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Clinical Cancer Research Vol. 8, 3955-3960, December 2002
© 2002 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Suradista NSC 651016 Inhibits the Angiogenic Activity of CXCL12-Stromal Cell-derived Factor 1{alpha}1

Gregory P. Schneider, Rosalba Salcedo, Hui Fang Dong, Hynda K. Kleinman, Joost J. Oppenheim and O. M. Zack Howard2

Laboratory of Molecular Immunoregulation [G. P. S., R. S., J. J. O., O. M. Z. H.], Center for Cancer Research, Intramural Research Support Program, Science Applications International Corporation-Frederick [H. F. D.], National Cancer Institute-Frederick, Frederick, Maryland 21702, and the Cell Biology Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland 20892 [H. K. K.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
CXCL12 (stromal cell-derived factor 1{alpha}), a ligand for CXCR4, has been shown to induce endothelial cell chemotaxis and to stimulate angiogenesis, suggesting that it may be a significant target for antiangiogenic therapy. Here we have tested suradista NSC 651016, a compound known to inhibit CXCL12-induced monocyte chemotaxis, for its ability to inhibit CXCL12-induced angiogenic activity. NSC 651016 inhibited CXCL12-mediated endothelial cell chemotaxis in a dose-dependent manner. In addition, new vessel sprouting, by both rat and chick aorta in an angiogenesis model, was inhibited. Additionally, in vitro capillary-like structure formation induced by CXCL12 was inhibited by NSC 651016. Furthermore, NSC 651016 inhibited CXCL12-mediated angiogenesis in an in vivo s.c. assay. These data indicate that suradista NSC 651016 possesses in vitro and in vivo antiangiogenic activity and has the potential to interfere with neovacularization of tumors and their metastases.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
CXCL12 (stromal cell-derived factor 1{alpha}) was originally isolated from bone marrow stromal cells (1) . CXCL12 binds CXCR4 (2) , and both ligand and receptor are highly conserved across diverse species (3) , suggesting they have fundamental biological importance. Murine knockouts of CXCL12 and CXCR4 genes display a similar embryonic lethal phenotype with deficiencies in B-cell development and myelopoiesis (4) , abnormal neuronal and cardiac development (5) , and defects in vasculogenesis (6) . CXCR4 is also a coreceptor for T-lymphocyte tropic strains of HIV-1, and CXCL12 can inhibit the fusion and replication of HIV-1 in CD4+ and CXCR4+ cells (7 , 8) .

Recent data demonstrated that CXCL12 has angiogenic activity (9 , 10) . CXCR4 is constitutively expressed on human umbilical vein endothelial cells, and receptor expression is up-regulated by either VEGF3 or bFGF (10) . Because CXCL12 is expressed by several tumors, including pancreatic cancer (11) and glioblastoma (12, 13, 14) , tumor-derived CXCL12 and its receptor, CXCR4, expressed on endothelial cells may be important in tumor neovascularization and promote the metastatic spread of tumors. CXCL12 and CXCR4 may therefore be therapeutic targets.

Suradista NSC 651016 (Fig. 1)Citation inhibits in vitro replication of HIV-1 at a concentration range of 1–10 µM (15 , 16) . Additionally, NSC 651016 inhibits CXCL12-mediated chemotaxis by inhibiting ligand binding to CXCR4 and by inducing receptor internalization. This activity was structure specific rather than merely charge related (17 , 18) . We hypothesized that NSC 651016 could inhibit CXCL12-induced angiogenesis and have tested for inhibition of angiogenic activity in several model systems. We show here that NSC 651016 inhibited CXCL12-induced endothelial cell chemotaxis in a dose-dependent manner and inhibited angiogenic sprouting from an aorta angiogenesis model. Finally, NSC 651016 inhibited CXCL12-mediated angiogenesis in a murine s.c. Matrigel assay. These data indicate that NSC 651016 may have potent therapeutic antiangiogenic activity.



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  		Fig. 1. Graphic representation of NSC 651016 structure.

 

   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Factors and Chemicals.
Recombinant CXCL12 and recombinant VEGF were obtained from the National Cancer Institute cytokine repository. ECGS was purchased from Sigma (St. Louis, MO). Matrigel was purchased from BD Biosciences (San Diego, CA). The distamycin analogue NSC 651016 (2,2'[4,4'[[aminocarbonyl] amino]bis[N, 4'-di[pyrrole-2-carboxamide-1,1'-dimethyl]]-6,8 napthalenedisulfonic acid]hexasodium salt) was provided to the National Cancer Institute by Pharmacia and Upjohn/Farmaitalia. The Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program Division of Cancer Treatment, National Cancer Institute was the immediate source of the reagent used in this study. All other compounds were purchased from Sigma unless noted.

Cell Culture.
HMVECs were obtained from Cell Systems Corp. (Kirkland, WA). Cells were cultured (37°C, 5% CO2) on collagen type I-coated plastic culture flasks (Biocoat; Becton Dickinson, Bedford, MA) in endothelial growth medium (BioWhittaker, Walkersville, MD) containing 5% FBS, VEGF (10 ng/ml), bFGF (10 ng/ml), glutamine (2 mM), and gentamicin (10 units/ml). HMVEC cultures were tested for their expression of CD31 and von Willebrand’s factor by flow cytometry. Preparations containing >98% positively staining cells were used for chemotaxis. BAECs, a kind gift from Dr. Adriana Haimovitz-Friedman (Memorial Sloan-Kettering Cancer Center), were cultured (37°C, 10% CO2) in DMEM (BioWhittaker) containing 10% FBS (HyClone, Logan, UT), 2 mM glutamine, and 100 units/ml penicillin and streptomycin (Quality Biologicals, Gaithersburg, MD). Medium was supplemented with 1 ng/ml bFGF (R&D Systems) every other day until the cells reached confluence. At confluence, the medium was changed to 5% FBS-DMEM and used for experiments 36 h later.

Endothelial Cell Migration Assay.
HMVEC and BAEC chemotaxis was performed using polycarbonate filters (10-µm pore size; NeuroProbe, Cabin John, MD), which were coated with either fibronectin or collagen I (10 µg/ml; Sigma) overnight at 4°C. Chemotaxis medium containing 1% BSA in RPMI 1640 and 25 mM HEPES (pH 8.0), with or without 100 µg/ml CXCL12, was placed in the lower chamber, and 50 µl of HMVEC resuspended at a concentration of 0.5 x 106 cells/ml in chemotaxis medium were added to the upper compartment. The chambers were incubated for 3–4 h at 37°C. After incubation, filters were removed from the chamber, and the upper surface was scraped, fixed in methanol, and stained with Rapid Stain (Richard Allen, Kalamazoo, MI). Membranes were analyzed using the Bioquant program (R&D Biometrics, Inc., Nashville, TN), and the results expressed as the mean ± SD of 10 fields of migrated cells/x100 magnification field. Each sample was tested in triplicate.

Aortic Ring Assay.
Aortas were obtained from Sprague Dawley rats that weighed <=100 g. The thoracic aorta was obtained from chick eggs (13–15 days). Excess perivascular tissue was removed, and transverse sections (1–2 mm) were cut, and the resulting aortic rings were washed in medium 199 (Life Technologies, Inc., Grand Island, NY). The rings were embedded in Matrigel (Becton Dickinson) in 48-well plates (Costar, Corning, NY) with the lumen perpendicular to the base of the well. The ring was covered with Matrigel, which was allowed to gel. Serum-free medium with or without stromal cell-derived factor 1{alpha}, and inhibitors (at indicated concentrations) were added to the wells. Plates were incubated (37°C, 5% CO2) for up to 46 h. The degree of neovessel growth was scored relative to the positive control by a blinded observer.

In Vitro Tube Formation Assay.
Trypsinized BAEC (50,000 cells) were resuspended in endothelial cell basal medium (Life Technologies, Inc.) and seeded in 48-well plates coated with 150 µl of Matrigel (0.5–1 h, 37°C; Becton Dickinson). Human CXCL12 (100 ng/ml) or ECGS (Sigma) in the absence or presence of NSC 651016 at indicated concentrations was added to the wells. After incubation (37°C, 10% CO2, 20 h), capillary-like structure formation was examined using an inverted phase photomicroscope. Cells were fixed and photographed. Assays were performed with six replicates/treatment.

In Vivo Matrigel Plug Angiogenesis Assay.
Matrigel (0.2 ml) alone or mixed with recombinant human VEGF and/or recombinant human CXCL12 (1000 ng/ml) and NSC 651016 (50 µg/ml) or an inactive Suradista, PNU 151749 (50 µg/ml), was injected s.c. into the flank of BALB/c mice. On day 7, the mice were euthanized, and the plugs were removed. The plugs were weighed and dissolved in 0.5 N HCl (1 ml, 100°C, 2.5 min). The tubes containing the dissolved pellet were centrifuged at 10,000 x g (5 min, 4°C). The resultant supernatant was assayed for heme at an UV absorbance of 450 nm.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Endothelial Cell Migration.
NSC 651016 inhibited endothelial cell chemotaxis in a dose-dependent manner with significant inhibition observed at 10-10 M (51.8 ± 2.5% inhibition) with maximal inhibition observed at 10-5 M (81 ± 6.7% inhibition; Fig. 2Citation A). Cell viability at these doses of NSC 651016 was >99%. In a parallel study, NSC 651016 was observed to inhibit CXCL12-mediated chemotaxis of BAEC in a similar manner to that of human endothelial cells. Significant inhibition was observed at 10-7 M (64.4 ± 18.8%) NSC 651016, whereas the maximal inhibition was observed at 10-5 M (112 ± 12.8%; Fig. 2Citation B). The apparent greater sensitivity of HMVEC over BAEC to NSC 651016 was reproducible in all experiments and likely reflects species differences in the CXCR4 receptor. Interestingly, at subnanomolar concentrations, NSC 651016 appears to stimulate BAEC migration, suggesting that there is partial agonistic effect on the receptor before receptor internalization. However, when evaluated for statistical significance, there is no significant reduction at the lower concentrations.



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  		Fig. 2. A, NSC 651016 inhibits CXCL12-induced HMVEC chemotaxis. B, NSC 651016 inhibits CXCL12-induced BAEC chemotaxis. Endothelial cells were incubated with increasing amounts of NSC 651016 before being placed in the upper wells of a microBoyden chamber, whereas CXCL12 was placed in the lower wells of a microBoyden chamber. The percentage of inhibition is shown on the Y axis, whereas increasing concentrations of NSC 651016 are indicated on the X axis. Each condition was performed in triplicate. Each assay was performed a minimum of three times. As compared with medium alone control (0), NSC 651016, all inhibitory conditions are at Ps <= 0.01 ANOVA analysis.

 
Aortic Ring Vessel Formation Assay.
Aortic rings treated with NSC 651016 exhibited decreased CXCL12-mediated sprouting in an in vitro angiogenesis assay (Fig. 3)Citation . ECGS, a stimulant of angiogenesis, induced a 2-fold increase in vessel sprouting as compared with media alone. CXCL12 (50 ng/ml; empirically optimized) also induced vessel sprouting. Concurrent addition of NSC 651016 decreased the CXCL12-induced vessel sprouting to background levels. The degree of inhibition was equivalent to that achieved with neutralizing anti-CXCL12 antibody treatment (data not shown).



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  		Fig. 3. Aortic ring neovessel formation studies. A, rat aortic rings were cultured with either no stimulant, 50 ng/ml CXCL12, 50 ng/ml CXCL12 + 10 µM NSC 651016, or a mixture of growth factors ECGS. B, chick aortic rings were cultured for 46 h before they were fixed and photographed. Rings were cultured with media alone to provide a negative control or ECGS to provide a positive control. The test conditions contained either 50 ng/ml CXCL12, 1 µM NSC 651016, or the combination of 50 ng/ml CXCL12 + 1 µM NSC 651016. C, after culture, the degree of neovessel formation was scored by blinded observer. The rings were scored based on the number and length of vessels observed after the incubation. A score of 0 indicated no vessel growth, whereas a score of 5 indicated multiple long vessels as compared with the positive control. The median value for 5 rings and the SE are shown here. Negative control is culture medium alone. Positive control is ECGS containing culture medium. The figure is representative of three performed experiments. There is no statistical difference between negative control and NSC 651016 alone-treated rings.

 
In Vitro BAEC Capillary-like Tube Formation.
When CXCL12 (100 ng/ml; empirically optimized) was added to wells containing bovine aortic endothelial cells, capillary-like tube formation was induced (Fig. 4, A and B)Citation , similar to that seen with ECGS (200 µg/ml; Fig. 4CCitation ). NSC 651016 inhibited CXCL12-mediated capillary-like formation in a dose-dependent manner with complete inhibition at 25 µM (Fig. 4, D and E)Citation . As expected, because ECGS contains both endothelial cell growth factors and angiogenic factors, NSC 651016 partially inhibited ECGS-induced tube formation.



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  		Fig. 4. Bovine aortic endothelial cell neovessel formation assay. Primary cells were cultured under the noted conditions. After 20 h, the cultures were photographed. The treatments are indicated below the photograph. The figure is representative of three performed experiments.

 
In Vivo Matrigel Angiogenesis Assay.
The inhibitory effect of NSC 651016 on in vivo angiogenesis was determined by measuring the level of heme present in solubilized Matrigel plugs from mice inoculated with Matrigel containing various treatments. A statistically significant increase in the presence of heme was observed in the CXCL12-treated plugs (Fig. 5)Citation . The addition of NSC 651016 significantly inhibited CXCL12-induced angiogenesis. A structurally related compound, PNU 151749, which does not block CXCR4, did not block CXCL12-induced angiogenesis. NSC 651016 alone did not statistically increase or decrease in vivo angiogenesis.



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  		Fig. 5. NSC 651016 inhibits CXCL12-induced angiogenesis in an in vivo model. CXCL12-induced angiogenesis as measured by the presence of heme in Matrigel (A450). Each bar is the average of data collected from 5 animals ± SE. A structurally related but inactive suradista, PNU151749, was used as an additional control. The experiment was performed twice with similar results.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The data reported herein show the capacity of NSC 651016 to act as an inhibitor of CXCL12-mediated angiogenesis in a variety of in vitro and in vivo angiogenesis assays. Furthermore, these data suggest the potential application of NSC 651016 as an antiangiogenic therapy because it blocked endothelial cell migration, capillary-like tube formation, and angiogenesis. Furthermore, NSC 651016 may have wider applications in cancer therapy. CXCL12 has been implicated in the proliferation of astrocytes (14) by activating extracellular signal-regulated kinase 1/2 but not p38 or stress-activated protein kinase/c-Jun NH2-terminal kinase pathways (14) , therefore, CXCL12 may have a direct role in pathological glial cell proliferation such as reactive gliosis and brain tumor formation. Thus, blockade of CXCL12 function by NSC 651016 may have direct therapeutic benefits for certain brain cancers, one of the most refractory tumor types known. Additionally, CXCL12 participates in cancer cell metastasis by acting as a homing factor (19) . Neutralizing antibodies to CXCL12 significantly inhibited metastasis of breast tumor cells to lymph nodes and to the lung in a xenogeneic murine model (19) . CXCL12 is normally produced by the lymph node, lung, liver, and bone marrow (19) and could be a key signal for tumor cells to migrate to those organs. Consequently, blockade of CXCL12 by NSC 651016 may prevent metastasis. Additionally, CXCL12 expression may subvert the adaptive immune response to the tumor. CXCL12 induces increased Jurkat CD4+/CXCR4+ T-cell line apoptosis via the CD95-CD95L pathway (20) . This suggests that tumor-derived CXCL12 may prevent the development of antitumor cytotoxic T-cell responses, thus allowing the tumor to escape immunological rejection. This observation suggests that NSC 651016 may, by blocking CD4+/CXCR4+ T-cell apoptosis, promote cytotoxic T-cell destruction of tumor tissue. Taken together, these investigations suggest that tumor-derived CXCL12 contributes to tumor neovascularization, glial cell proliferation, and metastatic spread. Therefore, suradista NSC 651016, by inhibiting CXCL12 activity, is a potential inhibitor of tumor neovascularization and metastases and may permit the development of antitumor cytotoxic T lymphocytes.

The function of other sulfonic distamycin derivatives, structurally related to NSC 651016 but distinct from NSC 651016, has been investigated. Pretreatment of syngeneic murine reticulosarcoma and melanoma tumor models with two suradista analogs inhibited spontaneous lung and liver metastasis (20 , 21) . These suradista analogs are not known to inhibit CXCL12, but it has been proposed that they block the binding of proinflammatory cytokines, e.g., interleukin 1 or proangiogenic factors, e.g., VEGF, to target cells. Previous research has shown that interleukin 1ß, tumor necrosis factor {alpha} (9) , and VEGF (10) enhance CXCR4 expression, leading to the speculation that these suradista analogs may block proinflammatory and proangiogenic factor-mediated CXCR4 expression and thereby block metastasis. Still other suradista analogs were shown to bind to (disassociation constants of 10-6-10-7 M) and block the activity of bFGF in vitro and in vivo (17) . Additional investigation into the structure and function of the various suradista derivatives indicated that the conformation of the backbone of the molecule was modified by side chain additions. Thus, the distance between the two naphthalene groups (see Fig. 1Citation ) determines the binding affinity of various suradista analogs for individual receptors and ligands (22) . In the case of NSC 651016, which was previously shown to inhibit CXCL12-mediated chemotaxis by inhibiting ligand binding to CXCR4 and induction of receptor internalization (16) , the position of the sulfonic acid groups is critical. This suggested to us that mechanism of action for this class of compounds is varied. Furthermore, because NSC 651016 has specific inhibitory effects on the function of some chemokines and their receptors and is completely bioavailable with no in vivo toxicity (18) , it is likely to be a valuable therapeutic.

A compound related to the suradistas, suramin, now considered to be a classic failed antineoplastic agent, was used in a variety of cancer clinical trials (23 , 24) . The toxic side effects of suramin negated its antitumor effects (25 , 26) . However, recent studies have focused on comparing suradistas to suramin. These studies suggest that suradistas have anticancer effects without the toxicity of suramin (27) . Furthermore, comparative studies have shown that a suradista analogue was as effective as suramin at inhibiting the growth of sp-hst/KS3: FGF1–154-transformed NIH/3T3 xenografts in athymic nude mice at half the dose of suramin (50 mg/kg for suradista versus 100 mg/kg for suramin; Ref. 28 ). These results suggest that suradista compounds, in general, are likely to provide a less toxic alternative to the antineoplastic suramin compound. Studies are currently underway to evaluate the preclinical efficacy of NSC 651016 in several tumor models. Furthermore, we propose that in addition to the antimetastatic effects of some suradistas, this class of compounds are also antiangiogenic and combinations of suradistas may yield more forceful antitumor activities.


   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 This publication has been funded in whole or in part with federal funds from the National Cancer Institute, NIH under Contract No. NO1-CO-12400. Back

2 To whom requests for reprints should be addressed, at National Cancer Institute-Frederick, P. O. Box B, Frederick Maryland 21702. Phone: (301) 846-1348; Fax: (301) 846-7042; E-mail: howardz{at}mail.ncifcrf.gov Back

3 The abbreviations used are: VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; ECGS, endothelial cell growth supplement; HMVEC, human dermal microvascular endothelial cell; BAEC, bovine aortic endothelial cell; FBS, fetal bovine serum. Back

Received 3/ 4/02; revised 7/25/02; accepted 7/30/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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