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Experimental Therapeutics |
Institut National de la Santé et de la Recherche Médicale, Research Unit 403, Faculty of Medicine Laënnec, Lyon 69372 [P. F., S. B., J. G., M. C., P. C.], and Centre National de la Recherche Scientifique, UPR 9079, Villejuif 94801 [S. F., F. C.] France
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS |
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Cell Proliferation Assay.
Human umbilical vein endothelial cells (Promocell, Heidelberg, Germany) and human prostate PNT1a epithelial cells (a gift from Dr. Thierry Guillaudeux, INSERM U435, Rennes, France) were seeded in flat-bottomed 96-well plates (4 x 103 cells/well and 3 x 103 cells/well, respectively). After a 48-h incubation, growing cells were washed and additionally cultured in complete medium for 3 days in the presence or absence of increasing concentrations of a BP. Cell proliferation was measured using MTT at a concentration of 5 mg/ml (20 µl/well). MTT is reduced by the mitochondrial dehydrogenase of viable cells to a blue formazan product. After a 5-h incubation at 37°C, cells were solubilized in 0.01 n HCl containing 10% SDS for an additional 16-h incubation at 37°C to dissolve the blue formazan product. The absorption was measured spectrophotometrically at 550 nm using a 96-well plate reader (MR7000; Dynatech, Chantilly, VA). All of the experiments were run in sextuplicate.
Flow Cytometry-based Apoptosis Assay.
Untreated, BP-treated, and Taxol-treated endothelial cells were harvested with trypsin-EDTA, and resuspended in phosphate-buffered saline containing 2% (m/v) bovine serum albumin (106 cells/ml for each experimental condition). Detection of apoptosis in endothelial cells in suspension was performed using the TACS Annexin V apoptosis detection kit (R&D Systems Europe, Abingdon, United Kingdom). The staining was analyzed on a Galaxy flow cytometer (Dako, Trappes, France) as described previously (6)
.
Capillary-like Tube Formation Assay.
The surface of 24-well plates was coated with the basement membrane Matrigel (400 µl/well; 10 mg/ml) in the presence or absence of increasing concentrations of different BPs. Matrigel was then allowed to polymerize at 37°C for 30 min. Endothelial cells were laid on Matrigel-coated plates in the presence of complete medium (4 x 104 cells/ml/well). After a 16-h incubation at 37°C in a 5% CO2 incubator, the wells were photographed. The total length of the tube network on photographed well areas was measured using a semiautomatic analyzer (Videoplan, Kontron, Munich, Germany), and results were expressed as µm/cm2.
Cell Transfection and Luciferase Activity Measurement.
Androgen-dependent LNCaP prostatic cells (gift from Dr. Leland Chung, University of Virginia Health Science Center, Charlottesville, VA) were grown in DMEM (Invitrogen, Cergy Pontoise, France) supplemented with 5% (v/v) FCS, 5 mg/ml insulin (Sigma), 13.6 pg/ml triiodothyronine (Sigma), 5 mg/ml apo-transferrin (Sigma), 0.25 mg/ml biotin (Sigma), 25 mg/ml adenine (Sigma), 100 units/ml penicillin (Invitrogen), and 100 mg/ml streptomycin (Invitrogen). Cells were transiently transfected overnight using the calcium phosphate precipitation method with a luciferase gene reporter vector containing or not containing four times androgen-responsive-elements in the promotor (500 ng, gift from Dr. Chinghai Kao, Indiana University School of Medicine, Indianapolis, IN; Ref. 14
). After transfection, cells were washed and refed with fresh complete medium. After a 10-h incubation, cells were washed again then treated with a synthetic analogue of testosterone (R1881; NEN, Zaventem, Belgium; 10 ng/ml in DMEM) in the presence or absence of increasing concentrations of zoledronic acid. Twenty-four h later, cells were solubilized, and the luciferase activity was measured using a luminometer (Analogical Luminescence Laboratory).
Quantification of the Vascularization in Bone Biopsy Specimens from Patients with Paget’s Disease before and after Clodronate Treatment.
The effect of clodronate treatment on clinical, biochemical, and histomorphometrical evaluation of patients with Paget’s disease has been published previously (12
, 15)
. Twenty-three patients received a daily treatment with clodronate for 6 months. These patients were randomly assigned to receive 400, 800, 1600, or 2400 mg/day of clodronate. For each patient, a transiliac bone biopsy was performed before therapy and after 6 months of treatment. For each bone biopsy, microvessels present in the bone marrow were enumerated microscopically at a high magnification (x20, area 0.142 mm2) in five nonoverlapping HPFs. The microvessel score for each biopsy was expressed as the mean counts per HPF. Each evaluation was performed independently by two examiners and was done in a blinded fashion. In case of disagreement between examiners, bone biopsies were reviewed and a consensus opinion was obtained.
Animals, Treatments, and Immunohistochemistry.
All of the procedures were performed on adult male Sprague Dawley rats (weight 330 grams; IFFA CREDO, Saint Germain sur l’Arbresle, France). Studies involving animals, including housing, care, method of euthanasia, and experimental protocols, were conducted in accordance with a code of practice established by the local animal ethical committee in Lyon. Franck-Lissbrant et al. (16)
have shown that castration induces regression, and testosterone stimulates regrowth of the prostatic vasculature in castrated rats, suggesting that this experimental model can be used to study factors regulating angiogenesis in the prostate. Therefore, the castration of animals and the administration of testosterone were performed according to the protocol described by these authors (16)
. Twenty-one days after castration, animals received a s.c. pellet of long-acting testosterone (15 mg/pellet; Innovative Research of America, Sarasota, FL) for 6 days. On testosterone treatment, rats were randomized into groups of 5–10 animals, and then received either a BP or the vehicle (PBS; pH 7.0), administrated s.c. at doses ranging from 5 to 100 µg/kg/day for 6 days. At sacrifice, on day 6, the ventral prostate was dissected, formalin-fixed, and paraffin-embedded. Five-µm sections of the ventral prostate were then subjected to immunohistochemistry after a method described previously (17)
using an antibody directed against endothelial cell CD31 (Santa Cruz Biotechnologies, Santa Cruz, CA). The lumen area of 40 immunostained vessels within each ventral prostate section was measured using a semiautomatic analyzer (Biocom, Paris, France), and results were expressed as the average area per vessel (µm2) for each immunostained section.
Pharmacokinetic Analysis.
Male rats received a single, s.c. dose of [14C]clodronate (2 mg/kg), [14C]ibandronate (100 µg/kg), or [14C]zoledronic acid (60 µg/kg), and animals were then sacrificed at different time points (15 min, 30 min, 1 h, 2 h, 4 h, and 24 h). After sacrifice, organs (lungs, spleen, liver, kidney, femur, and prostate) were collected, solubilized, and the radioactivity was measured using a liquid scintillation analyzer (Tri-carb 2100TR; Packard Bioscience, Rungis, France).
Statistical Analysis.
Data obtained in patients with Paget’s disease were analyzed using paired Student’s t test. Unpaired Student’s t test was used to analyze all of the other experiments, and results were expressed as the mean ± SD. These analyses were performed using the Stat-View v5.0 software. All of the statistical tests were two-sided, and differences were considered to be statistically significant when P < 0.05.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Concomitantly to this decreased cell proliferation, zoledronic acid induced endothelial cell apoptosis (Fig. 1B)
. Apoptosis was assessed by a flow cytometry-based assay using annexin V conjugated to fluorescein (annexin V preferentially binds to phosphatidylserine exposed on the surface of cells undergoing apoptosis). As shown in Fig. 1B
, there was a rightward shift in the histograms when endothelial cells were treated with zoledronic acid or Taxol® (a well-known proapoptotic drug). A 3-day exposure of endothelial cells to other BPs (ibandronate, risedronate, and clodronate) at a 10-4 M concentration also resulted in significant inhibition of cell proliferation (Fig. 1C)
. Beside the inhibitory effect of BPs on endothelial cell proliferation, zoledronic acid dose-dependently inhibited capillary-like tube formation, reaching 62% inhibition at 10-4 M (Fig. 2A)
. Half maximal (IC50) inhibition achieved with zoledronic acid was 5 x 10-6 M. As exemplified in Fig. 2B
, the formation of capillary-like tubes in the presence of zoledronic acid (10-4 M) was immature, and many endothelial cells remained, forming colonies without elongation. Ibandronate, risedronate, and clodronate used at a 10-4 M concentration were as effective as zoledronic acid at inhibiting capillary-like tube formation (Fig. 2C)
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, there was a marked reduction in the number of blood vessels in pagetic bone marrow after clodronate treatment when compared with that observed in bone biopsies before treatment (mean ± SD: 9 ± 4 and 15 ± 7 vessels/HPF, respectively; P = 0.0001 using a paired t test). However, despite the use of different doses (400, 800, 1600, and 2400 mg/day) there was no dose-dependent inhibitory effect of clodronate on the vascularity. Similarly, the number of osteoclasts per mm2 is significantly decreased in patients treated with clodronate, with no significant difference among the four doses (12
, 15)
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. As expected, a substantial concentration of [14C]BP was also observed in the kidney because it is the only eliminating organ for the drugs (Fig. 4)
. In addition, the amount of the different drugs in noncalcified tissues like the lung, spleen, and liver was negligible (Fig. 4)
. In sharp contrast, [14C]zoledronic acid, [14C]ibandronate, and [14C]clodronate accumulated in the prostate, reaching a peak at 30–60 min, then declined rapidly with time (Fig. 4)
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. Similar results were obtained with ibandronate at a 10-4 M concentration, whereas clodronate had no significant inhibitory effect under these experimental conditions (results not shown).
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. However, as exemplified in Fig. 6A
, the size of the prostate gland was consistently smaller in castrated rats treated with testosterone + zoledronic acid. Indeed, ibandronate and zoledronic acid at a dose of 20 µg/kg/day induced a 17% and 35% reduction in the prostate weight, respectively, when testosterone was combined with one of these two different BPs (Fig. 6B)
. Treatment of castrated rats with testosterone in combination with clodronate (20 mg/kg/day) did not significantly inhibit prostate regrowth (Fig. 6B)
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, top and bottom left panels). Morphometric analysis revealed that the average area per vessel was significantly increased in the ventral prostate of castrated animals treated with testosterone when compared with that observed in the absence of treatment (Table 1)
. A daily treatment of castrated rats with zoledronic acid for 6 days, at a dose (20 µg/kg) that inhibited prostate weight, resulted in a 47% reduction of the revascularization of the prostate gland under testosterone stimulation (Fig. 7)
. Similarly, ibandronate at a dose of 20 µg/kg/day for 6 days induced a 51% reduction of the prostate revascularization (Fig. 7)
. This reduction of the prostate revascularization in the presence of zoledronic acid or ibandronate was highly significant (P = 0.01 and P = 0.007, respectively). In contrast, clodronate (20 mg/kg/day) did not significantly inhibit the revascularization of the prostate gland under testosterone stimulation (30% reduction; P = 0.147). In the light of these findings, additional in vivo experiments were performed with zoledronic acid at doses ranging from 5 to 100 µg/kg/day (Table 1)
. A daily treatment of castrated rats with zoledronic acid at a dose of 5 µg/kg/day for 6 days did not inhibit testosterone-stimulated vascular regrowth (8% reduction; Table 1
). However, a 41–54% reduction of vascular regrowth was observed on treatment with testosterone in combination with zoledronic acid at doses of 10 and 100 µg/kg/day, respectively (Table 1)
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. There was a decreased luciferase activity observed with zoledronic acid at a 10-4 M concentration. However, this was because of a direct cytotoxic effect of this BP on LNCaP cells (results not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Mechanisms by which BPs accumulate in the prostate gland to inhibit testosterone-stimulated prostate regrowth are presently unclear. The accumulation of different BPs (alendronate, clodronate, and pamidronate) in liver and spleen has been reported previously in rats when using high i.v. doses of BPs (10–40 mg/kg; Ref. 19 ). When the drug concentration is too high, BPs form large complexes with metals (iron, calcium, and magnesium), and the phagocytosis of these complexes accounts for the retention of BPs in noncalcified tissues like the liver and spleen (19) . However, the retention of BPs in the liver and spleen is observed only after i.v. administration but not after i.p. or s.c. injection at the same dose (19) . In the present study, we were using low doses of BPs (ranging from 5 to 100 µg/kg), administrated s.c. in rats. Negligible amounts of these different drugs were present in the lung, spleen, and liver. Thus, it is most unlikely that a phagocytosis process accounted for the specific accumulation of these BPs in the prostate. In contrast, it has long been known that the prostate gland contains the highest level of zinc of all of the organs in the body (20) . We have shown previously that zoledronic acid, ibandronate, and clodronate chelate zinc (6) . Therefore, it is most conceivable that the transient retention of BPs in the prostate gland was because of zinc chelation. Similarly, the high affinity of BPs for bone mineral is because of the chelation of calcium phosphate crystals by these compounds (1) .
Because of their avidity for bone mineral, high concentrations of BPs (10-4-10-3 M) can be achieved locally at sites of active bone resorption in vivo (21)
. Such high concentrations of BPs cause apoptosis in osteoclasts, breast, and prostate cancer cells in vitro (1
, 7
, 8)
, and it has been suggested that these high BP concentrations in metastatic bone lesions could induce apoptosis of cancer cells in vivo (22)
. Similarly, in patients with Paget’s disease, it is most likely that high clodronate concentrations achieved in bones account for the marked reduction of the vascularity we observed here in pagetic bone biopsies. However, we could not rule out the possibility that this decreased vascularity in the bone marrow on clodronate treatment was secondary to a reduction of bone resorption. To overcome this potential confounding effect of BPs, we have used an angiogenesis model in the prostate gland (16)
. We have shown that zoledronic acid and ibandronate inhibited the revascularization of the prostate under testosterone stimulation. These findings are clinically relevant because the lowest effective dose of zoledronic acid used to inhibit vascular regrowth (10 µg/kg/day for 6 days) is equivalent to a single 4-mg dose used currently in the treatment of patients with bone metastases. Mechanisms through which zoledronic acid and ibandronate inhibit the revascularization of the prostate gland are unknown. It is possible that these BPs are acting directly on blood vessels. In our in vitro experiments, maximal inhibitory effects of BPs on inhibition of endothelial cell functions were achieved at a 10-4 M concentration. Although it may be considered that such a concentration is high, it is important to note that zoledronic acid and ibandronate amounts in prostate and bone tissues were very similar for at least 30–60 min after their s.c. administration in rats (Fig. 4)
. For example, 30 min after the s.c. administration of [14C]zoledronic acid, concentrations in bone, prostate, and lungs were 19 ± 6, 20.7 ± 1, and 2.8 ± 0.6 ng/100 mg protein, respectively. On the basis of the high concentrations of BPs achieved in bone (10-4-10-3 M; Ref. 21
), it is therefore possible that blood vessels in the prostate gland are exposed (for 30–60 min) to similar high local concentrations of BPs that substantially inhibited endothelial cell functions in our in vitro experiments. This assumption is supported by the fact that a 1-h pulse treatment with the BPs zoledronic acid and ibandronate (10-4 M) was as efficient as a continuous treatment with these drugs in inhibiting endothelial and epithelial cell proliferation in vitro. In this respect, BPs may also be active on the prostate epithelium in vivo. For example, testosterone treatment increases vascular endothelial growth factor mRNA expression in the prostate epithelium (16)
. It is possible that BPs indirectly act on blood vessels by inhibiting the angiogenic activity elaborated by the prostate epithelium under testosterone stimulation. This is in agreement with the fact that the BP pamidronate decreases circulating levels of vascular endothelial growth factor in cancer patients (23)
. Recent findings strongly support the hypothesis that nitrogen-containing BPs (including ibandronate and zoledronic acid) inhibit enzymes of the mevalonate pathway, thereby preventing the prenylation of GTPases that are essential for osteoclast function (1)
. Whether ibandronate and zoledronic acid exert their cellular effect on endothelial and epithelial cells via inhibition of protein prenylation warrants additional investigation. Finally, the antiangiogenic activity of BPs was not restricted to our in vivo model of prostate revascularization. Clodronate, pamidronate, and zoledronic acid exert an antiangiogenic activity in the chicken-chorioallantoic membrane assay (24
, 25)
. In addition, zoledronic acid and, to a much less extent, pamidronate inhibit angiogenesis induced by s.c. implants impregnated with basic fibroblast growth factor (25)
.
In conclusion, this study has demonstrated that BPs inhibit endothelial cell functions in vitro and inhibit the revascularization of the prostate under testosterone stimulation. Because angiogenesis is essential for the growth of metastases of solid tumors (13) , these observations are of potential relevance to improve therapy and prevention of bone metastasis. In addition, our results extend the potential clinical use of BPs to patients with early prostate cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by grants from Institut National de la Santé et de la Recherche Médicale (to P. C.), the Comité Départemental du Rhône de la Ligue Nationale contre le Cancer (to P. C.), Novartis Pharma AG (Basel, Switzerland; to P. C.), Leiras Oy (Turku, Finland; to P. C.), Roche Diagnostics GmbH (Mannheim, Germany; to P. C.), and Procter and Gamble Pharmaceuticals (Cincinnati, OH). P. F. is a recipient of a fellowship from the Association pour la Recherche sur les Tumeurs de la Prostate. 
2 These authors contributed equally to this work.
3 To whom requests for reprints should be addressed, at Institut National de la Santé et de la Recherche Médicale, Research Unit 403, Faculté de Médecine Laënnec, Rue Guillaume Paradin, 69372 Lyon Cedex 08, France. Phone: 33-4-78-78-57-37; Fax: 33-4-78-77-86-63; E-mail: clezardin{at}lyon.inserm.fr
4 The abbreviations used are: BP, bisphosphonate; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; HPF, high power field.
Received 6/11/02. Accepted 9/20/02.
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K. Hashimoto, K.-i. Morishige, K. Sawada, M. Tahara, R. Kawagishi, Y. Ikebuchi, M. Sakata, K. Tasaka, and Y. Murata Alendronate Inhibits Intraperitoneal Dissemination in In vivo Ovarian Cancer Model Cancer Res., January 15, 2005; 65(2): 540 - 545. [Abstract] [Full Text] [PDF]
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T. Yuasa, M. Nogawa, S. Kimura, A. Yokota, K. Sato, H. Segawa, J. Kuroda, and T. Maekawa A Third-Generation Bisphosphonate, Minodronic Acid (YM529), Augments the Interferon {alpha}/ss-Mediated Inhibition of Renal Cell Cancer Cell Growth Both In vitro and In vivo Clin. Cancer Res., January 15, 2005; 11(2): 853 - 859. [Abstract] [Full Text] [PDF]
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 S.-i. Yamagishi, R. Abe, Y. Inagaki, K. Nakamura, H. Sugawara, D. Inokuma, H. Nakamura, T. Shimizu, M. Takeuchi, A. Yoshimura, et al. Minodronate, a Newly Developed Nitrogen-Containing Bisphosphonate, Suppresses Melanoma Growth and Improves Survival in Nude Mice by Blocking Vascular Endothelial Growth Factor Signaling Am. J. Pathol., December 1, 2004; 165(6): 1865 - 1874. [Abstract] [Full Text] [PDF]
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J. R. Green Bisphosphonates: Preclinical Review Oncologist, September 1, 2004; 9(suppl_4): 3 - 13. [Abstract] [Full Text] [PDF]
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 N. H. Bjarnason, A. S. Chan, S. M. Ott, S. L. Ruggiero, B. Mehrotra, H. G. Bone, and A. C. Santora Ten Years of Alendronate Treatment for Osteoporosis in Postmenopausal Women N. Engl. J. Med., July 8, 2004; 351(2): 190 - 192. [Full Text] [PDF]
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T. Hiraga, P. J. Williams, A. Ueda, D. Tamura, and T. Yoneda Zoledronic Acid Inhibits Visceral Metastases in the 4T1/luc Mouse Breast Cancer Model Clin. Cancer Res., July 1, 2004; 10(13): 4559 - 4567. [Abstract] [Full Text] [PDF]
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 O. Peyruchaud, C.-M. Serre, R. NicAmhlaoibh, P. Fournier, and P. Clezardin Angiostatin Inhibits Bone Metastasis Formation in Nude Mice through a Direct Anti-osteoclastic Activity J. Biol. Chem., November 14, 2003; 278(46): 45826 - 45832. [Abstract] [Full Text] [PDF]
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M. Bezzi, M. Hasmim, G. Bieler, O. Dormond, and C. Ruegg Zoledronate Sensitizes Endothelial Cells to Tumor Necrosis Factor-induced Programmed Cell Death: EVIDENCE FOR THE SUPPRESSION OF SUSTAINED ACTIVATION OF FOCAL ADHESION KINASE AND PROTEIN KINASE B/Akt J. Biol. Chem., October 31, 2003; 278(44): 43603 - 43614. [Abstract] [Full Text] [PDF]
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D. Santini, U. Vespasiani Gentilucci, B. Vincenzi, A. Picardi, F. Vasaturo, A. La Cesa, N. Onori, S. Scarpa, and G. Tonini The antineoplastic role of bisphosphonates: from basic research to clinical evidence Ann. Onc., October 1, 2003; 14(10): 1468 - 1476. [Abstract] [Full Text] [PDF]
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D. Santini, B. Vincenzi, G. Dicuonzo, G. Avvisati, C. Massacesi, F. Battistoni, M. Gavasci, L. Rocci, M. C. Tirindelli, V. Altomare, et al. Zoledronic Acid Induces Significant and Long-Lasting Modifications of Circulating Angiogenic Factors in Cancer Patients Clin. Cancer Res., August 1, 2003; 9(8): 2893 - 2897. [Abstract] [Full Text] [PDF]
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D. Santini, B. Vincenzi, G. Tonini, S. Scarpa, and A. Baldi Correspondence Re: E. Corey et al., Zoledronic Acid Exhibits Inhibitory Effects on Osteoblastic and Osteolytic Metastases of Prostate Cancer. Clin. Cancer Res., 9: 295ndash;306, 2003. Clin. Cancer Res., August 1, 2003; 9(8): 3215 - 3215. [Full Text] [PDF]
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B. Vincenzi, D. Santini, L. Rocci, and G. Tonini Bisphosphonates: new antiangiogenic molecules in cancer treatment? Ann. Onc., May 1, 2003; 14(5): 806 - 807. [Full Text] [PDF]
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