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Second Department of Medical Biochemistry, School of Medicine, Ehime University, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan
1To whom correspondence should be addressed. E-mail: yokim{at}m.ehime-u.ac.jp.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • resveratrol • antitumor activity • antimetastaic activity • angiogenesis • mice
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Furthermore, we reported
that resveratrol strongly inhibited the formation of 5-lipoxygenase
products, 5-hydroxy-6,8,11,14-eicosatetraenoic acid, leukotrienes
B4 and C4, and the
cyclooxygenase product thromboxane B2 from
arachidonic acid (2
3
4)
. We also showed the inhibitory
effect of resveratrol on arachidonic acid–induced platelet aggregation
(2)
. Resveratrol and its derivatives have been further
shown to strongly inhibit the degranulation of human polymorphonuclear
leukocytes (4)
. Recently, there have been a number of
reports that resveratrol inhibits tumor growth and causes apoptosis as
a cancer chemopreventive mechanism (5
6
7
8
9
10
11
12)
. Tumor
angiogenesis involves the directional sprouting of new vessels toward a
solid tumor. It should be noted that angiogenesis is no less important
to the growth of secondary tumor colonies than it is to the growth of
primary solid tumors. Secondary tumors often give rise to ternary
tumors in distant organs by a process termed metastatic cascade
(13
14
15
16)
. Previously, we reported that piceid
(resveratrol-3-O-D-glucoside)
inhibited the lung metastasis and the capillary-like network
formation induced by Matrigel from human umbilical vein endothelial
cells
(HUVEC)2
(17)
, and it has been suggested that piceid administered
orally may be converted to an aglycone form of resveratrol by
hydrolysis (17)
. The inhibition of distant
metastasis to lung or liver from primary solid-tumors by
resveratrol is as yet unproven. In the present study, we examined the
effects of resveratrol isolated from Polygonum cuspidatum
root on tumor growth and lung metastasis in mice bearing highly
metastatic Lewis lung carcinoma (LLC) tumors, and angiogenesis in
tumor-induced in vivo and in vitro models. |
MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Melting points, determined using a Yamato MO-21 capillary apparatus (Yamato Science, Tokyo, Japan), are uncorrected. Infrared and UV spectra were measured using a Shimadzu IR-400 spectrometer (Shimadzu, Kyoto, Japan) and a JASCO ORD/UV-5 spectrometer (JASCO, Tokyo, Japan), respectively. The 1H nuclear magnetic resonance (NMR) (4899.83 Hz) spectrum was recorded in DMSO-d6 and solvent plus D2O using a Varian Unity Inova 500 spectrometer (TOSO, Tokyo, Japan). Column chromatography was performed using silica gel 60 (70–230 mesh, ASTM, Merck KGaA, Darmstadt, Germany) and polyamide (ICN Pharmaceuticals, Costa Mesa, CA).
Materials.
Stilbene such as resveratrol (3,5,4'-trihydroxystilbene) and piceid
(resveratrol-3-O-D-glucoside) were isolated
from the roots of P. cuspidatum by the method described
previously (18
,19)
. Briefly, the dried crushed roots (1
kg) were extracted with methanol (3 L) three times under reflux, and
the extract solution was removed by reduced pressure to give dark brown
extracts (210 g). Methanol extract (200 g) was chromatographed on a
silica gel column eluted with a mixture of chloroform/methanol (3:1 to
1:1, v/v) and polyamide column–eluted methanol to give resveratrol and
piceid. Resveratrol and piceid were identified by direct comparison
with authentic samples. Furthermore, resveratrol and piceid were
identified as trans forms by the measurement of the UV
and 1H NMR spectra. Mouse lymphocyte separation medium
(Lympholytes-Mouse) was purchased from Dainippon Pharmacy (Osaka,
Japan). Fluorescein isothiocyanate (FITC)-labeled anti-mouse CD 4,
CD8 and phycoerythrin (PE)-labeled anti-mouse natural killer
(NK)1.1 were purchased from Serotec (Oxford, England). Propidium
iodide, 3'-O-acetyl-2',7'-bis(carbocyethyl)-4 or
5-carboxylfluorescein (BCECF)-AM solution (1 mmol/L) and RNase A
were purchased from Wako Pure Chemical (Osaka, Japan). Matrigel
basement membrane matrix was obtained from Becton Dickinson Labware
(Bedford, MA). [Methyl-3H]-thymidine (specific activity;
740 GBq/mmol) and 125I-vascular endothelial growth factor
(VEGF) (specific activity; 4.26 MBq/µg) were purchased
from NEN Life Science Products, (Boston, MA). Dulbecco’s modified
Eagle’s medium (DMEM), endothelial basal medium (EBM) and CS-C
medium kits were obtained from Nissui Pharmaceutical (Tokyo, Japan),
Clonetic (San Diego, CA) and Cell Systems (Kirkland, WA), respectively,
and used as culture media. Antibiotic and antimycotic solutions (100
x) containing 106 U penicillin, 10 g
streptomycin and 25 mg amphotericin B/L in 9 g/L NaCl were purchased
from Sigma Chemical (St Louis, MO). Fetal bovine serum (FBS) was
purchased from Gibco BRL (Auckland, New Zealand). The 6-, 12-, 24-, 48-
and 96-well plates were purchased from Corning Glass Works (Corning,
NY). Collagen (Type I)-coated 6- and 24-well plates were purchased from
Toyobo Engineering (Osaka, Japan) and Sumitomo Bakelite (Tokyo, Japan),
respectively.
Cells.
The highly metastatic, drug-resistant mouse LLC cells were obtained from Riken Gene Bank (Tukuba, Japan) and maintained in DMEM supplemented with 100 mL/L FBS, penicillin (1 x 105 U/L), streptomycin (100 mg/L) and amphotericin B (0.25 mg/L). HUVEC and bovine aorta endothelial cells (BAEC) were purchased from Clonetics (San Diego, CA) and Sannkou Junyaku (Tokyo, Japan), respectively; the HUVEC and BAEC were seeded onto collagen (Type I)-coated 24- or 6-well plates and maintained in Clonetics endothelial basal medium supplemented growth factor (EGM) or CS-C media.
Animals.
Female C57BL/6 strain mice (5 wk old) were obtained from Clea Japan (Osaka, Japan). They were housed for 1 wk in a room maintained at 25 ± 1°C with 60% relative humidity and given free access to nonpurified diet [(per 100 g diet): water 8 g, crude carbohydrate 51.3 g, crude protein 24.6 g, crude lipid 5.6 g, crude fiber 3.1 g, mineral mixture 6.4 g and vitamin mixture 1 g; Oriental Yeast, Osaka, Japan] and water. The room was illuminated for 12 h/d starting at 0700 h. Animals were treated according to the ethical guidelines of the Animal Center, School of Medicine, Ehime University.
Measurement of tumor growth and metastasis to lung in LLC-bearing mice.
Solid-type LLC was prepared by subcutaneous transplantation of 5 x 105 cells (0.5 mL) into the backs of C57BL/6 female mice on d 0. Resveratrol (0.6, 2.5 or 10 mg/kg body) was administered intraperitoneally once (at 0700 h) daily for 21 consecutive days, starting 12 h after implantation of the tumor cells. Untreated mice (normal) and LLC-implanted mice (control) were given distilled water alone on the same schedule. The tumor volume was determined every 2–3 d by direct measurement with calipers and calculated using the formula, [width2 (mm2) x length (mm)]/2. On d 22, the mice were killed by cervical dislocation, and the spleen, thymus and lung quickly removed and weighed. The metastases to the lung were counted using a stereoscopic microscope. The spleen tissues were gently teased to release cells by means of dissecting forceps in cold PBS (pH 7.4). The cell suspension (5 mL) was layered on Lympholytes-Mouse (5 mL) and centrifuged at 1500 x g for 30 min to isolate the lymphocytes. The number of lymphocytes was measured using a Coulter Counter. The cell concentration was adjusted to 2 x 1010 cells/L, and the 10 µL of FITC-labeled anti-mouse CD4, CD8 or PE-labeled antimouse NK1.1. was added to 100 µL of the cell suspension. After incubation for 30 min at 4°C, the lymphocytes were rinsed three times with 1 mL of PBS and centrifuged at 700 x g for 5 min. Subsequently, the CD4+, CD8+ and NK1.1.+ T-cell populations were analyzed by flow cytometry using a FACS Calibur (Becton Dickinson, Mountain View, CA).
Measurement of DNA synthesis in LLC cells.
LLC cells were placed in DMEM supplemented with 100 mL/L FBS at 1 x 104 cell/well in 24-well culture plates. After the cells were cultured overnight, the medium was changed to fresh DMEM with 100 mL/L FBS and cells were exposed to the indicated amounts of resveratrol for 20 h; then the medium was replaced with [3H]thymidine (18.5 kBq = 0.5 µCi/well) in DMEM with 100 mL/L FBS. After further incubation for 4 h, the cells were washed twice with PBS, immersed in 1 mL of 50 g/L trichloroacetic acid (TCA) for 1 h at 4°C, washed twice with 50 g/L TCA and solubilized with 100 µL of 0.2 mmol/L NaOH containing 5 g/L Triton X-100. Thymidine incorporation into the cells was determined by liquid scintillation counting.
Measurement of apoptosis and the cell cycle in LLC cells.
LLC cells were placed in DMEM containing 100 mL/L FBS at 1 x 106 cells/well in 6-well culture plates. After the cells were cultured overnight, the medium was changed to fresh medium and cells were exposed to the indicated amounts of resveratrol for 20 h. The detached (nonadherent) cells were collected, and the attached (adherent) cells were then dispersed by adding PBS (pH 7.4) containing 2.5 g/L trypsin and 1 mmol/L EDTA. Adherent and nonadherent cells were sedimented at 200 g for 10 min, washed with ice-cold PBS and fixed in ice-cold 700 mL/L methanol for 2 h at 4°C, and then further washed twice with ice-cold PBS. The fixed cells were incubated with 1 mL of 0.25 mg/L RNAase A for 1 h at 37°C, washed twice with PBS, stained with propidium iodide (final concentration of 50 mg/L), and subjected to apoptosis and cell cycle analysis by flow cytometry using a FACS Calibur.
Measurement of angiogenesis induced by tumor cells.
In vivo angiogenesis was assayed by the dorsal air-sac method. Briefly, 3 x 106 cultured LLC cells were suspended in DMEM and packed into a round-shaped nitrocellulose membrane chamber with a diameter of 14 mm (pore size 0.45 µm; Millipore, Bedford, MA) and implanted onto the dorsal air sac of female C57BL/6 mice on d 0. Resveratrol (0.6, 2.5 or 10 mg/kg) was administered intraperitoneally twice daily from d 1 to 5. The mice were killed on d 6, and skin hair in contact with the chamber was carefully shaved. The formation of new blood vessels in the subcutaneous region was photographed.
Measurement of DNA synthesis in BAEC and HUVEC.
BAEC were placed in CS-C medium containing 100 mL/L FBS at 2 x 104 cell/well in collagen-coated 24-well culture plates. After the cells were cultured overnight, the medium was changed to fresh CS-C medium containing 100 mL/L FBS, and cells were exposed to the indicated amounts of stilbenes for 20 h. Then the medium was replaced with [3H]thymidine (18.5 kBq = 0.5 µCi/well) in CS-C medium containing 10% FBS. After further incubation for 4 h, cells were washed twice with ice-cold PBS, and the thymidine incorporation was measured by the same methods described above for LLC cells. HUVEC (1 x 104 cells per well) were seeded onto Matrigel (10 µg/well)-coated 96-well culture plates in CS-C medium containing 100 mL/L FBS. After the cells were cultured overnight, the medium was changed to fresh medium, and the cells were exposed to the indicated amounts of stilbenes for 20 h; thymidine incorporation was measured by the methods described above.
LLC cell adhesion to HUVEC.
Confluent HUVEC monolayers (second passage) grown on collagen-coated 24-well culture plates were incubated with the indicated amounts of stilbenes for 6 h at 37°C in a humidified chamber containing 5% CO2 in CS-C medium containing 100 mL/L FBS. After the incubation period, HUVEC monolayers were washed twice with CS-C medium containing 100 mL/L FBS, and then BCECF-labeled LLC cells (1 x 104 cells per well) were seeded onto HUVEC monolayers treated with stilbenes and incubated for 2 h. After the incubation period, HUVEC were gently washed three times with the above medium to remove nonadherent LLC cells. LLC cells that adhered to HUVEC were solubilized by adding 5 g/L Triton X-100 (1 mL), and the fluorescence of BCECF released from the LLC cells was measured by fluorimetry (FP-777, JASCO) with excitation at 500 nm and emission at 540 nm. LLC cell adherence to HUVEC monolayers is expressed throughout as the percentage of adherence, and the fluorescence released from the BCECF-labeled LLC cells seeded in each well of the 24-well plates was taken as 100% total fluorescence intensity.
Measurement of tube-like network formation from HUVEC induced by Matrigel.
Matrigel (150 µL) was placed into each well of a 48-well culture plate at 4°C and allowed to polymerize by incubation for 1 h at 37°C. HUVEC (second passage, 2 x 104 cells) were seeded onto the Matrigel in 270 µL of DMEM supplemented with 200 mL/L FBS and incubated with the indicated amounts of resveratrol at 37°C for 24 h in a humidified 5% CO2 atmosphere. Four different phase-contrast microscopic fields (x40 and x100 magnification) per well were photographed, and the photomicrograph images were stored in a computer. The total length of tube structures in each photograph (x40 magnification) was measured using Adobe Photoshop software (Adobe, Tokyo, Japan).
Binding of 125I-labeled VEGF to HUVEC.
HUVEC were cultured to subconfluency on collagen-coated 24-well
culture plates. The HUVEC were incubated with the indicated amounts of
resveratrol for 30 min at room temperature. Subsequently,
125I-VEGF (
5.6 x 104 dpm; specific
activity 4.26 MBq/µg) was added and incubated for
3 h in a humidified 5% CO2 atmosphere. After unbound
radioligand was removed, the cells were solubilized in 10 g/L SDS. The
amount of 125I-VEGF bound to HUVEC was measured using a
gamma counter (COBRA II, Packard, Meriden, CT).
Statistical analysis.
All values are expressed as means ± SEM. Data were analyzed by one-way ANOVA, and then differences among means were analyzed using Fisher’s protected Least Significant Difference multiple comparison test. Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Tumor growth and final tumor weight were significantly inhibited by the
intraperitoneally administered resveratrol at doses of 2.5 and 10
mg/kg, but 0.6 mg/kg of resveratrol had no effect (Fig. 1A
and
B). Resveratrol (2.5 and 10 mg/kg) significantly reduced the number of
tumor cell colonies that metastasized to the lung compared with the
LLC-bearing mice (Fig. 2
).
|
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Resveratrol had no effect on either initial or final body weight in
LLC-bearing mice compared with that in normal mice (Table 1
). In LLC-bearing mice, the spleen weight was significantly greater
than that of the normal mice. In contrast, thymus weight of
LLC-bearing mice was significantly lower than that of normal mice.
Resveratrol tended to prevent the increase of spleen weight and the
reduction of thymus weight in LLC-bearing mice (Table 1)
. The
number of lymphocytes in the spleens of LLC-bearing mice
significantly increased to 7.29 ± 0.74 x 106 from 2.90 ± 0.33 x 106 in normal mice. In contrast, the splenic
CD4+ and CD8+ cells in
LLC-bearing mice were significantly reduced to 7.69 ± 0.85
and 14.1 ± 1.65% from 22.5 ± 0.97 and 42.9 ± 3.29%
in normal mice, respectively. NK1.1.+ T cells
were not affected. The increase in splenic lymphocyte and reductions of
CD4+ and CD8+ T cells were
not prevented by the intraperitoneally administered resveratrol (data
not shown).
|
Resveratrol inhibited the DNA synthesis in LLC cells with a 50%
inhibitory concentration (IC50) of 6.8
µmol/L (Fig. 3
). Treatment with 100 µmol/L resveratrol for 24 h
increased apoptosis to 20.6 ± 1.35 from 12.1 ± 0.36% in
LLC cells (Table 2
). In addition, resveratrol decreased the S phase population at
concentrations of 50 and 100 µmol/L. The proportion
of LLC cells in the G2/M phase of the cell cycle
was increased by the treatment with 50 µmol/L
resveratrol.
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Five days after implantation of the LLC cells, which were packed into
the membrane chamber, neovascularization was evident in the region in
contact with the chamber containing LLC cells. The intraperitoneally
administered resveratrol (2.5 and 10 mg/kg twice per day) prevented the
neovascularization induced by LLC cells (Fig. 4
). HUVEC formed capillary-like networks on Matrigel 24 h after
seeding. Resveratrol dose dependently inhibited angiogenesis of HUVEC
at 5–100 µmol/L concentrations (Fig. 5
).
|
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Resveratrol significantly inhibited DNA synthesis of BAEC at concentrations of 50–500 µmol/L, but not at 5 and 10 µmol/L (data not shown). The inhibition ratios were 45.5% at 50 µmol/L, 81.5% at 100 µmol/L and 68.4% at 500 µmol/L, respectively, with an IC50 of 54 µmol/L. Furthermore, resveratrol inhibited DNA synthesis of HUVEC at of 100 µmol/L; its inhibition ratio was 69.3%, but not at concentrations of 5, 10 and 50 µmol/L; the IC50 was 89 µmol/L (data not shown).
Adherence of LLC cells and binding of 125I-VEGF to HUVEC (in vitro).
When LLC cells were seeded onto the HUVEC monolayer, the adherence of
LLC cells to HUVEC was increased from 10.4 ± 2.8 to 50.8 ± 6.4% of total cells. Resveratrol had no effect on adherence of LLC
cells to HUVEC (data not shown). Resveratrol significantly inhibited
the binding of VEGF to HUVEC at 10–100 µmol/L
concentrations (Fig. 6
).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,6)
, the inhibitory action by resveratrol on distant
metastases to other organs from primary solid-tumors is as yet
unproven. In this study, we examined the effects of resveratrol
contained in medicinal plants on tumor growth and metastasis to the
lung using mice bearing the highly metastatic, drug-resistant mouse
tumor, LLC. It has been reported that LLC-bearing C57BL/6 mice had
lung metastasis in addition to tumor growth (20
21
22
23)
. We
found that tumor growth and lung metastasis were inhibited by the
intraperitoneal administration of resveratrol [2.5 and 10 mg/(kg ·
d)] for 21 consecutive days in LLC-bearing C57BL/6 mice. Mu et al.
(24)
and Brunda et al. (25)
reported that
metastases to distant organs and tumor growth were prevented through
natural killer cell and cytotoxic T lymphocyte activation by the
administration of interleukin-12. Because the intraperitoneal
administration of resveratrol did not affect the numbers of
CD4+, CD8+ T cells or
NK1.1+ T cells in the spleens of LLC-bearing
mice, the inhibitory effects of resveratrol on tumor growth and lung
metastasis could not be explained by natural killer and cytotoxic T
lymphocyte activation. Next, we examined the effects of resveratrol on
the DNA synthesis of LLC cells. The results showed that resveratrol
inhibited the DNA synthesis with an IC50 of 6.8
µmol/L. Resveratrol at 100 µmol/L caused
apoptosis, decreased the S phase population at 50 and 100
µmol/L and increased the
G2/M phase at 50 µmol/L in LLC
cells. Ragion et al. (7)
reported that 30
µmol/L resveratrol arrested the cell division cycle at the
S/G2 phase transition in the promyelocitic cell
line HL-60. Clément et al. (11)
reported that the
cell death induced by 32 µmol/L resveratrol in HL 60 cells
is tumor specific, and reported findings supporting the involvement of
the Fas-Fas ligand system as the apoptotic trigger. These findings
suggest that resveratrol may contribute to the inhibition of primary
tumor growth and metastasis to distant organs through the inhibition of
DNA synthesis of tumor cells by resveratrol. However, the discrepancy
between apoptotic and DNA synthesis inhibitory concentrations of
resveratrol are unknown; therefore, further studies are warranted.
Tumor cell interactions with platelets, endothelial cells and the
subendothelial matrix are considered essential intermediate steps for
the completion of the metastastic cascade for tumors
(14
,26
27
28)
. To test the antimetastatic activity of
resveratrol, we examined the effects of resveratrol on the interactions
of LLC cells with HUVEC. Resveratrol had no effect on the adherence of
LLC cells to monolayer HUVEC (data not shown), indicating that the
antimetastatic activities of resveratrol are not due to inhibition of
the adherence of LLC cells to HUVEC.
Angiogenesis is the growth of new capillary blood vessels from
preexisting capillaries and postcapillary venules. The solid tumors
cause neovascularization, and the resultant angiogenesis from solid
tumors stimulates growth and metastasis (14
,15
,22
,29
30
31
32
33)
.
Resveratrol inhibited tumor-induced neovascularization (in vivo)
and capillary-like network tube formation of HUVEC (in vitro). But
resveratrol also had no effect on DNA synthesis of BAEC and HUVEC at
the same concentrations. Tumor cells are thought to secrete angiogenic
factor(s) that induce neovascularization around the tumors
(34
35
36)
. VEGF is a secretory angiogenic factor
(37)
. Asano et al. (38)
reported that
monoclonal antibody to VEGF prevented the tumor growth and
tumor-induced neovascularization. Resveratrol inhibited the binding
of VEGF to HUVEC at concentrations of 10–100 µmol/L. In
summary, the inhibition ratios for DNA synthesis of LLC cells,
capillary-like network formation DNA syntheses of BAEC and HUVEC,
and VEGF binding to HUVEC by resveratrol at 10 µmol/L were
65.6, 45.5, -7.1, -21.3 and 15.8%, respectively. Therefore, these
findings suggest that the mechanism of antitumor and antimetastatic
actions of resveratrol might be due to the inhibition of DNA synthesis
in LLC cells and the inhibition of tumor-induced neovascularization
through the inhibition of capillary-like network formation from
HUVEC.
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FOOTNOTES |
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Manuscript received December 7, 2000. Initial review completed January 12, 2001. Revision accepted March 12, 2001.
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