. administration of 100 µg of HAT for 4 weeks; (c) daily i.p. administration of 0.06 mg/kg PS-341 on days 0–20 and 27–41; and (d) with combination treatment of group 2 and 3. The efficacy of the treatments was monitored by measuring the serum levels of ß₂µ and sIL-2R by ELISA (R&D Systems). We demonstrated previously that these assays represent valuable surrogate markers of the efficacy of therapeutic agents in our model (15) . Kaplan-Meier plots were used to reflect the cumulative survival of mice in different treatment groups.

Statistics.
The average levels of ß₂µ and sIL-2R among individual treatment groups at different time points were compared using Student’s t test. The statistical differences among these treatment groups with regard to survival time were calculated with the PHREG procedure using SAS program (SAS Institute Inc., Cary, NC), which employs a discrete logistic model. P < 0.05 was considered to be statistically significant.

	RESULTS

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PS-341 Blocked the Degradation of IB in the Cytoplasm and Weakened NF-B DNA Binding Activity in the Nucleus.
Using a thymidine incorporation assay, we found that PS-341 inhibited the growth of the Jurkat and C81-66-45 cell lines (data not shown). A luciferase reporter plasmid with the B enhancer region was transfected into Jurkat cells. Results showed that after an 18-h incubation with 10 nM PS-341, the luciferase activity was abolished (data not shown). Similar findings were reported recently in other cell culture systems (11) . Transactivation of NF-B was one but not the only target of PS-341 to arrest cell growth.

The targeting of IB, the cytoplasmic inhibitory subunit complexed to NF-B, for degradation by the proteasome is known to occur in response to a variety of stress activators (6) . In this study, we attempted to investigate whether PS-341 stabilized IB by inhibiting the 26S proteasome, thereby decreasing the translocation of NF-B into the nucleus. Western blot analysis revealed that when MET-1 cells were treated with 1 µM PS-341, levels of IB remained unchanged. Meanwhile, the slower-migrating form of phosphorylated IB accumulated gradually. Incubation with PS-341 resulted in increased levels of the ubiquitinated proteins in whole cells, suggesting the impaired processing activity of the proteasome (Fig. 1) .

View larger version (97K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Effect of PS-341 on levels of IB, phosphorylated IB, and ubiquitinated proteins in MET-1 cells. MET-1 cells were incubated in the absence or presence of 1 µM PS-341 for the time periods indicated above each lane. Proteins from whole cell extracts were resolved by SDS-PAGE and immunoblotted with antibody against either IB, ubiquitin, or vinculin, as described in "Materials and Methods." With PS-341 treatment, the phosphorylated form of IB, the slower-migrating form of IB, accumulated markedly over the 4-h incubation period. The inhibition of 26S proteasome activity with PS-341 treatment was reflected in increased levels of ubiquitinated proteins. All samples had comparable levels of vinculin.

View larger version (47K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Effect of PS-341 on NF-B DNA binding activity in MET-1 cells. A, in a supershift assay, nuclear extracts from MET-1 cells were preincubated with NF-B subunit-specific antibody as indicated above each lane before the addition of a 32P-radiolabeled probe. Results showed that the components of NF-B protein in MET-1 cells consisted of p50/p50 homodimer and p65/p50 heterodimer. B, after treatment for the indicated time periods with 1 µM PS-341, MET-1 cells were lysed, and nuclear extracts were analyzed by EMSA as described in "Materials and Methods." Compared with the control samples, the samples with PS-341 treatment showed weakened NF-B DNA binding activity, although they all had similar Oct-1 DNA binding activity.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. The progression of ATL in MET-1 NOD/SCID mice (8 mice/treatment group). Spleen cells of MET-1 NOD/SCID mice were transferred to naïve NOD/SCID mice. Once the mice had sIL-2R levels of 1,000–10,000 pg/ml, therapy with HAT, PS-341, and the combination of HAT + PS-341 was initiated. Serum levels of sIL-2R (A) and ß2µ (B) were measured to monitor ATL progression, and they were presented as the average values of eight mice of each group plus the respective SD. The mice treated with PS-341 alone had statistically lower serum levels of sIL-2R and ß2µ than those in the PBS control group until 42 days after initiation of treatment. HAT, either alone or in combination with PS-341, significantly lowered the serum levels of sIL-2R and ß2µ when compared with those seen in the PBS control group during the entire course of the study.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. Kaplan-Meier survival plot of MET-1 NOD/SCID mice. The survival of mice treated with PS-341 alone was not statistically different from that of the PBS control group. HAT, either alone or in combination with PS-341, significantly prolonged the life span of MET-1 NOD/SCID mice compared with mice treated with PBS or PS-341 alone.

	DISCUSSION

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The aim of this study was to explore the potential use of PS-341, a synthetic dipeptidyl boronic acid, in the treatment of ATL. Due to its potent and reversible inhibition of the 26S proteasome, we reasoned that PS-341 would add therapeutic value to the treatment of ATL because NF-B is constitutively active in the ATL cells (17) . Recent studies have provided some insights into the multiple aspects of NF-B involvement in oncogenesis, including the control of apoptosis, the cell cycle, cellular differentiation, and cell migration (6) . By targeting the nuclear translocation and activation of NF-B, proteasome inhibitors have the potential to affect multiple cascades of events, thereby yielding anticancer activities (18) . On the other hand, because ubiquitin-proteasome proteolysis is the principle pathway for intracellular turnover of numerous key regulatory proteins in all eukaryotic cells (19) , the inhibition of this ubiquitous pathway may be inevitably accompanied by severe side effects. Moreover, it may not be feasible to block the NF-B pathway for extended periods because NF-B has an indispensable role in the maintenance of proper host defense responses. Indeed, in our NOD/SCID mouse model, i.p. administration of PS-341 at 0.1 mg/kg twice a day was very toxic to the mice and caused a 100% death rate within a 2-week period following 6 days of treatment. The treatment dose of PS-341 at 0.06 mg/kg (i.p., daily for 5 weeks) used in the present study was tolerated, although there was still noticeable toxicity. Nevertheless, PS-341 is tolerable at a dose up to 1 mg/kg when the drug is p.o. or i.p. administered to Balb/C mice twice a day for 2–3 weeks (13) . It can be p.o. administered to Lewis rats at 0.3 mg/kg daily for 3–4 weeks with acceptable toxicity (12) .

The failure of PS-341 alone to prolong survival of the tumor-bearing mice at the dosing regimen adopted in the present study may reflect the short duration of therapy that could be used. Nevertheless, PS-341 enhanced the anti-ATL activity of simultaneously administered HAT monoclonal antibody. PS-341 is currently undergoing several Phase I/II human clinical trials to evaluate its anticancer activity in patients with advanced cancer. The results of this study support a trial of this drug in ATL patients, preferably as an agent combined with HAT therapy.

	ACKNOWLEDGMENTS

 
We are grateful to Jennifer Mariner and Drs. Nazli Azimi and Yutaka Tagaya for helpful discussions. We also thank Carl Kaulfersch and Dr. Meili Zhang for technical assistance.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at Chief, Metabolism Branch, National Cancer Institute, NIH, Building 10, Room 4N115, 10 Center Drive, Bethesda, MD 20892-1374.

² The abbreviations used are: NF-B, nuclear factor B; HTLV, human T-cell lymphotrophic virus; ATL, adult T-cell leukemia; HAT, humanized anti-Tac; IL-2R, interleukin 2 receptor; sIL-2R, soluble interleukin 2 receptor; NOD/SCID, nonobese diabetic/severe combined immunodeficient; EMSA, electrophoretic mobility shift assay; ß₂µ, ß₂-microglubulin.

Received 8/31/01. Accepted 12/17/01.

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