[CANCER RESEARCH 45, 4048-4052, September 1985]

Inhibitory Effects of Dipyridamole on Growth, Nucleoside Incorporation, andPlatelet-activating Capability in the U87MG and SKNMC Human Tumor CellLines1

Eva Bastida,2 Josefina del Prado, Lourdes Almirall, G. A. Jamieson, and Antonio Ordinas

Hospital ClÃ-nico,Servicio de Hemoterapia y Hemostasia, Universidad de Barcelona, Casanovas, 143, 08036 Barcelona, Spain [E.B., J.d.P., LA., A.O.], and American RedCross BiomédicalResearch Laboratories, Bethesda, Maryland [E.B., G.A.J., A.O.]

ABSTRACT

The effects of dipyridamole on tumor cell function were examined in cultures of two lines of human origin, the SKNMCneuroblastoma line that activates platelets by a mechanismwhich is dependent on the release of adenosine 5'-diphosphate

and the U87MG glioblastoma line that induces platelet activationby the generation of thrombin. Cells grown in the presence ofdipyridamole at 1 MM showed >80% inhibition of uptake ofadenosine, thymidine, and undine with both lines. At 5 nM tumorcell growth was inhibited by 70% (U87MG) and 90% (SKNMC)but without concomitant cytotoxicity as determined by clono-genic assay (50% inhibitory concentration -20 MM). At 10 MMdipyridamole cyclic adenosine 3':5'-monophosphate levels in

creased 150% with both cell lines but no changes above baselinevalues were seen at 2.5 MM.The two cell lines showed differentresponses to being cultured in the presence of dipyridamole interms of their ability to subsequently activate platelets. U87MGcells cultured in 10 MM dipyridamole showed a doubling of thelag time as compared with cells grown in the absence of dipyridamole but with full aggregation; with SKNMC cells the aggregation rate was reduced and cells grown in 10 MMdipyridamoleshowed no reversible first wave, a 5-fold increase in lag time and

a 75% inhibition in total aggregation. Since therapeutic doses ofdipyridamole result in plasma concentrations of ~3.5 MM these

results suggest that potential antimetastatic effects of dipyridamole could be direct arising from inhibition of important steps intumor cell metabolism or indirect by suppressing one or more ofthe mechanisms involved in the ability of tumor cells to activateplatelets.

INTRODUCTION

Platelets may be involved in the metastatic spread of tumors(7, 26, 30), and although some laboratory findings support thishypothesis (16, 23) other results are ambiguous (12, 17). However, recent results showing a reduction in the number of lungcolonies in animals treated with an antiplatelet antibody (24)confirm earlier observations about the role of platelets in thedevelopment of secondary métastases(8).

Several laboratories have found that both animal (9, 11, 14)and human tumor cells (1, 13, 22) are able to activate plateletsin vitro. In our laboratory we have characterized two differentmechanisms of platelet activation by tumor cell lines (2). Onemechanism (ADP dependent) involves the stimulation of platelets

'This work was partially supported by the Spanish Comisión Asesora de

Investigación CientÃ-ficay Técnicano. 962 and by a grant from Boerhinger IngelheimSpain. Additional support was provided by USPHS Grants CA 30538 and RR05737.

•To whom requests for reprints should be addressed.

Received 2/7/85; revised 5/28/85; accepted 6/11/85.

by ADP while the other mechanism (thrombin dependent) depends on the generation of thrombin by tissue factor present onmicrovesicles shed by the tumor cells (3).

These experimental data suggest that the administration ofantiplatelet drugs could be of help in the treatment of cancerpatients. Although some few clinical studies in this respect havebeen completed they have been inconclusive (10, 20). Dipyridamole is one of the most used inhibitors of platelet function (21).Besides its antiplatelet phosphodiesterase activity (4) dipyridamole has also been shown to increase the synthesis of vascularprostacyclin (28) and to be a potent inhibitor of nucleosidetransport (19, 25). Dipyridamole also causes inhibition of lympho-

proliferation (6), killing of rat hepatoma cells (31), and enhancement of the toxicity of deoxyadenosine and deoxycoformycin toa mouse leukemia line (15).

In the present studies we report the effects of dipyridamoleon the U87MG and SKNMC human tumor cell lines with regardto tumor cell proliferation, nucleoside incorporation, cAMP3 lev

els, and modifications in tumor cell proaggregant and procoag-

ulant activities.

MATERIALS AND METHODS

Cell Culture. Two human tumor cell lines were used in the presentstudy, the U87MG line derived from a glioblastoma and the SKNMC linederived from a neuroblastoma. Both had been kindly provided by thelate Dr. JörgenFogh of the Sloan Kettering Institute, Rye, NY.

U87MG and SKNMC cells were grown in 95% air-5% CO2 as mono-

layers in polycarbonate flasks (Nunc Corp., Denmark) using minimalessential medium supplemented with 1% nonessential amino acids,gentamycin (50) mg/ml, 2 mw glutamine, and 20 mw 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer. The concentration of fetal calf

serum was 15 and 10% for the U87MG and SKNMC cell lines, respectively. The cells were passaged twice weekly.

For the metabolic studies the tumor cells were harvested by trypsin-

ization (0.25%) for 2 min and the viability was determined by trypanexclusion; in no case was viability less than 90%. For platelet aggregationexperiments and for the procoagulant activity tests the cells were harvested in the absence of proteases by decanting the culture medium andthen washing the monolayers twice with Hanks' balanced salt solution

without Ca2+ and Mg2*. Washed cell monolayers were treated for 1 hwith 5 HIM ethyleneglycol bisOJ-aminoethyl ether)-/v,/v,/v',/v'-tetraaceticacid in HBSS at 37°C.The detached cells were then centrifuged (100 x

g for 10 min) and the cell pellets were resuspended in the same solutionto yield a cell concentration of approximately 1 x 107 cells/ml. Viability

was measured by trypan blue exclusion and in no case was lower than90%.

Inhibition of Incorporation of Labeled Nucleosides. The 3H-labeled

nucleosides studied here were thymidine (20 iiC\/^mo\), adenosine (17.8

3The abbreviations used are: cAMP, cyclic AMP; HBSS, Hank's balanced salt

solution; TCA, trichtoroacetic acid.

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EFFECTS OF DIPYRIDAMOLE ON CULTURED TUMOR CELLS

l), and uridine (27.1 /jCi/itmol) (New England Nuclear, Boston,MA), made up as solutions of 33 //Ci/ml before use. For measuring theincorporation of labeled nucleosides, 3 x 105 tumor cells were seeded

into 2.5 cm macrotiter wells (Costar, Cambridge, MA) containing 2.5 mlof culture medium. Aliquots of 0.5 ml of medium without or with appropriate concentrations of dipyridamole were immediately added to thewells. For each experiment triplicate wells were run for controls and fordipyridamole-treated cells. After 24 h of incubation at 37°Cthe labeled

nucleosides were added to the culture medium in appropriate volumesto give a final concentration of 1 /iCi/ml. Incubation was then continuedfor 1 h at 37°C.After this period of time the medium was removed, the

wells were maintained on ice, and the cell monolayers were washedtwice with cold HBSS and three times with 3 ml of cold trichloroaceticacid (5% w/v) allowing each aliquot of TCA to stand for 10 min in contactwith the cell monolayers. Finally and at room temperature the monolayerswere washed twice with absolute ethanol (10 min each wash). Anyremaining liquid was evaporated under nitrogen and 1 ml of 0.3 N NaOHwas added to dissolve the residue. After 1 h at 37°C 750 n\ of the

solution were pipeted from each well, neutralized with 150 n\ of 1.5 NMCI, and placed in a scintillation vial to which 9 ml of scintillation fluid(Aquasol II; New England Nuclear, Boston, MA) were added.

Growth Inhibition Studies. Logarithmically growing U87MG andSKNMC tumor cells were harvested and seeded into 25 cm2 flasks atconcentrations of 2 x 10°cells/flask. Triplicate samples were used for

each experiment. In certain experiments a fixed concentration of dipyridamole was added to the medium and the cells were incubated fordifferent periods of time. In other experiments graded concentrations ofthe drug were added to the medium and the cells were harvested after24 h of incubation. In either case the cells were harvested by trypsin-

ization (0.25%) for 2 min and the viability was determined by the trypanblue exclusion test.

Clonogenic Assay. Clonogenic assays were performed as describedby Salmon ef al. (27). Briefly logarithmically growing U87MG and SKNMCcells were seeded at 500 cells/25 cm2 flask. Immediately after this

dipyridamole in various concentrations from 2 to 30 UM was added andthe cells were allowed to grow. After 7 days incubation the medium wasdiscarded and the cells were stained with a saturated solution of crystalviolet. Colonies consisting of more than 50 cells were counted and thenumber of surviving colonies in the dipyridamole-treated group was

calculated as a percentage of the number of colonies found with untreated cells. The 50% inhibitory concentration values for the cytotoxicityof dipyridamole were calculated by linear regression analysis.

Intracellular cAMP Levels. U87MG and SKNMC cultures grown inthe presence and absence of dipyridamole were trypsinized after 24 hof incubation. An aliquot was withdrawn from the cell suspension in orderto determine the cell recovery and the remainder was centrifuged. Cellpellets were resuspended in HBSS and sonicated in a Branson sonifierequipped with a microtip (Branson Sonic Power Co., Danbury, CT). Thesonicate was treated with 2 ml of cold 5% TCA and the protein precipitatewas removed by centrifugation at 10,000 x g for 10 min. The supernatantfractions were extracted 5 times each with 3 volumes of diethyl ether toremove TCA and the extracted aqueous samples were then evaporatedunder nitrogen at 50°C. The residues were redissolved in 0.2 ml of

acetate buffer (pH 5.4) prior to assay. cAMP content of the tumor cellswas determined by radioimmunoassay according to a standard technique(29) using a commercially available kit (Amersham Corporation, ArlingtonHeights, IL). Recovery of cAMP was 92 ±10% (SD) as determined byusing added [3H]cAMP (New England Nuclear, Boston, MA) and calcu

lated concentrations were corrected accordingly.Platelet Aggregation. Blood from healthy donors who had not taken

platelet-affecting drugs for at least 10 days before phlebotomy was used.

Blood was drawn by venipuncture and anticoagulated with heoarin (5 U/ml). Platelet-rich plasma was prepared by centrifugation at 100 x g for

10 min and platelet aggregation was measured by aggregometry (22).Clotting Assays. The recalcification time was measured in a Fibro-

meter (Becton Dickinson, Rutherford, NY). The procoagulant activity of

the tumor cells was measured using the one-stage assay. Pooled,citrated, platelet-poor normal human plasma (100 »I)was incubated with100 /¿Iof the tumor cell suspension at 37°C in the control buffer for 1

min followed by addition of 100 n\ of 25 mM Cad? and the clotting timewas recorded.

RESULTS

Effect of Dipyridamole on Tumor Cell Growth. Two differenttypes of experiments were performed in order to evaluate theeffects of dipyridamole on tumor cell growth. In one case thenumber of cells was determined in U87MG and SKNMC culturesduring growth in the presence of a fixed amount (5 »M)ofdipyridamole (Chart 1). The growth of both cell lines was reducedcompared with the control cultures and the SKNMC line wasmore sensitive than U87MG to the presence of dipyridamole atall of the time points examined.

In a second type of experiment a dose-response curve was

constructed to evaluate the effect of dipyridamole on tumor cellproliferation (Chart 2). Tumor cells (1 x 105/rnl) without and with

different concentrations of dipyridamole were seeded into 25cm2 flasks and allowed to incubate at 37°Cfor 24 h. At the end

of this period cultures were harvested and the cell count and cellviability were determined. Dipyridamole inhibited cell proliferationin both tumor cell lines in a dose-dependent fashion and maxi

mum inhibition was reached at approximately 5 UM. AgainSKNMC cells were more sensitive to dipyridamole than wereU87MG cells at all concentrations examined. None of the concentrations studied displayed a cytotoxic effect since the viabilityof the cells cultured in the presence of dipyridamole was in thesame range as that of controls (approximately 90%) as measuredby trypan blue exclusion.

Cytotoxic Effects of Dipyridamole on U87MG and SKNMCTumor Cell Cultures. Determination of cytotoxicity by dono-

genie assay indicated that the 50% inhibitory concentration fordipyridamole was 23 UMfor U87MG cells and 19 MMfor SKNMCcells (Chart 3). These cytotoxic concentrations are much higherthan the drug concentrations which gave maximal inhibition ofcell growth in both lines (~5 /¿M).

24 48

TIME OF HARVEST (hours)

72

Chart 1. Effects of 5 UMdipyridamoleon growth of U87MGcells(•)and SKNMCcells (O) at different harvest times. Points, means of triplicate experiments; bars,SE.

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EFFECTS OF DIPYRIDAMOLE ON CULTURED TUMOR CELLS

1 103 A 5 6 7 8jjM DIPYRIDAMOLE

Chart2. Effect of dipyridamote concentration on growth of U87MG (•)andSKNMC (O) cells. Points, means of triplicate assays; bars, SE.

15 20 25 30

DIPYRIDAMOLE

for [3H]thymidine and [3H]uridine at 0.1 MM(Table 1). Inhibition

of nucleoside incorporation into SKNMC cells required higherconcentrations of the drug. Dipyridamole at 1 MMinhibited incorporation of the three nucleosides tested approximately 80%. Ata concentration of 10 /¿Mthere was complete inhibition of nucleoside incorporation with both cell lines.

Effect of Dipyridamole on Intracellular cAMP Levels. Baseline values for cAMP in cells grown in the absence of dipyridamolewere 3.8 ±0.6 pmols/106 cells and 4.6 ±0.3 pmols/106 cells

for U87MG and SKNMC cells, respectively (Table 2). Culturingthe cells in the presence of 2.5 MM dipyridamole caused nosignificant increase in these values. However, at 10 UM dipyridamole concentrations cAMP values were increased about 150%to a value of 6.2 ±1.1 for U87MG and 8.2 ±2.1 for SKNMC;values were significant at the level, P

EFFECTS OF DIPYRIDAMOLE ON CULTURED TUMOR CELLS

CONTROL

10MIN.

Chart 4. Representative tracings of the platelet-aggregating activity of tumorcells cultured in presence of 2.5 and 10 \a* dipyridamole.A, platelet-aggregationtracings obtained with 1x10° U87MG cells/ml; B, platelet-aggregationtracingsobtained with 1 x 10* SKNMC cells/ml.

//Mwere unable to induce the first wave of reversible aggregationand showed significantly less maximal aggregation (Chart 48).

Procoagulant Activity of Tumor Cells Cultured in the Presence of Dipyridamole. We have already demonstrated thatUS7MG tumor cells (but not SKNMC cells) display a strongprocoagulant activity that is able to significantly shorten therecalcification time of pooled normal platelet-poor plasma (3). Inthe present work the one-stage recalcification time was reduced

from 210 ±12 to 60 ±4 s by U87MG cells and this value wasunaffected when U87MG cells grown in the presence of dipyridamole were used.

DISCUSSION

Support for the use of antiplatelet drugs in the treatment ofcancer derives from experimental observations which ascribe arole to platelets in the spread of malignant disease (8, 24).However, the direct effect that inhibitors of platelet function mightexert on tumor cell biology has not been considered.

In our study we have correlated the effects of dipyridamole onthe growth, metabolism, and platelet-activating activity of two

tumor cell lines of human origin. Our data clearly show thatdipyridamole has an inhibitory effect on the growth of both tumorcell lines studied, that this effect is time and concentrationdependent, and that concentrations with maximal inhibitory effectshow no concomitant cytotoxicity. The plasma levels of dipyridamole when given at therapeutic doses as an antiplatelet drugreach a maximum value of approximately 3.5 ^M (21). Thisconcentration is in the same range as the concentrations we

have found to inhibit the growth of U87MG and SKNMC cells (5MM)and far below the cytotoxic concentrations determined byclonogenic assay (~20 /¿M).The results suggest that a potential

effect of the drug could be directed to the inhibition of tumor cellgrowth.

Incorporation of nucleoside into tumor cells was also markedlyinhibited by dipyridamole at concentrations well below therapeutic plasma levels. Nucleoside transport is the initiating step in theutilization of exogenous nucleosides for the salvage pathwayand it is known that the activities of the nucleoside salvageenzymes are increased in rat and human hepatomas (5,18). Ourresults demonstrate that dipyridamole at concentrations below1 MM is a powerful inhibitor of nucleoside incorporation in bothtumor cell lines studied.

The observed increase of intracellular cAMP in the tumor cellsinduced by dipyridamole could affect their ability to cause plateletaggregation. It is interesting to note that the platelet aggregatingability of the U87MG line which activates platelets by a thrombin-dependent mechanism is less affected when the tumor cells arecultured in dipyridamole than is the SKNMC line that operatesthrough an ADP-related mechanism. It is important to point out

that the procoagulant activity of the U87MG tumor cells wasunaffected after culturing the cells in the presence of dipyridamole. The procoagulant activity displayed by this cell line iscaused by the presence of tissue factor in the tumor cell membrane (3). Therefore this lack of effect on the generation of theprocoagulant activity suggests that dipyridamole does not alterthe structure of the U87MG cell membrane with regard to theexposure of tissue factor.

The above results suggest that the effect of dipyridamole ontumor cell metastasis could be direct by inhibiting importantsteps in tumor cell metabolism such as nucleoside incorporationor could be indirect by suppressing one or more of the mechanisms involved in the capability of tumor cells to activate platelets.

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1985;45:4048-4052. Cancer Res Eva Bastida, Josefina del Prado, Lourdes Almirall, et al. and SKNMC Human Tumor Cell LinesIncorporation, and Platelet-activating Capability in the U87MG Inhibitory Effects of Dipyridamole on Growth, Nucleoside

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