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1 Departments of Veterans Affairs; Departments of Cancer Biology and 2 Biostatistics, Vanderbilt University Medical Center; 3 Department of Microbiology, Meharry Medical College; and 4 Division of Hematology/Oncology, Vanderbilt Ingram Cancer Center, Nashville, Tennessee
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B is constitutively activated in melanoma, thereby promoting the proliferation of melanoma cells by inhibiting the apoptotic responses to chemotherapy. Nuclear factor B activity is regulated by phosphorylation and subsequent degradation of inhibitor of nuclear factor B by the ubiquitin-proteasome pathway. In this study, we show that the novel proteasome inhibitor, bortezomib, inhibited the growth of melanoma cells in vitro at a concentration range of 0.1–10 nM and in combination with the chemotherapeutic agent temozolomide, the inhibitory effect on melanoma cell growth was even more prominent. Data from a murine model showed reduced tumor growth when bortezomib was administered to human melanoma tumors. Strikingly, animals receiving bortezomib in combination with temozolomide achieved complete remission of palpable tumors after only 30 days of therapy, lasting >200 days. Our data indicate strongly that bortezomib in combination with chemotherapeutic agents should be studied additionally for the treatment of melanoma. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B (NFB) pathway (5
, 6)
.
Constitutive activation of NFB is an emerging hallmark of various types of tumors including breast, colon, pancreatic, ovarian, and melanoma (7, 8, 9, 10, 11, 12)
. In the healthy human, NFB regulates the expression of genes involved in normal immunological responses (e.g., generation of immunoregulatory molecules such as antibody light chains) in response to proinflammatory cytokines and byproducts of microbial and viral infections (13, 14, 15)
. However, increased activation of NFB results in enhanced expression of proinflammatory mediators, leading to acute inflammatory injury to lungs and other organs and development of multiple organ dysfunctions. NFB also modulates the expression of factors responsible for growth as well as inhibitors of apoptosis (13
, 15 , 16)
.
There are five known mammalian NFB subunits, each characterized by ankyrin repeat elements: (a) Rel (c-Rel); (b) p65 (RelA); (c) RelB; (d) p50; and (e) p52. The NFB protein is composed of two subunits, which may vary affecting the transcriptional activity of the protein. In the absence of activation, NFB complexes (homo- and heterodimers composed of above the mentioned subunits) are sequestered in the cytoplasm because of their association with an inhibitor of B protein (IB). The IB protein binds to the nuclear localization signal of NFB Rel proteins, thereby inhibiting translocation of the complexes into the nucleus (13, 14, 15)
. When the cell is exposed to activating signals, such as tumor necrosis factor-
, the IB protein is phosphorylated by IB kinase, ubiquitinated, and then broken down in the 26 S proteasome (17)
. This frees the NFB to translocate into the nucleus, where it binds to B sites in the promoter/enhancer regions of specific genes, including the promoter/enhancer for IB, to transactivate transcription (13
, 15
, 17)
.
Persistent activation of NFB inhibits apoptosis and promotes proliferation leading to hyperplasia (13
, 16
, 18
, 19)
. Previous studies in our laboratory have shown an elevated basal IB kinase activity in Hs294T melanoma cells, which leads to an increased rate of IB phosphorylation and degradation. This increase in IB- phosphorylation and degradation leads to an 
19-fold higher nuclear localization of NFB (20)
. We have shown that this constitutive activation of NFB facilitates the immortalization and proliferation of melanocytes and provides a means to escape apoptosis (20, 21, 22, 23)
. These findings suggest that NFB may represent an effective molecular target in melanoma tumorigenesis.
To date, many different strategies have been used to inhibit NFB activity in tumors with various degrees of success. We propose to use the target 26 S proteasome for inhibition of NFB activity in melanomas. Among proteasome inhibitors, bortezomib (VELCADE), formerly known as PS-341, inhibits more specifically the chymotryptic enzyme activity of the proteasome. Bortezomib is a low molecular weight, water-soluble dipeptide that binds to the proteasome with very high affinity and dissociates slowly, imparting stable but reversible proteasome inhibition (24
, 25)
. Bortezomib has shown great promise in the preclinical studies for cancers such as ovarian, lung, squamous cell carcinoma, prostate, and pancreatic (26, 27, 28, 29, 30)
, and many clinical trials for the treatment of these cancers have been initiated (31
, 32)
. More recently, bortezomib received accelerated approval from the United States Food and Drug Administration for the treatment of patients with refractory multiple myeloma who failed prior chemotherapy (33)
, highlighting the potential effectiveness of the drug in the treatment of cancer.
This is the first study to investigate the efficacy of bortezomib in melanoma cells and in a murine xenograft model of melanoma to inhibit NFB and, in turn, melanoma tumor progression. In particular, we were interested in the combination therapy involving bortezomib and TMZ. TMZ is currently one of the most prescribed chemotherapeutic treatments for metastatic melanoma despite its marginal effectiveness (3)
. We hypothesized that the combination of chemotherapy with proapoptotic therapy could result in a synergistic effect, providing a more effective strategy to eliminate melanoma tumors.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Culture.
The human melanoma cell line Hs294T was obtained from American Type Culture Collection (Manassas, VA), and normal retinal pigment epithelial cells, RPE-476, were generously provided by Glenn Jaffe at Duke University (Durham, NC). The cells were grown in 50% DMEM, 50% F-12 supplemented with 10% fetal bovine serum, 1% nonessential amino acids, 100 mg/ml penicillin, and 100 mg/ml streptomycin. Cell cultures were maintained at 37°C.
Cell Growth Response.
Melanoma cell lines SK-MEL-5, SK-MEL-28, WM 115, and Hs 294T (5 x 105 cells/well) were seeded in six-well plates. Cells were treated with increasing doses (0–25 nM) of bortezomib for 48 h, and the number of viable cells was scored after addition of trypan blue using a hemocytometer. The results are reported as sigmoidal dose-response curve depicting the mean sensitivity of the 4 melanoma cell lines using the software GraphPad Prism. The GI50 value was calculated by the same software. RPE 476 and Hs294T cell lines were seeded in six-well plates and treated with 1 nM bortezomib and/or TMZ at increasing doses of 10, 100, and 1000 µM 12 h after plating. Control groups were culture medium alone and 5% DMSO. Cell counts were performed after addition of trypan blue to the cells, using the hemocytometer on day 3 of treatment.
Tumor Growth Response.
BALB/C-nu/nu female mice were assigned to each of the following groups with 5 mice/group: (a) Control; (b) bortezomib; (c) TMZ; (d) bortezomib and TMZ. One million Hs 294T cells were injected s.c. (day 0). Treatment began on day 8, when tumors were palpable. Each mouse received 1.25 mg/kg bortezomib peritumorally and/or 20 mg/kg TMZ peritumorally dissolved in 100 µl of saline on a twice-weekly schedule. The control group received the vehicle. Bidimensional tumor measurements were assessed three times weekly using microcalipers. The Vanderbilt University Institutional Animal Care and Use Committee approved experimental protocols.
Immunoblot Analysis.
Whole cell extracts were obtained according to our standard protocol using radioimmunoprecipitation assay buffer. Extracts from tumor tissue were made according to our standard protocol. Briefly, tumor tissues were snap frozen in liquid nitrogen. The tissue was homogenized in tissue homogenizer containing TNN buffer [150 mM NaCl, 50 mM Tris HCl (pH 8.0), and 0.05% NP40]. The homogenized tissue was centrifuged for 10 min at maximum speed, and the cleared supernatant was collected for analysis. The lysates were subjected to SDS-PAGE and probed with appropriate antibodies. Antibodies used were anti-p21, anti-p53, anti-MDR-1, and antiactin from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-MRP1 was obtained from Chemicon International (Temecula, CA). For secondary antibodies, horseradish peroxidase-conjugated antimouse, goat, or rabbit IgG were obtained from Chemicon International. The antibodies were visualized using an enhanced chemiluminescence kit from Amersham Biosciences (Piscataway, NJ).
Immunohistochemistry.
Paraffin-embedded tumor sections were deparaffinized with xylene. The antigen was unmasked by heating samples in 10 mM of sodium citrate buffer (pH 6.0) for 5 min and quenching with 0.03% hydrogen peroxide. Samples were immunostained for activated RelA/p65 with anti-RelA/p65 (1:25) or CD31 (1:400). The ABC biotin/avidin reagent kit was used to visualize the immunolocalization of the antigen using NovaRed from Vector Laboratories (Burlingame, CA), and cell contents were counterstained with hematoxylin. Stained sections were photographed using the Nikon light microscope at x20 and x100 magnifications. For CD31 staining quantitation, the Image Pro Plus software was used. Anti-NFB p65 was obtained from Chemicon International, and anti-CD31was obtained from Research Diagnostics, Inc. (Flanders, NJ).
Terminal Deoxynucleotidyl Transferase-Mediated Nick End Labeling Assay.
DeadEnd Fluorimetric terminal deoxynucleotidyl transferase-mediated nick end labeling system (Promega Corporation, Madison, WI) was used to detect apoptosis in tumor tissue embedded in paraffin. Briefly, tissue sections were deparaffinized in xylene and rehydrated in graded ethanol washes. Sections were fixed with methanol-free paraformaldehyde and permeabilized with 20 µg/ml proteinase K. After washing, sections were incubated inside a humidified chamber with terminal deoxynucleotidyltransferase incubation buffer containing equilibration buffer, nucleotide mix, and terminal deoxynucleotidyltransferase enzyme for 60 min at 37°C. The reaction was terminated by immersing the sections into 2x SSC. After staining sections with 500 ng/ml propidium iodide, the sections were analyzed under a fluorescence microscope using a standard fluorescein filter set to view the green fluorescence of fluorescein at 520 nm and red fluorescence of propidium iodide at >620 nm.
ELISA Assay.
For in vitro quantitation of CXCL1 and interleukin 8, cleared supernatants of Hs 294T cell culture medium were collected. Briefly, 1.5 x 105 of Hs 294T cells/well in six-well plates were seeded in serum-free DMEM/F12 medium and incubated at 37°C for 12 h. After washing in serum-free medium, the monolayers were incubated with 10 nM bortezomib and/or 100 µM TMZ in serum-free medium for 48 h at 37°C. The supernatant was collected and subjected to Quantikine ELISA assay from R&D Systems Inc. (Minneapolis, MN) for hCXCL1 and hCXCL-8 according to the manufacturer’s instructions. For quantitation of vascular endothelial growth factor levels in the Hs 294T tumors, cleared homogenates of tumor tissue (see "Immunoblot Analysis") were subjected to the hVEGF Quantikine ELISA kit.
Statistical Analysis.
The in vitro cell survival data and differences in mean tumor volume at day 36 were evaluated by ANOVA and t test statistic. ANOVA with repeated measures was used to compare the differences in the tumor volumes over time (performed in SAS; version 8.2) as well as for CD31 counts.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Treatment of cells with bortezomib inhibited cell growth in a dose-dependent response, and the average GI50 for the cell lines was 6 nM. To assess whether bortezomib increases the sensitivity of melanoma cells to the chemotherapeutic agent TMZ, Hs 294T cells were exposed to 1 nM of bortezomib ± 10–1000 µM of TMZ for 72 h (Fig. 1B)
. Results show that Hs 294T cells show an increased sensitivity toward TMZ with the addition of bortezomib, because the lower concentrations of TMZ, when used in combination with bortezomib, have the same effect on cell growth as high-toxic dose TMZ. More interestingly, the sensitivity to the drug was much greater in melanoma cell line Hs 294T than in the normal human cell line, retinal pigment epithelial RPE-476 cells (Fig. 1C)
. Altogether, the data indicate that melanoma cells are more sensitive to bortezomib than normal cells and that bortezomib reduces the resistance of melanoma cells to TMZ.
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B Target Genes.B activation in many cancers, and because melanomas show constitutive activation of NFB and are highly resistant to chemotherapy, we determined the effect of bortezomib on NFB inhibition after treatment with TMZ in Hs 294T cells. TMZ (100 µM for 24 h) increased significantly the secretion of the NFB-regulated chemokine, CXCL8, although the number of viable cells decreased by half that of control cells (Fig. 2A)
. However, when cells are treated with TMZ (100 µM) in combination with 10 nM bortezomib, the CXCL8 induction by TMZ is no longer detected. The data suggest that TMZ induces NFB activation and subsequent CXCL8 production, and cotreatment with bortezomib inhibits this induction. Similar results were obtained for the NFB-regulated chemokine, CXCL1 (data not shown).
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B in drug resistance and evidence that chemotherapeutic agents may induce multidrug resistance genes, the expression level of family members MDR-1and MRP1were also investigated (Fig. 2B)
. Treatment of melanoma cells with TMZ at a dose of 100 µM induces MDR-1and MRP1expression. However, the expression of both proteins is abrogated when cells are treated with TMZ in combination with bortezomib. Altogether, the in vitro data indicate that bortezomib may be an excellent drug to use in combination with other chemotherapeutics in the treatment of melanomas.
Enhancement of TMZ-Mediated Antitumor Activity by Bortezomib.
To determine whether combining TMZ treatment with the administration of proteasome inhibitor bortezomib could enhance the chemosensitivity of melanoma tumors, a Hs 294T xenograft model was used (Fig. 3)
. In these experiments, s.c. administration of bortezomib at 1.25 mg/kg or TMZ at 20 mg/kg alone to growing melanoma tumors initially resulted in a significant decrease in tumor size (P < 0.0001 and P < 0.0002, respectively) when compared with the control group receiving saline alone (Fig. 3A)
. However, when single agent treatments were withdrawn by day 36 after tumor implantation, tumor growth was recommenced quickly in these groups, and subsequent treatment with either drug did not result in effective tumor growth inhibition (Fig. 3B)
. Combined treatment with 1.25 mg/kg bortezomib and 20 mg/kg TMZ resulted in complete remission of all of the animals within the group with an average tumor size of 3.51 mm2 and average tumor growth time of 27.75 days. Interestingly, the treatment group that received combined administration of bortezomib and TMZ was the only group to undergo a true tumoricidal response, where a persistent regression of tumor growth was observed in all of the animals to the point that the animals were cured of their tumor burden by day 36. The complete remission persisted even after the withdrawal of both agents for >200 days.
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. As illustrated by the images, the tumors in the control group as well as the TMZ group exhibit low levels of apoptosis. However, a marked increase in apoptosis is observed in tumors treated with bortezomib. The increase in apoptosis was typical for all of the tumors in the bortezomib group, and the terminal deoxynucleotidyl transferase-mediated nick end labeling-positive cells were detected within the entire area of the tumor in contrast to nontreated tumors or tumors treated with TMZ, where slight staining was seen in the periphery of tumors. Thus, these findings suggest that the tumoricidal response to treatment with bortezomib appears to result from markedly increased levels of apoptosis throughout the tumors.
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B, we performed immunohistochemical analysis on sections of fixed, embedded tumors using antibody against the nuclear NFB subunit, RelA/p65 (Fig. 5)
. The immunohistochemical analysis shows that p65 accumulates in the nucleus in the control tumors at high levels (Fig. 5, A and B)
and that treatment with TMZ additionally increases p65 nuclear localization even more (Fig. 5, C and D)
, confirming that TMZ is an inducer of NFB. However, tumors that were treated with bortezomib alone exhibited a much reduced nuclear p65 level (Fig. 5, E and F)
, indicating that bortezomib actively inhibits the translocation of NFB into the nucleus and, thus, inhibits NFB activity in these tumors.
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. Treatment with bortezomib resulted in stabilization of both p53 and p21, suggesting that one potential mechanism of action of the drug may be through the stabilization of p53 and p21. Because altered expression levels of MDR-1 and MRP1 were observed in the Hs 294T cell line treated with bortezomib and TMZ, we also evaluated the expression of these ATP-binding cassette transporters in the tumors. Both MDR-1 and MRP1 were up-regulated in tumors treated with TMZ, whereas in tumors treated with bortezomib, MDR-1 was undetectable, and MRP1 was detected at very low level. These data suggest that bortezomib has the potential for enhancing chemosensitivity through regulation of ATP-binding cassette transporters as well as induction of apoptosis.
Bortezomib Inhibits Angiogenesis in Tumors.
To determine whether the significant decrease in the tumor size that resulted from bortezomib treatment was because of decrease in the microvasculature within the tumor, tumor sections were stained for endothelial cells using antibody against the endothelial cell marker CD31 (Fig. 6, A–C)
. Quantitative analysis of the tumor sections shows a significant decrease in tumor vessel density for tumors treated with bortezomib (P < 0.001) compared with treatment with TMZ or control (Fig. 6D)
. Interestingly, all of the TMZ-treated tumors exhibited slightly higher levels of microvasculature than the control tumors.
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B has been reported to induce the expression of the potent angiogenic factor vascular endothelial growth factor, which is required for tumor growth and metastasis, we next asked whether the significant decrease in tumor microvasculature after bortezomib treatment was due to decreased vascular endothelial growth factor production by the tumor tissue. ELISA analysis revealed that tumors in the bortezomib group exhibit a decrease in the level of vascular endothelial growth factor, whereas the tumors in control and TMZ treatment groups show high production of this growth factor (Fig. 6E)
. This result is consistent with the CD31 immunostaining of the tumors. Thus, the significant inhibition of tumor growth response of mice treated with bortezomib may be attributed partly to decreased angiogenesis in these tumors. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Its effectiveness is widely debated, but even supporters acknowledge its benefit as small, accompanied by a large cost in toxicity (34)
. Patients with metastatic disease (stage IV) have a median survival of 6–10 months with a 5-year survival of <5% (4)
. Effective treatment options are limited at best. Although both active and passive immunotherapy has been pursued vigorously over the past few decades, no melanoma vaccine has proven effective, and only interleukin 2 therapy has led to durable remission in only 5–8% of patients treated (35)
. The expectation is that novel treatment agents that target signaling pathways important to melanoma may offer hope for an otherwise dismal disease.
A growing body of evidence suggests that melanomas acquire the ability to attenuate signals that would normally lead to apoptosis by using major transcriptional regulators such as p53 and NFB. The tumor suppressor protein p53 plays an important role in the regulation of the mitochondrial apoptotic pathway by transcriptional activation of proapoptotic Bcl-2 family members (such as Bax, Bam, Puma, and Noxa; reviewed in Refs. 36
, 37
) and by repression of antiapoptotic Bcl-2 family proteins (38
, 39)
. Although p53 is not mutated in the majority of human melanomas, altered or impaired transcriptional activities of p53 have been reported (40
, 41)
. NFB, on the other hand, attenuates tumor necrosis factor--induced apoptosis by up-regulating expression of c-IAP1, c-IAP2 (42
, 43)
, TRAF-1, TRAF-2 (43
, 44)
, and c-FLIP (45)
. Advanced melanomas often exhibit a high level of TRAF-2 expression (46)
, which results in constitutively active stress kinases and constitutive activation of the IB kinase pathway, resulting in the elevated levels of activated NFB, thus feeding back into the circuit (23
, 46, 47, 48)
. In addition to its role in protection against apoptosis, NFB may also play an important role in resistance to conventional chemotherapy (49)
by inducing expression of ATP-binding cassette transporters (50
, 51)
. Thus, targeting these pathways may prove to be advantageous in the treatment of malignant melanoma.
The aim of this study was to explore the potential use of the proteasome inhibitor bortezomib in the treatment of melanoma. Recent studies have shown that proteasome inhibitors represent novel anticancer therapeutic agents by inhibiting degradation of cell cycle regulatory proteins such as cyclins, cyclin-dependent kinase inhibitors, as well as other important regulatory proteins such as IB. Our report highlights the capacity of bortezomib to overcome chemoresistance to conventional melanoma therapy and induce apoptosis in malignant melanoma tumors.
We first showed that bortezomib acts directly to inhibit the growth of melanoma cancer cell lines, more so than normal cell lines, and that this antimelanoma activity is enhanced when cells are treated with bortezomib in combination with the chemotherapeutic agent TMZ. Our data confirm additionally that the inhibitory effects of bortezomib on cell growth in vitro are potentially because of down-regulation of NFB and, in turn, NFB regulated genes such as cytokines CXCL8 and CXCL1 that play an important role in promoting growth and metastasis of melanomas. bortezomib also reduces expression of the ATP-binding cassette drug transporter family members MDR-1 and MRP1, rendering it a noteworthy candidate to be used in combination with many antineoplastic therapies, such as doxorubicin, that are inactivated through this pathway. Furthermore, bortezomib results in increased accumulation of important cell cycle regulatory proteins such as p53 and p21. Our study demonstrates that the in vitro data were comparable with in vivo studies in mice, which is evidenced by substantial tumor growth inhibition. Additional analysis of the tumor tissues revealed decreased NFB activation as well as decreased vascular endothelial growth factor production, leading to decreased tumor microvasculature and, hence, an increased level of apoptosis in tumors. Although NFB is a key factor in bortezomib-induced selective toxicity against melanoma, bortezomib acts also through multiple pathways to block cell proliferation and induce apoptosis in melanoma. One might assume that bortezomib may also act on other important survival signaling pathways in melanoma such as phosphatidylinositol 3'-kinase/AKT and Raf/mitogen-activated protein kinase pathways, both of which have been shown to be disregulated in melanoma and to impinge on the NFB pathway (52)
, therefore, warranting the use of bortezomib in combination with inhibitors of these pathways for future studies.
Our studies demonstrate that the proteasome inhibitor bortezomib both induces apoptosis and abrogates angiogenesis in human melanoma tumors. Moreover, bortezomib sensitizes these tumors to conventional TMZ chemotherapy. Given the impressive result from combination therapy of bortezomib with TMZ of human tumors in mice, these studies provide the framework for ongoing clinical trials of bortezomib in melanoma in the hope of improving the outcome for patients with advanced melanoma, who have a dismal prognosis with few therapeutic options available.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
Requests for reprints: Ann Richmond, Department of Cancer Biology, 771 PRB, Vanderbilt University School of Medicine, Nashville, TN 37232. Phone: (615) 343-7777; Fax: (615) 343-4539; E-mail: Ann.Richmond{at}vanderbilt.edu
Received 2/24/04. Revised 4/28/04. Accepted 5/ 7/04.
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M. L. Guzman, R. M. Rossi, L. Karnischky, X. Li, D. R. Peterson, D. S. Howard, and C. T. Jordan The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells Blood, June 1, 2005; 105(11): 4163 - 4169. [Abstract] [Full Text] [PDF]
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