In vitro antiproliferation in prostate cancer cell lines with cytostatics and combinations with resistance modifiers.
ABSTRACT The treatment of prostate cancer in an advanced state is still unsatisfactory. In the event of the ineffectiveness of total androgen blockade (TAB) therapy, cytostatic administration may be attempted. In this study, we modelled the drugs used in practice on human prostate cancer cell lines. Studies aimed at decreasing multidrug resistance were performed on PC-3 cells. With the use of various cytostatics, the cell proliferation-inhibiting effects were measured under in vitro conditions on human prostate cancer cell lines LNCaP-FGC and PC-3. Under the given experimental conditions, the examined cytostatics exhibited antiproliferative effects on each of the investigated cell lines. Our results indicate that it is not necessary to wait until the development of a hormone-resistant state. In the studies on the PC-3 cell line, we did not find a multidrug-resistant efflux activity responsible for the resistance of the tumour.
- SourceAvailable from: aacrjournals.orgThe Journal of Urology 08/2002; 168(1):9-12. · 3.70 Impact Factor
- Annual Review of Biochemistry 02/1989; 58:137-71. · 27.68 Impact Factor
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ABSTRACT: Gemcitabine (2',2'difluoro-2'deoxycytidine, dFdC) is a synthetic antimetabolite of the cellular pyrimidine nucleotide metabolism. In a first series of in vitro experiments, the drug showed a strong effect on the proliferation and colony formation of the human androgen-sensitive tumor cell line LNCaP and the androgen-insensitive cell lines PC-3 and DU-145. Maximal inhibition occurred at a dFdC concentration as low as 30 nM. In contrast to the cell lines which were derived from metastatic lesions of prostate cancer patients, no inhibitory effects were found in normal primary prostatic epithelial cells at concentrations up to 100 nM. The effect of gemcitabine was reversed by co-administration of 10-100 microM of its natural analogue deoxycytidine. In view of a future clinical application of this anti-tumor drug in advanced prostatic carcinoma, we have compared the effect of gemcitabine on prostatic tumor cells with that on bone marrow granulopoietic-macrophage progenitor cells, because neutropenia is a common side effect of gemcitabine treatment. The time course of action on the two kinds of cells was markedly different. Colony formation of tumor cells was inhibited by two thirds at a gemcitabine concentration of about 3.5 nM. The same effect on granulopoietic-macrophagic progenitor cells required a concentration of 9 nM. Co-administration of deoxycytidine to gemcitabine-treated tumor cell cultures completely antagonized the effect of gemcitabine whereas addition of deoxycytidine after 48 hr of gemcitabine treatment could not prevent gemcitabine action on the tumor cells. In contrast, more than half of the granulopoietic-macrophagic progenitor cells could still be rescued by deoxycytidine administration after 48 hr. These findings and the marked difference in the susceptibility of neoplastic and normal prostatic cells suggest that gemcitabine is a promising substance which should be further evaluated as to its efficacy in the treatment of advanced prostatic carcinoma.The Prostate 04/1996; 28(3):172-81. · 3.84 Impact Factor
Abstract. The treatment of prostate cancer in an advanced
state is still unsatisfactory. In the event of the ineffectiveness of
total androgen blockade
administration may be attempted. In this study, we modelled
the drugs used in practice on human prostate cancer cell lines.
Studies aimed at decreasing multidrug resistance were
performed on PC-3 cells. With the use of various cytostatics,
the cell proliferation-inhibiting effects were measured under in
vitro conditions on human prostate cancer cell lines LNCaP-
FGC and PC-3. Under the given experimental conditions, the
examined cytostatics exhibited antiproliferative effects on each
of the investigated cell lines. Our results indicate that it is not
necessary to wait until the development of a hormone-resistant
state. In the studies on the PC-3 cell line, we did not find a
multidrug-resistant efflux activity responsible for the resistance
of the tumour.
(TAB) therapy, cytostatic
Prostate cancer is one of the most frequent diseases among
men above the age of 50, and occupies a leading position
among the causes of death. Hormone therapy has been
known since the 1940s. It was reported by Huggins and
Hodges that some tumour cells that develop in the prostate
gland are sensitive to androgen withdrawal (1). In general,
four consecutive stages are distinguished in the progression
of the tumour tissue. The local phase is followed by the
development of a locally advanced stage, and then by the
emergence of advanced and finally hormone-refractory
prostate cancer. Certain researchers consider that cells,
which earlier were androgen-sensitive, adapt to androgen-
ablation treatment (2-4). More or less fixed procedures have
been established for the treatment of the individual states.
In consquence of the well-known screening examinations
introduced in the developed countries, the number of
patients first seen in an advanced state has declined
substantially. The chances of a cure are considerably
increased by early recognition and radical surgery or
irradiation. However, the literature data reveal that, in spite
of surgery, the disease recurs in 19-30% of the cases. As
described above, the process progresses in the direction of
the hormone-resistant state. In Hungary, almost 80% of
prostate cancer patients are first seen in an advanced stage.
After 24-36 months, total androgen blockade is ineffective,
and a new treatment mode is required. The overall number
of patients who are operated on and who undergo medical
treatment is considerable, but, following progression, their
therapy is not solved. There have been a number of reports
on the use of cytostatics. Opinions are divided as to the
effectiveness of such treatment. An improvement was found
in 10-30% of the cases. These studies, made in the 1980s,
remain valid. Chemotherapeutic research on other solid
tumours can boast an advantage of close to 20 years relative
to the cytostatic treatment of prostate cancer. The 14th
International Congress on Anti-Cancer Treatment, held in
Paris in 2003, concluded that, despite this 20-year delay, a
new attitude, such as that leading to good results with other
tumours, should be applied to combat prostate cancer. It is
now known that advanced prostate cancer is a dynamic
disease, with varying treatment targets. On this basis, we
attempted to find new approaches to the therapy (5).
The curing of hormone-resistant prostate cancer remains
in dispute, and at present no standard therapeutic protocol
is available (6). The contradictory opininions and our own
experience led us to seek appropriate treatment forms via
in vitro model experiments carried out under experimental
In the human prostate cancer cell lines LNCaP-FGC
(containing androgen receptors) and PC-3 (androgen
receptor-free), measurements were made of the ability of
various cytostatics (already tested in clinical practice) to
inhibit cell proliferation under experimental conditions. The
individual cytostatics were combined and were
Correspondence to: Dr Olivér Pintér, Department of Urology, Medical
Faculty, University of Szeged, Szeged Kálvária sgt. 57. H-6722,
Hungary. Tel: (+) 36-62-490-590, e-mail: email@example.com-
Key Words: Multidrug resistance, prostate cancer cell line,
in vivo 19: 253-260 (2005)
In Vitro Antiproliferation in Prostate Cancer Cell Lines with
Cytostatics and Combinations with Resistance Modifiers
OLIVÉR PINTÉR1, ILONA MUCSI2and JOSEPH MOLNÁR2
1Department of Urology and 2Department of Microbiology,
Medical Faculty, University of Szeged, Szeged, Hungary
supplemented with the known resistance modifiers,
Anafranil and Novantrone.
We investigated the drug sensitivities of these prostate
cancer cells, and measured the drug accumulation in the
presence and in the absence of the resistance modifiers. The
PC-3 cell line was applied in these studies. The multidrug
resistance-dependent drug uptake by the tumour cells was
followed flow-cytometrically via the uptake of Rhodamine
123, a fluorescent dye indicator that is a "cytostatic
Materials and Methods
Chemicals. The chemotherapeutic agents used in this study were
Cisplatin (Platidium inj. Lachema, A.S. Brno, Czech Republic),
Mitoxantrone hydrochloride (Novantron inj., Wyeth Medical
Ireland, Newbridge, Ireland), Estramustine phosphate (Estracyt
inj.,Pharmacia and Upjohn AB, Stockholm, Sweden), Gemcitabine
hydrochloride (Gemzar inj., Lilly France S.A. Fegersheim, France),
Cyproterone acetate (Androcur Depot inj. Schering AG Pharma,
Germany), and Clomipramine hydrochloride (Anafranil inj.,
Novartis, Basel, Switzerland). 3-[4,5-Dimethylthiazol-2-yl]-2-5-
diphenyltetrazolium bromide (MTT) and sodium dodecyl sulfate
(SDS) were purchased from Sigma Chemical Co, (St. Louis, USA).
Cell cultures. The LNCaP-FGC-10 cell line was isolated by
Horoszewicz et al. from an aspiration cytological sample taken
from a supraclavicular lymph node on the left side in a 50-year-old
man, which had proved to be metastatic prostate cancer. The cell
line contained androgen and oestrogen receptors (7). The PC-3 cell
line was isolated from a bone metastasis caused by prostate cancer
in a 62-year-old man; this did not contain either androgen or
oestrogen receptors and was suitable for the modelling of a
hormone-resistant state (8). The PC-3 cells were grown in RPMI
1640 medium supplemented with 10% heat-inactivated fetal bovine
serum. The LNCaP-FGC cell line was cultured in RPMI 1640
medium supplemented with 10 mM Hepes, 1.0 mM sodium
pyruvate and 10% fetal bovine serum.
Cell proliferation assay. The antiproliferative effects of the
chemotherapeutic agents alone and in combination were tested
with the MTT assay. The compounds were diluted with culture
medium in 96-well flat-bottom culture plates in 100 Ìl
volume/well, and 50 Ìl or 100 Ìl cell suspension was then added
to the wells with the exception of the medium controls. 1x104PC-
3 cells/well and l.5-2x104LNCaP-FGC cells /well were used in
these experiments. The final volume per well was 150 or 200 Ìl.
Cell controls and medium controls were set up in each plate. The
culture plates were further incubated at 37ÆC for 2-3 days. After
the incubation period, 20 Ìl MTT solution (from 5 mg/ml stock
solution), depending on the volume in the wells, was added to
each well and the plates were further incubated for 4 h at 37ÆC.
One hundred Ìl SDS solution was then added to the wells and the
plates were further incubated overnight at 37ÆC. The inhibitory
effect on the cell proliferation was determined by measuring the
optical densities (ODs) of the wells. The absorbance was recorded
at 540 nm; the reference wavelength was 630 nm; a Multiscan EX
reader was used for evaluation. The average values were
calculated for parallel wells of each sample and the controls. The
percentage inhibitory effect or cytotoxic activity was determined
according to the formula:
OD sample – OD medium control
100 – x 100
OD cell control – OD medium control
Assay of cytotoxicity. Monolayer cultures of the cells were grown in
96-well tissue culture plates for 24 h and were then treated with 100
Ìl medium/well containing the compounds at different
concentrations for 24 h. The cell viability was tested by means of the
MTT assay and the cytotoxicity was evaluated as described above.
Fluorescence uptake assay. The effects of different compounds on
the fluorescence uptake of PC-3 cells were investigated. The PC-3
cells were propagated in RPMI l640 medium supplemented with
10% heat-inactivated fetal bovine serum. For the fluorescence
uptake assay, the adherent cell culture was trypsinized and the cells
were adjusted to a density of 2xl06/ml, resuspended in serum-free
culture medium and distributed into 0.5 ml aliquots in Eppendorf
centrifuge tubes. The test compounds were added to 0.5 ml cell
suspensions in 1-20 Ìl stock solution and the samples were
incubated for 10 min at room temperature. Ten Ìl of the indicator
Rhodamine 123 (5.2 ÌM final concentration) was then added to the
samples and the cells were further incubated for 20 min at 37ÆC.
The cells were next washed twice and resuspended in 0.5 ml
phosphate-buffered saline (PBS) for analyses. The fluorescence of
each cell population was measured by flow-cytometry using a
Beckton Dickinson FACS scan instrument.
Since Novantron (Mitoxantrone) is used as monotherapy or
in combination with steroid in clinical practice, we studied
its antiproliferative effect. On the LNCaP cell line, the ID50
of Novantron alone was 0.04 Ìg/ml. When applied in
combination with 12.5 Ìg/ml Anafranil, the ID50of
Novantron was 0.02 Ìg/ml. Besides the considerable
antiproliferative effect of 25 Ìg/ml Anafranil, the ID50of
Novantron was in the low range (Figure 1).
On the PC-3 cell line, the ID50of Novantron was 1.25 Ìg/ml.
In the checkerboard experiment, a 1:2 dilution series of 5 Ìg/ml
Novantron was combined with 50, 25, 12.5 or 6.25 Ìg/ml
Melipramin on the PC-3 cell line. The ID50 of Novantron in
the presence of these combinations of Melipramin was <0.035,
0.035, 0.3 and 0.6 Ìg/ml, respectively.
The PC-3 cell line was also subjected to combined
treatment with Novantron and Depersolon. Depersolon
alone and Novantron alone had ID50values of 20.0 and 1.1
Ìg/ml, respectively. The ID50 of Novantron in the
combination varied as a function of the concentration of
Depersolon: at 125 Ìg/ml Depersolon in the combination,
the ID50 of Novantron was 0.2 Ìg/ml.
It is well known that, in the event of the ineffectiveness
of TAB treatment, the drug of first choice is Estracyt. On
the LNCaP cell line, the ID50of Estracyt in a concentration
of 100 Ìg/ml was not attained.
in vivo 19: 253-260 (2005)
On the PC-3 cell line, the antiproliferative effect of
Estracyt alone was indicated by an ID50of 185 Ìg/ml. The
ID50 of Estracyt was decreased significantly by its
combination with 5 or 1 Ìg/ml Taxol. At 5 Ìg/ml Taxol, the
ID50of Estracyt was 50 Ìg/ml (Figure 2).
When the effectiveness of treatment with Gemzar alone was
examined on the LNCaP line, its ID50proved to be 0.01 Ìg/ml.
The combination of Estracyt and Gemzar was also studied on
the oestrogen and androgen receptor-free PC-3 cell line. The
ID50of Estracyt in combination with 1 Ìg/ml Gemzar was
140 Ìg/ml, which fell to 125 Ìg/ml at 10 Ìg/ml Gemzar. It
remained at around this value independently of the amount
of Estracyt, indicating that the effect of Gemzar was
manifested (Figure 3).
Pinter et al: Inhibition of Cell Proliferation in Prostate Cancer Cell Line
Figure 1. Combined antiproliferative effect of Novantron and Anafranil at different concentrations on the LNCaP cell line.
Figure 2. Antiproliferative effect of Estracyt at different concentrations combined with Taxol on the PC-3 cell line.
The effect of Farmorubicin on the PC-3 line was
investigated too. When the starting concentration of 100 Ìg/ml
was varied in a dilution series of 1:2, the ID50was found to be
1.5 Ìg/ml. Examination of the antiproliferative effect of
Farmorubicin on the LNCaP cell line, using a starting
concentration of 10 Ìg/ml and 1:2 dilution series, revealed an
ID50of 0.03 Ìg/ml.
The ID50of Anafranil alone as resistance modifier on the
LNCaP cell line proved to lie in the range 25-50 Ìg/ml. The
variation in the effect of Farmorubicin on the LNCaP line
was investigated in the presence of this resistance modifier.
On the addition of 12.5 Ìg/ml Anafranil, the ID50of
Farmorubicin was 0.015 Ìg/ml; the ID50remained high
when 25 Ìg/ml Anafranil was added (Figure 4).
Taxol as monotherapy proved effective on the PC-3 cell
line. Its ID50was 3.23 Ìg/ml. At concentrations higher than
this, the extent of inhibition was 90-100%.
The antiproliferative effect of Cisplatin too was examined
on the PC-3 cell line. It may be stated that many of the
preparations employed in combination in practice are
effective. The ID50was found to be 6.13 Ìg/ml (Figure 5).
Of the resistance modifiers, the effects of Pipolphen
and Anafranil on the PC-3 line were studied. The ID50 of
Pipolphen was 50 Ìg/ml, while that of Anafranil was 25-
The mechanism of action of the GnRH analogues is
known: they exhaust the receptors of the tumour tissue
according to a cascade principle. Their antiproliferative
effects on cells are not known. Hence, we studied their
possible antiproliferative action on PC-3 cells. Our
investigations revealed that both the Decapeptyl depot and
Lucrin depot were without effect.
Of the antiandrogens, the antiproliferative action of
Androcur on the LNCaP line was studied. This agent did
not have any essential effect on cell proliferation.
The cells of the PC-3 line exhibited a significant
Rhodamine 123 accumulation. Depending on their
concentrations, Novantron and Estracyt slightly depressed
the Rhodamine 123 uptake by the cells. A study was made
of the drug interactions in the Novantron-Depersolon and
Novantron-Esracyt combinations, which caused further
decreases in the Rhodamine 123 uptake by the tumour cells.
The labelling was investigated in the presence of various
resistance modifiers (Verapamil,
Pipolphen). It emerged that the Rhodamine 123
accumulation decreased in response to the customary
resistance modifiers, but the fluorescence of the cytosol
barely changed; they were ineffective on this cell line.
Novantron as monotherapy was effective on both cell lines.
When Novantron was combined with Anafranil treatment
on the LNCaP cell line, the ID50decreased considerably,
since Anafranil itself has an antiproliferative effect on both
cell lines. This observation can be utilized in clinical
practice. Anafranil reduces pain and appreciably improves
the condition of the patient as an antidepressant. If
in vivo 19: 253-260 (2005)
Figure 3. Antiproliferative effect of Estracyt at different concentrations combined with Gemcitabine on the PC-3 cell line.
Anafranil enhances the action of Novantron, a combination
of the two drugs may be effective in vivo.
The ID50of Novantron was substantially higher on the
PC-3 cell line than on the LNCaP cell line. This may
possibly indicate that the effect may be achieved at a higher
dose in hormone-resistant states.
The effect of Melipramin monotherapy (similar to that of
Apomorphine) on the PC-3 cell line revealed that it did
inhibit cell proliferation, but less markedly than did
On the PC-3 cell line, combined treatment with
Novantron and Melipramin considerably modified the ID50
Pinter et al: Inhibition of Cell Proliferation in Prostate Cancer Cell Line
Figure 4. Combined antiproliferative effect of Farmorubicin and Anafranil at different concentrations on the LNCaP cell line.
Figure 5. Antiproliferative effect of Cisplatin at different concentrations on the PC-3 cell line.
of Novantron. As an antidepressant, Melipramin may be
administered as supplementary treatment in clinical
practice, and it cannot be excluded that it improves the
effect of Novantron.
Novantron and Depersolon treatment proved effective on
the PC-3 cell line, and this is a mode of therapy applied
clinically. The steroid treatment results in a temporary
substantial improvement, but, unfortunately, the condition
of the patient deteriorates within a short time, and death
generally occurs within 6 months.
Estracyt is the drug of choice after primary TAB treatment.
This drug was originally intended for the treatment of breast
cancer, but, interestingly, it acquired an important role in the
therapy of prostate cancer (9). Because of its oestrogen
content, this product decreases the serum testosterone level,
while its mustard nitrogen content allows it to act as an
alkylating agent, inhibiting the proliferation of tumour cells by
blocking the microtubules (10). It exerts an antiproliferative
effect on both the PC-3 and the LNCaP cell lines.
The combination of Estracyt and Taxol in clinical practice
is known from the literature (11). We found that 5 Ìg/ml
Taxol decreased the ID50of Estracyt to nearly one-third in
the LNCaP cell line.
Gemzar, as monotherapy, was effective even in very low
amounts on the LNCaP cell line, and it is known from the
literature that it has a strong antiproliferative effect on both
cell lines examined here (12).
A study was made of the co-administration of Estracyt
and Gemzar to the cells of the LNCaP line, which contains
oestrogen and androgen receptors. Ten Ìg/ml Gemzar
decreased the ID50 of Estracyt considerably. Then,
independently of the quantity of Estracyt, the level of
inhibition remained at about the same level in consequence
of the effect of Gemzar.
We have applied Farmorubicin most frequently in clinical
practice. This drug was effective on both cell lines. On the PC-
3 and LNCaP cell lines, the ID50was 1.5 Ìg/ml and 0.03 Ìg/ml,
respectively. Accordingly, the latter cells responded more
sensitively to this monotherapy.
When the effect of Farmorubicin was investigated on
the LNCaP cell line in the presence of the resistance
modifier Anafranil, it was observed that 12.5 Ìg/ml
Anafranil considerably reduced the ID50of Farmorubicin,
from 0.03 Ìg/ml to 0.015 Ìg/ml.
On the basis of their mechanisms of action, the GnRH
analogues, Decapeptyl depot and Lucrin depot, were not
expected to exhibit antiproliferative effects, and they were
indeed found to be ineffective.
The products of multidrug resistance genes are able to
pump certain chemotherapeutic agents out of cells. One of
the causes of the ineffectiveness of many drugs may be their
intracellularly decreased concentration. The best known
member of the transporter family is MDR1; this gives rise
to the product P-glycoprotein (Pgp), an ATP-binding
transmembrane transport protein. Operating as an efflux
pump, this reduces the intracellular concentrations of
antitumour drugs to below the therapeutic level. Pgp170,
coded by the MDR1 gene, is a glycolyl transmembrane
protein. Its efflux pump activity was first described by
Gottesmann et al. (13, 14). A number of agents are known
which inhibit the pump mechanism in vitro. In our
experiments, we applied the resistance modifiers Verapamil,
Melipramin and Pipolphen. These compounds did not alter
the extent of drug uptake by the cells. It could, therefore,
be stated that the efflux pump was not operating. The
reason for this may have been that the examined cell line
did not contain Pgp.
Under experimental conditions, known cytostatics were
demonstrated to be effective on two different prostate
cancer cell lines. Therapy with Taxol and Gemzar is
currently undergoing clinical testing in cases of advanced
prostate cancer. These drugs have not yet been officially
approved for such treatment in Hungary, though their
application would represent a new possibility in therapy.
It is noteworthy that Farmorubicin, Estracyt and their
combination exhibited low ID50values on the LNCaP cell
line, which contains oestrogen and androgen receptors.
Consequently, it is perhaps not necessary to wait until the
development of a hormone-resistant state before
cytostatic administration. Systematic following of the PSA
is of good prognostic value: if the post-TAB treatment
PSA level increases 2-fold, it may be recommended to
change the treatment mode to mono- or combined
chemotherapy. Multidrug resistance efflux activity
responsible for tumour resistance was definitely not
operative in the prostate cancer cell line investigated. It
follows from this that the hormone resistance that
developed here requires further clarification.
The authors express their appreciation to Dr David Durham for his
advice in preparation of this manuscript and for the grant of the
Szeged Foundation of Cancer Research, Hungary.
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Received July 23, 2004
Revised November 24, 2004
Accepted December 21, 2004
Pinter et al: Inhibition of Cell Proliferation in Prostate Cancer Cell Line