[CANCER RESEARCH 41, 1879-1883, May 1981]
0008-5472/81 /0041-OOOOS02.00
Effect of Inhibitors of Plant Cell Division on Mammalian Tumor Cells
in Vitro
Shmuel Zilkah,1 Michael E. Osband, and Ronald McCaffrey
Section of Medical Oncology. Evans Memorial Department
Pediatrie Hematology-Onco/ogy.
Department of Pediatrics,
School of Medicine, Boston, Massachusetts 02118
of Clinical Research, and the Department of Medicine, University Hospital, Boston 02118: Division of
Boston City Hospital, Boston 021 )8. and Departments of Medicine and Pediatrics, Boston University
ABSTRACT
We studied the activity of 14 compounds, all of which have
been shown to interfere in plant cell division, in two animal
tumor cell cultures, EL-4 and L1210. Four compounds [propham, chlorpropham, bensulide S-(O,O-diisopropylphosphorodithioate) ester of A/-(2-mercaptoethyl)benzenesulfonamide),
and siduron] had a 50% inhibitory dose less than 10~4 M; six
[2,3,5-triiodobenzoic
acid, (2,4-dichlorophenoxy)acetic
acid,
bromacil, (2,4,5-trichlorophenoxy)acetic
acid, naptalam, and
(4-chloro-2-methylphenoxy)acetic
acid] had a 50% inhibitory
dose between 10~" and 10~3 M, and the remaining four 2,3:
4,6-di-O-isopropylidene-2-keto-L-gulonate,
eptam, maleic hydrazide, and 4-(methylsulfonyl)-2,6-dinitro-/\/,N,-dipropylaniline] had a 50% inhibitory dose at higher than 10~3 M. There
was a significant correlation between the effect on the two cell
lines as well as between the inhibition of cell proliferation and
that of thymidine and leucine uptake. More detailed study of
cell proliferation and leucine and thymidine uptake for bensu
lide and 2,3,5-triiodobenzoic
acid revealed a dose-response
pattern of inhibition starting shortly after exposure of the cells
to the compounds. These results indicate that some inhibitors
of plant cell division are capable of inhibiting the proliferation
of animal tumor cells.
INTRODUCTION
The major sites of mitotic activity in plants are stem and root
tips. The growth of these tissues, termed meristematic tissues,
is inhibited by a variety of plant growth regulators and herbi
cides. Because both meristematic tissue and mammalian tu
mors contain dividing cells, we have asked whether those
herbicides which are active against meristematic tissue might
also inhibit the growth of mammalian tumor cells.
While there has been extensive research of herbicides as
potential carcinogenic agents (9, 10, 12, 17), there have been
very few reported attempts to study the potential of these
compounds as inhibitors of mammalian cells (2, 6, 16, 18, 19,
21). The obvious discrepancies between plant and animal life
might lead to differences in drug responsiveness; nonetheless,
significant correlation was found between the ability of 17
samples to inhibit the formation of crown gall tumors in potato
discs and their inhibitory effect, in vivo, on P388 mouse leu
kemia (13).
In addition, it has been shown that phytotoxic compounds
classified as herbicides are less toxic to mammals than are
other pesticides (1, 3, 4).
' To whom requests
for reprints
should be addressed,
at the Section
Medical Oncology, University Hospital, 75 East Newton St., Boston,
02118.
Received December 23, 1980; accepted February 9, 1981.
of
Mass.
We report here the results of a study which examined the
effect of 14 inhibitors of plant cell division on the proliferation
of cultured EL-4 and L1210 cells.
MATERIALS
AND METHODS
Chemical Compounds. The 14 compounds tested are listed
in Table 1. All are commercially available herbicides or plant
growth regulators. Compounds of high purity were purchased
or provided by the manufacturers for use in these studies.
Propham, chlorpropham, maleic hydrazide, (2,4-dichlorophenoxy)acetic acid, (2,4,5-trichlorophenoxy)acetic
acid, and TIBA2
were purchased from Sigma Chemical Company (St. Louis,
Mo.). Nitralin and (4-chloro-2-methylphenoxy)acetic
acid were
purchased from Chem Service (West Chester, Pa.). Naptalam
was obtained from Uniroyal (Naugatuck, Conn.), dikegulac was
obtained from Maag Agrochemicals (Vero Beach, Fla.). Bro
macil and siduron were obtained from E. I. DuPont de Nemours
& Co., Inc., (Wilmington, Del.), and eptam and bensulide were
obtained from Stauffer Chemical Corporation (Richmond, Va.).
Stock solutions were prepared freshly for each experiment by
dissolving the compounds in ethyl alcohol (final v/v concentra
tion of the ethyl alcohol in growth medium, 0.15 to 0.4%)
except for nitralin, which was dissolved in acetone (0.3% final
v/v concentration), and maleic hydrazide and dikegulac, which
were dissolved directly in growth medium.
Cell Culture. L1210 mouse leukemia cells and EL-4 mouse
lymphoma cells were obtained from Drs. M. Bennet and V.
Kumar at the Boston University School of Medicine. The cells
were cultured routinely in growth medium consisting of Roswell
Park Memorial Institute Medium 1640 (M. A. Bioproducts,
Walkersville, Md.) containing 10% fetal bovine serum, strep
tomycin, penicillin, nonessential amino acids, sodium pyruvate,
and glutamine (all from Microbiological Associates, Bethesda,
Md.). The cells were incubated at 37° in moist air containing
5% CC-2 in tissue culture flasks (25 sq cm/50 ml; Costar,
Cambridge, Mass.).
Growth Inhibition Studies. The inhibition studies were con
ducted in tissue culture flasks containing 6 ml of growth me
dium and 2x10"
cells/ml.
The stock solutions of the plant inhibitors were diluted in the
growth medium to achieve a variety of concentrations. Control
experiments were performed using identical final concentra
tions of the various solvents. The effect of herbicide exposure
2 The abbreviations used are: TIBA, 2,3,5-triiodobenzoic
acid; ID50. 50%
inhibition dose. The trivial names used are: nitralin, 4-(methylsulfonyl)-2,6-dinitroN.W-dipropylaniline;
dikegulac. 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonate;
bensulide,
S-(O.O-diisopropylphosphorodithioate)
ester of A/-(2-mercaptoethyObenzenesulfonamide.
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1879
S. Zilkah et al.
Table 1
Toxicity and action of plant inhibitors and regulators tested
usedCode"
Compound
namePropham
letterABCOEFQHICommon
p.o. 50% lethal
(mg/kg)9,000
dose
nameIsopropyl
(IPOChlorpropham
carbonilateIsopropyl-m-chlorocarbanilate1
ity1' cat
egoryIVIIIIIIIVIVIIIll-lllIIIIIIHIVNotes
actionInhibits
on
(rats)3.000
(mice)3.800
root and apical growth, dis
proteinand
rupts cell division, inhibits
synthesisInhibits
amylase
(CIPC)Maleic
(rats)5.000
root and apical growth, sup
(rabbits)>5,000
presses transpiration and respira
tion, disrupts cell division,
inhibitsRNA
synthesis.A
and protein
,2-Dihydro-3,6-pyridazinedione4-(Methylsulfonyl)-2,6-dinitro-rV,W-di-propylaniline(2,4-Dichlorophenoxy)acetic
(MH)Nitralin2,4-D2,4.5-TMCPATIBANaptalamChemical
hydrazide
(rats)>2,000
antimetabolite.Selective
uracil
mice)300-1,
(rats,
herbicide.mitotic
preemergence
poison.Affects
acid(2,4,5-Trichlorophenoxy)acetic
(rats.rabbits)300
000
foodreserves.Similar
cell division, respiration,
20202020117,
14,
acid(4-Chloro-2-methylphenoxy)aceticacid2,3,5-Triiodobenzoic
(rats)100
(dogs)800
(mice)81
2.4-D.Plant
acidN-1-Naphthylphthalamic
acidAcute
(rats)>8,200
3
for acid (rats)Toxic
1.770 for sodium salt
(rats)
(rats)5,200
000
regulator.Affects
growth
mitosis, apical dominance.Ref.2020207,
15, 20
(rats)>7,500
div-sion
photosynthesis
meristems.Root
in primary
inhibitor.At
growth
JKLMNDikegulacBromacilSiduronEptam
(rats)1
2,4-D.Hormone-type
to
action, similar to
apical meristems, growth re
enhancer.Inhibits
tardant, ripening
25and
8,
Foot
c.7.20202020
note
and cell
(EPTC)Bensulide2.3:4.6-Di-O-lsopropylidene-2-keto-L-gulonate5-Bromo-3-sec-butyl-6-methyluracil/vH2-Methylcyclohexyl)-W'-phenylu-reaS-EthyldipropylthiocarbamateS-(O,
(rats)3.160
.652
meristematicgrowth.Inhibits
low dose, inhibits
(mice)770
O-Diisopropylphosphorodi-thioate)
(rats)IVIVIVIIIIIIIIIInhibits
root growth.5,
W-(2-mercapto-ethyDbenzene-sulfonamide31,
ester of
8 Code letters are used in Charts 1 and 2.
" Toxicity categories as determined by the Environmental
50 to 500 mg/kg; III. from 100 to 5000 mg/kg;
c W. H. de Silva, personal communication.
on cell proliferation
Protection Agency, based on acute p.o.
tested at concentrations
was calculated by the equation
Treated cultures (no. of cells at conclusion of incubation
- no. of cells at beginning)
Control cultures (no. of cells at conclusion of incubation
- no. of cells at beginning)
x 100
Cell viability was determined by trypan blue dye exclusion. All
experiments were performed at least in duplicate.
[3H]Thymidine and [3H]Leucine Uptake. Aliquots (0.2 ml) of
cell suspension were removed from each flask at various times
and placed in wells of a microtiter plate (Flow Laboratories,
Hamden, Conn.). [3H]Thymidine, 0.15 ¿iCi(2 Ci/mmol; New
England Nuclear, Boston, Mass.), or [3H]leucine, 0.3 /¿Ci
(5 Ci/
mmol; New England Nuclear), was added to the wells. After
incubation at 37°for 1.5 hr, the cells were harvested onto filler
mats using Titertek Cell Harvester (Flow Laboratories),
radioactivity was determined.
and the
RESULTS
The 14 inhibitors of plant cell division used are listed in Table
1. As can be seen, they are of relatively low toxicity, as defined
by the Environmental Protection Agency on the basis of the
acute 50% lethal p.o. dose for animals (11). No compounds
were in Category I, the highest toxicity; one compound was in
Category II, 8 compounds were in Category III, and 5 com
pounds were in Category IV.
Inhibition of Cell Proliferation. All 14 compounds were
1880
50% lethal dose (11): I. up to and including 50 mg/kg;
II, from
IV, greater than 5000 mg/kg.
of 10~5, 10~4, and 10~3 M for their
ability to inhibit in vitro proliferation of EL-4 and L1210 cells.
From these experiments, the ID50was calculated (Chart 1). The
compounds varied in their ID50.Although dikegulac and nitralin
had an inhibitory effect at lower concentrations, the ID5o was
higher than 10~3 M. Eptam and maleic hydrazide had virtually
no effect at that concentration. The compounds related to the
phenoxy acid group, such as (2,4-dichlorophenoxy)acetic
acid,
(4-chloro-2-methylphenoxy)acetic
acid, and (2,4,5-trichlorophenoxy)acetic acid, showed a moderate inhibition (ID50 be
tween 10~4 and 10~3 M). The carbamates (propham and chlorpropham as well as bensulide had a relatively potent inhibitory
ability, achieving an ID50 around 10~5 M. Chart 1 also shows
that there was an overall high correlation for all the compounds
in their effects against the 2 different cell lines (p < 0.01).
[3H]Thymidine and [3H]Leucine Uptake. As in the experi
ments measuring cell proliferation, the compounds were tested
at concentrations of 10~5, 10~", and 10~3 M. The concentration
of compound necessary to inhibit by 50% [3H]thymidine and
[3H]leucine incorporations is given in Chart 2 in addition to the
ID50of cell proliferation. In both L1210 and EL-4 cells, there is
a highly significant correlation between the ID50 of cell prolif
eration and that of either [3H]thymidine or [3H]leucine uptake
(p < 0.001). However, both the carbamate compounds (pro
pham and chlorpropham) demonstrated a preferential effect
against cell proliferation compared to their effect on thymidine
or leucine uptake. This is also true, but to a lesser degree, with
siduron. Overall, however, it appears that the effect of the
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41
Plant Cell Inhibitors and Mammal/an Tumor Cells
inhibition of cell proliferation (data not shown).
Dose Response and Kinetics of TIBA and Bensulide. In
order to study more carefully the effect of such plant inhibitors
on animal cells, detailed data for 2 such agents, TIBA and
bensulide, are given in Charts 3 to 5. The dose response of
these 2 inhibitors of plant cell division on proliferation of EL-4
and L1210 cells is given in Chart 3. As can be seen, the
inhibition of growth is concentration
dependent. Bensulide
inhibits up to 100% over a concentration range of 5 to 100
/¿M;
with TIBA, comparable inhibition is seen over a concentra
tion range of 50 to 250 /¿M.
The kinetics of the TIBA and bensulide inhibition of prolifer
ation and thymidine and leucine uptake of EL-4 and L1210
io-3
8
6
4
, 10-"
i
8
,®
io-
I
4
6 8 I
IDSO(M)
'*
4
2
6 8 1Q-3
L1210
Chart 1. Inhibition of cell proliferation of L1210 and EL-4 tumor cells by
various inhibitors of plant cell division. The code letters correspond to the
compounds listed in Table 1, Column 1. The ID50 was determined for each
compound as explained in the text and is given on the abscissa for L1210 cells
and on the ordinate for EL-4 cells. The correlation between the ID50 for the 2 cell
lines is significant at p < 0.01.
10-3-1
cells is presented in Charts 4 and 5. Cells were inoculated at
the same density into a series of tissue culture flasks in control
medium or in medium containing various concentrations of the
2 compounds. At various times, the cultures were checked for
cell number, and thymidine and leucine uptake was deter
mined.
In control cultures, the average doubling time for cell number
was 20 hr. Thymidine and, to a lesser degree, leucine uptake
did not correlate with cell number but occurred at a slower rate
(Chart 4).
TIBA, at 3 x 10~4 M, caused immediate inhibition of thymi
dine and leucine uptake, although some cell proliferation con
tinued. The greatest inhibitory effect of the compound occurred
on the first day (Chart 4). A lower concentration of drug, 1 x
10~4 M, produced similar effects, although to a lesser extent.
The viability of the 10~4 M TIBA-treated cells was not signifi
cantly different from that of the control cultures. The viability of
3 x 10~4 M TIBA-treated cells, although lower than control,
was relatively high (72 to 83%) in view of the strong inhibition
of cell proliferation (90%) seen at that concentration.
The effect of various concentrations of bensulide on cell
proliferation and thymidine uptake of EL-4 cells is shown in
Chart 5. The inhibition of cell proliferation is dose dependent,
120
_ 100
-C
Z
80
O)
io-"bi
10"5
2
4
6 810 «2
4 6 10~310"52
4
Thymidine
68-|o'2
4
6 1CT
Leucine
ID„„|M)
'H uptake
Chart 2. Inhibition of thymidine and leucine uptake in L1210 and EL-4 cells
by inhibitors and correlation with the inhibition of cell proliferation. The code
letters refer to the compound as listed in Table 1. Column 1. The ID50 for cell
proliferation is on the ordinate; the ID50 for thymidine and leucine uptake is on
the abscissa. The correlation between the ID50 for cell proliferation and either
thymidine or leucine uptake is p < 0.001.
compounds on thymidine and leucine uptake is similar to their
effect on cell proliferation. This implies that the metabolic
machinery of the remaining treated cells in culture is not
significantly changed. This conclusion is supported by the
finding that the viability of the cells, as measured by trypan
blue, is not significantly decreased at intermediate levels of
MAY
i
?
60
S.
"5
£ 40
I
~0
20
-10
2.5
2.5
5
10-4
2.5
concentration (M)
Chart 3. Inhibition of L1210 and EL-4 cells by various concentrations of TIBA
and bensulide. Ordinate, percentage of added growth compared to control
cultures.
1981
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1881
S. Zilkah et al.
30
— 20
X
I 10
è s
.S
ja
6
I
4
bensulide (M)
•0-control
D 3 x 10-7
O 3x IO-6
A 10~5
3x 10-5
ts.e.
)%viability
60
40
—20
O
x
r 10
E
X
a>
8
8
8
6
4
(11)
(17)
0123
DAYS
Chart 4. Kinetics of inhibition of cell proliferation and thymidine and leucine
uptake in L1210 cells by TIBA. Numbers in parentheses in body of chart,
percentages of remaining cells which are viable as defined by trypan blue
exclusion.
being greatest at 3 x 1CT5 M. In addition, the viability of the
cells treated with that concentration is very low (4 to 17%).
There is a similar dose-dependent inhibition of total thymidine
uptake. However, when the thymidine uptake is determined
per viable cell, no inhibition is seen (data not given). While the
2 lowest concentrations of bensulide still produce demonstra
ble inhibition of cell proliferation, there was no corresponding
inhibition of thymidine uptake.
DISCUSSION
Much data have been accumulated concerning the efficacy,
mode of action, and toxicity of a variety of compounds active
on plant life. Very little of this data has been applied to the
study of animal tumors.
We report in this paper the results of in vitro testing of a
variety of herbicides against EL-4 mouse lymphoma cells and
L1210 mouse leukemia cells. The 14 compounds tested in
1882
Chart 5. Kinetics of inhibition of cell proliferation and thymidine uptake in EL4 cells by bensulide. Number in parentheses in body of chart, percentages of
remaining cells which are viable as defined by trypan blue exclusion.
these experiments were chosen for 2 reasons: (a) each of them
has been identified as an inhibitor of plant cell division, making
it possible that some of them would be capable of inhibiting the
growth of dividing animal tumor cells; and (b) because the
toxicity of these compounds (Table 1) is lower than that of
other groups of herbicides (1, 4), it might be possible to test in
vivo any compounds found to be active in vitro.
Initially, we have chosen to study these compounds in vitro
in a manner similar to that done in plant cell cultures for the
study of phytotoxicity (22-24). Animal cell cultures used in this
way are a sterile and homogeneous system in which all cells
are metabolically active, and there are fewer problems con
cerning the administration, inter- and intracellular transport,
and absorption of compounds.
Also, although the testing of herbicides identified previously
as inhibitors of plant cell division has not been conducted in
any organized way, a few reports have discussed the results of
studying the effect of isolated compounds on animal cells (2,
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Plant Cell Inhibitors and Mammalian
6, 16, 18, 19, 21). Interestingly, in all of these reports, the
results indicated a biological effect by some of the compounds
tested.
The compounds demonstrated marked variability in their
inhibition of cell proliferation. Some compounds (dikegulac,
eptam, maleic hydrazide, and nitralin) were active only in high
concentrations (10~3 M), while bensulide and the carbamates
(propham and chlorpropham) achieved an ID50 at less than
10~4 M. There was good correlation in the effect of the various
compounds on the 2 cell lines (Chart 1).
It is impossible to determine why certain compounds which
are capable of inhibiting plant cell growth did not show that
activity in these experiments. Especially interesting is that
eptam, a thiocarbamate similar to the carbamates (propham
and chlorpropham) in general structure, is a potent inhibitor of
growth in plants but has no activity against the 2 mammalian
lines tested.
Another interesting compound is dikegulac. This compound
is used primarily as a pinching agent (8) (a compound which
inhibits specifically apical meristematic growth, thereby stimu
lating lateral growth). This compound never showed greater
than 40% inhibition in any of the concentrations used.
Another compound that we tested, maleic hydrazide, was
shown in another study to be protective against tumorigenesis
(2) but was inactive in our experiments.
We were interested as well in the possible effect of the
various compounds on cell metabolism, even if it did not result
in actual inhibition of proliferation. We therefore studied the
effect of these compounds on protein and DMA synthesis,
using leucine and thymidine uptake, respectively.
In general, there was good correlation between the ID50 for
inhibition of cell proliferation and that for inhibition of thymidine
and leucine uptake (Chart 2). The most important exceptions
to this are the carbamate compounds, which have an ID50 of
about 10~5 M for cell proliferation but require a 10-fold higher
concentration for comparable inhibition of leucine and thymi
dine uptake. The significance of this discrepancy is uncertain.
One possible explanation is that these compounds are cycle
specific and are thereby selectively enriching the proportion of
cells with a high metabolic rate.
In order to better understand the kinetics of these com
pounds, 2 which showed high activity, TIBA and bensulide,
were selected for more detailed study.
Bensulide demonstrates inhibition in a dose-responsive pat
tern, as does TIBA. The range of effect of both of these
compounds is very narrow, being only approximately an order
of magnitude between a concentration without any effect and
that with maximal inhibition (Chart 3).
The viability of TIBA-treated cells is relatively high, given the
strong inhibition of cell proliferation (Chart 4). This result might
mean that the TIBA-treated tumor cells were viable until their
destruction. In support of this hypothesis is the result that
thymidine uptake per viable cell is not significantly different
between TIBA-treated cells and control, implying that the re
maining cells possess a relatively normal metabolic rate.
Very few of the remaining cells were viable after treatment
with the highest concentration of bensulide (3x10~5
M) (Chart
5). However, when thymidine uptake per viable cell is deter
mined, there is little difference between treated cells and con
trol.
We believe that we have demonstrated clearly that some
Tumor Cells
inhibitors of plant cell division are active in vitro against animal
tumor cells. We are uncertain as to the significance of this. We
are doing further work, both in vitro as well as in vivo, to gain
a better understanding of the nature of these compounds and
their possible potential as tumor chemotherapeutics.
ACKNOWLEDGMENTS
We wish to thank Dylan Hamilton for technical assistance as well as Pat Perry
for secretarial services. We are grateful to those manufacturers who donated
compounds.
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Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1981 American Association for Cancer Research.
1883
Effect of Inhibitors of Plant Cell Division on Mammalian Tumor
Cells in Vitro
Shmuel Zilkah, Michael E. Osband and Ronald McCaffrey
Cancer Res 1981;41:1879-1883.
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Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1981 American Association for Cancer Research.