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Tumor Biology |
Division of Oncology/Hematology, Department of Medicine [Q. W., M. S. U., R. W.], and Department of Biochemistry and Molecular Biology [W. Y., S. C.], University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, ß, and 
; and retinoid X receptors , ß, and but were
not additive in MDA-MB-231 cells that lacked expression of estrogen
receptor, RAR, and RARß. The hormones used individually or in
combination induced up to 40–50% cell death by a trypan blue
exclusion assay in a dose-dependent manner up to concentrations of
10-7 M in MCF-7 and T-47D cells, more modestly
in MDA-MB-231 cells, and not at all in MCF-10 and MCF-12 nontransformed
mammary epithelial cells. Pretreating the cancer cell lines with
1,25(OH)2D3 and ATRA individually or in
combination for 3 days prior to a 1-h incubation with paclitaxel or
Adriamycin decreased the ED50 for inhibition of colony
formation or for cell death by trypan blue by up to 2 logs for
paclitaxel and up to 1 log for Adriamycin in all three cell lines but
had no effect on chemotherapy-induced MCF-12 cell death. The effects of
the hormones were synergistic with those of the chemotherapy agents in
all of the breast cancer cell lines, generally at the higher
concentrations. Cell death took place by apoptosis. To determine one
potential reason for the greater potentiation of the effects of
paclitaxel than those of Adriamycin, we determined the effects of
preincubation of MCF-7 cells on paclitaxel-induced phosphorylation of
Bcl-2. Pretreatment of MCF-7 cells with either
1,25(OH)2D3 or ATRA increased the
phosphorylation of Bcl-2 by variable concentrations of paclitaxel.
These data suggest that pretreatment of breast cancer with
1,25(OH)2D3 or ATRA lowers the threshold for
cell killing by chemotherapy agents and may provide a novel treatment
option for this disease. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Vitamin D3 and retinoic acid derivatives exert
their effects by binding to related members of the nuclear receptor
family that, together with their ligands, modulate transcription
through cognate response elements in the promoters of their target
genes (9)
. Both
1,25(OH)2D3 and ATRA
inhibit cell cycle progression in the G1 phase by
up-regulating transcription of the CDK inhibitor
p21WAF1/CIP1 through vitamin D response
elements (10)
and retinoic acid response elements
(11)
in the waf1 promoter. The
1,25(OH)2D3- and
ATRA-induced increases in p21WAF1/CIP1 are p53
independent (6
, 10)
.
1,25(OH)2D3 also
up-regulates p27KIP1 (12)
and
inactivates CDK 6 (13)
. 9-cis-Retinoic acid and
ATRA also inhibit CDK 4 and CDK 2 activity, expression of cyclins
D1 and D3, and
proliferation in MCF-7 and T-47D breast cancer cells, without affecting
the proliferation of MCF-10 nontransformed mammary epithelial cells
(14)
. Both
1,25(OH)2D3- and
ATRA-induced effects result in dephosphorylation of Rb (15
, 16)
. Retinoid treatment also reduces E2F1 promoter activity,
E2F1 mRNA and protein levels (16)
, and inhibits AP1
activity in MCF-7 cells but not in MDA-MB-231 cells that lack ER,
RAR, and RARß and express mutant p53 (6)
. Retinoids
can, however, promote cell death in a p53-independent manner and
increase the expression of cell death factor Bax and decrease Bcl-2
levels (6)
, and analogues of
1,25(OH)2D3 can
down-regulate Bcl-2 in cells expressing mutant p53 (3)
. In
addition, ATRA derivatives can induce apoptosis in a RAR-specific
manner, abrogating the need for RAR and RARß expression for that
effect (17)
.
Combinations of 1,25(OH)2D3 and retinoic acid family members can work cooperatively to inhibit proliferation (18 , 19) and promote apoptosis (20) in MCF-7 cells and squamous cell carcinoma cells (21) . The combined effects of retinoids and vitamin D3 derivatives are attributable to heterodimeric interactions between members of the nuclear receptor family. VDRs and RARs both heterodimerize with RXR, greatly enhancing their transcriptional activity (22, 23, 24) . In addition, VDRs and RARs form heterodimers that provide the signaling crossroads between the two classes of compounds (25) .
In this study, we attempted to modulate the susceptibility of breast cancer cells to chemotherapy agents by preincubating them with 1,25(OH)2D3 and ATRA, either individually or in combination, to render them more susceptible to the proapoptotic effects of two chemotherapeutic agents. Our data demonstrate a substantial increase in the sensitivity of three breast cancer cell lines to the effects of paclitaxel and Adriamycin while sparing nontransformed mammary epithelial cells.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Northern Blots.
Polyadenylated RNA was prepared from guanidinium thiocyanate-extracted
total cellular RNA (27)
using a poly-dT column (Life
Technologies) as described (28)
, electrophoresed in 1%
agarose gels, and transferred to nylon filters by capillary transfer
techniques. The membranes were hybridized with a
32P-labeled cDNA fragments for ER (a kind gift of
B. Katzenellenbogen, University of Illinois, Urbana, IL) for VDR,
RAR, and RARß (kind gifts of J. W. Pike, Baylor College of
Medicine, Houston, TX) and RXR (kind gift of D. Mangelsdorf,
University of Texas Southwestern Medical Center, Dallas TX). A cDNA
probe for ß-actin was used as a loading control. Sequences were
identified by exposure to Kodak XAR-5 film at -80°C. Band intensity
was quantitated using a Shimadzu C5900U densitometer dual flying spot
scanner (Shimadzu Scientific Instruments, Inc., Princeton, NJ) and
normalized against the actin loading control.
Western Immunoblots.
For receptor determinations, cells cultured in standard medium were
harvested when 60–70% confluent, and lysates were prepared using NP40
lysis buffer, containing 50 mM Tris-HCl (pH 7.4), 150
mM NaCl, 0.5% NP40, 1 mM
NaVO4, 1 mM DTT, 1 mM
phenylmethylsulfonyl fluoride, 1 µg/ml leupeptin (Sigma Chemical Co.,
St. Louis, MO), and 0.01 unit/ml aprotinin (26)
, and
analyzed as before (29)
. Western blots were stained with
antibodies to ER, VDR, RAR, RARß, and RAR and RXR, RXRß,
and RXR (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) and to
-tubulin (Sigma) used as a loading control.
To determine the effects on Bcl-2, cells were cultured to 
70%
confluence in standard medium, switched to stripped medium with and
without ATRA or 1,25(OH)2D3
for 3 days, and then incubated with paclitaxel in standard medium for
24 h. Cells were scraped from the plates in NP40 lysis buffer and
analyzed by Western immunoblot using a mouse monoclonal antibody to
human Bcl-2 (Dako Corp., Carpenteria, CA) or a monoclonal antibody to
-tubulin (Sigma) as a loading control, as described
(29)
. All blots were carried out at least twice.
Colony Assays.
To determine the colony-inhibitory effects of
1,25(OH)2D3 and ATRA, 2000
cells were incubated in triplicate 6-cm tissue culture plates and
allowed to adhere for 24 h in standard medium. The medium was
replaced by stripped medium or stripped medium supplemented with
1,25(OH)2D3 and/or ATRA at
1-log increments in concentrations from 10-10 to
10-7 M and incubated with the cells
for 3 days. This medium containing the supplements was renewed for 3
more days, after which it was replaced by standard medium, and the
cells were incubated further for 6 ± 2 days. In the
experiments designed to determine the potentiation effects of
1,25(OH)2D3 and ATRA on
colony inhibition by chemotherapy agents, the cells were incubated in
standard medium overnight, treated with
1,25(OH)2D3 and/or ATRA
10-9 M in stripped medium for 3
days, then incubated with variable concentrations of paclitaxel or
Adriamycin for 1 h, washed with PBS, and further incubated in
standard medium for 9 ± 2 days. The plates were stained
with methylene blue, and colonies 
1 mm were manually counted
(30)
. All experiments were carried out at least twice.
Trypan Blue Cell Death Determinations.
Cells incubated with
1,25(OH)2D3 and/or ATRA,
with and without treatment with the two chemotherapeutic agents, were
assayed for cell death by the uptake of trypan blue. Cells were
incubated in standard medium for 24 h, switched to stripped medium
or stripped medium containing variable concentrations of
1,25(OH)2D3 and/or ATRA
from 10-10 to 10-7
M for 3 days, and assayed for cell death. To determine the
ability of these compounds to potentiate chemotherapy-induced cell
death, after an initial 3-day incubation with
1,25(OH)2D3 and/or ATRA
10-8 M, the cells were incubated
with variable concentrations of paclitaxel or Adriamycin for 1 h,
washed with PBS, and further incubated in standard medium for 2, 3, or
4 days. After the incubations, in both sets of experiments, cells were
collected from the supernatants and combined with adherent cells
obtained by trypsinization, incubated in 0.2% trypan blue, and
manually counted at x100. The percentages of cells taking up blue dye
were calculated.
Measurement of DNA Fragmentation.
Cells were incubated on sterile microscope slide coverslips overnight
in standard medium. Medium was removed 24 h later and replaced
with either stripped medium or stripped medium containing
1,25(OH)2D3 or ATRA at
10-8 M alone or in combination for
72 h. Cells were then incubated with Adriamycin or paclitaxel at
the concentrations indicated for 1 h in standard medium, washed,
and incubated in standard medium. One, 2, or 3 days later, the cells
were permeabilized, and the DNA was 3'-OH end labeled with FITC-dUTP
using a Boehringer Mannheim (Indianapolis, IN) Fluorescein In
Situ Cell Death Detection kit to measure apoptosis. Cells were
photographed at x400 with the Olympus BX40 fluorescence microscope and
the PM20 photographic system.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and Northern blot (not shown) analysis. ER, RAR, and RARß were
only expressed in MCF-7 and T-47D cells. VDR, RAR, RXR, RXRß,
and RXR were expressed in all of the cells. The results from
Northern blots were in general agreement with the Western blot data.
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). Both
1,25(OH)2D3 and ATRA
inhibited colony formation in a dose-dependent manner in all three
breast cancer cell lines. The doses causing a 50% inhibitory effect
(ED50) are displayed in Table 1
. Colony inhibition by the two compounds used in combination was
synergistic in MCF-7 and T-47D cells, with Loewe’s Additivity Model
combination indices of 0.024 and 0.021, respectively (31
, 32)
. However, the effect of combining
1,25(OH)2D3 and ATRA in
MDA-MB-231 cells yielded a combination index of 0.96, indicating
additive effects within experimental error by the two compounds.
Nontransformed mammary epithelial cells did not form colonies in tissue
culture and, thus, could not be assayed using this technique.
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demonstrates that
these analogues of
1,25(OH)2D3 were even more
effective than the parent compound in inhibiting colony formation. The
ED50 for
1,25(OH)2D3,
1,25(OH)2-16-ene-23-yne-D3,
and
1,25(OH)2-16-ene-23-yne-26,27-hexafluoro-D3
were 5.6 x 10-8, 4.7 x 10-9, and 6.3 x 10-10, respectively.
To complement the clonogenicity studies, we investigated the effects of
1,25(OH)2D3 and ATRA on
their capacity to induce cell death in breast cancer cells and in
nontransformed mammary epithelial cell lines. Fig. 3
demonstrates that
1,25(OH)2D3 and ATRA,
either individually or in combination, induced cells to die in a
dose-dependent manner after a 3-day incubation. The
ED50 for
1,25(OH)2D3 and ATRA were
1.36 x 10-7 (extrapolated) and
5.27 x 10-8, respectively, for
MCF-7 cells but did not reach ED50 for any of the
other cells assayed at doses up to 1 x 10-7 M. The maximum cell death
achieved was 39% in T-47D cells by either
1,25(OH)2D3 or ATRA and 24
and 29% for 1,25(OH)2D3
and ATRA, respectively, in MDA-MB-231 cells. Combining the two agents
caused a 55% cell kill at 10-7 M in
T-47D cells that was statistically greater than killing by either
compound alone (P < 0.05 and
P < 0.02 for
1,25(OH)2D3 and ATRA,
respectively). However, combining the two hormones did not increase the
percentage of cell kill over that achieved by either compound alone in
MCF-7 and MDA-MB-231 cells, suggesting a less than additive effect on
inducing cell death in these cell lines. These data, demonstrating
different effects on colony inhibition and cell killing by these
agents, suggest that different mechanisms are responsible for these two
effects and that cell killing is only a subset of the effects that
result in colony inhibition.
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1,25(OH)2D3 and ATRA Predispose Breast
Cancer Cells to Chemotherapy-induced Cell Death.
To determine whether incubation of
1,25(OH)2D3 or ATRA prior
to treatment with two chemotherapy agents commonly used in the
treatment of breast cancer, paclitaxel and Adriamycin, affected the
potential of these drugs to decrease survival, we carried out colony
assays in a manner similar to experiments described above. Cells were
incubated for 3 days with
1,25(OH)2D3, ATRA, or the
combination at 1 x 10-9
M and then with variable concentrations of paclitaxel or
Adriamycin for 1 h. The cells were subsequently washed with PBS
and incubated in standard medium for 9 ± 2 more days.
Fig. 4
demonstrates that treatment of MCF-7 cells with either
1,25(OH)2D3, ATRA, or the
two agents in combination, prior to treatment with paclitaxel and
Adriamycin, caused a greater decrease in colony formation than
treatment with paclitaxel or Adriamycin alone. Comparisons of
fractional products of the measured effects on colony inhibition with
the effects predicted from the Bliss Interdependence Model indicated
synergy in MCF-7 cells with either paclitaxel or Adriamycin at all
concentrations tested (33)
. The interactions between
1,25(OH)2D3 and ATRA and
the chemotherapeutic agents in T-47D and MDA-MB-231 cells were mixed
between synergistic and additive and varied with the concentrations of
the drugs. The synergistic effects are presented in graphic form in the
lower graphs of Fig. 4
, where the data are graphed as a percentage of
untreated controls. Statistically significant divergence of the values
at each concentration are indicated by asterisks and denote synergy.
The ED50s for colony inhibition by paclitaxel and
Adriamycin are presented in Table 2
. The table includes the calculated fold decreases in the
ED50s by pretreatment of the cancer cells with
1,25(OH)2D3 and ATRA. The
potentiation of the effects of chemotherapy was observed with both
drugs, but the effects were consistently greater with paclitaxel than
with Adriamycin in all three cell lines.
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demonstrates that preincubation with 10-8
M 1,25(OH)2D3
or ATRA alone or in combination for 3 days sensitized breast cancer
cells but not MCF-12 nontransformed mammary epithelial cells to the
killing effects of paclitaxel and Adriamycin. All three cell lines were
subject to synergistic killing by the combined effects of both
chemotherapeutic agents and
1,25(OH)2D3 and ATRA, as
determined by the Bliss Interdependence Model (33)
. The
combined treatments were synergistic at the higher concentrations of
the drugs, generally, as denoted by the asterisks in the graphs. The
ED50s for cell killing for paclitaxel and
Adriamycin are presented in Table 3
. The table also lists the fold decreases in the
ED50s for the two drugs when the cells were
preincubated with
1,25(OH)2D3 and ATRA. The
decreases in ED50 for paclitaxel-treated cells
were all >10-fold and in the range of 100-fold under some conditions.
The decreases in ED50 for Adriamycin treatment
were generally lower than with paclitaxel but were still in the 10-fold
range under most conditions. These data confirm that pretreatment of
all of the breast cancer cells tested with
1,25(OH)2D3, ATRA or the
combination were synergistic with both chemotherapeutic agents in their
capacity to induce cell death. No interactions between the two
treatment modalities were observed in MCF-12 nontransformed mammary
epithelial cells.
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demonstrates that increased doses of paclitaxel induced
3'OH end labeling with FITC-dUTP in a dose-dependent manner.
Pretreatment of cells with
1,25(OH)2D3 and ATRA caused
a minimal increase in the amount of baseline labeling, but combining
preincubation with paclitaxel or Adriamycin treatment caused
substantial increases in the percentage of TUNEL-positive cells.
Although treatment of cells with paclitaxel or Adriamycin at 1.0 or 0.1
µM, respectively, resulted in 40%
TUNEL-positive cells, pretreated cells were 100% TUNEL positive at 0.1
and 0.05 µM paclitaxel and Adriamycin,
respectively, and demonstrated 50% positive TUNEL staining at 0.01
µM paclitaxel or Adriamycin, or a 2-log
increase in sensitivity to paclitaxel and a 1-log increase in
sensitivity to Adriamycin. Fig. 6B
demonstrates in graphic
form the TUNEL-positive percentages obtained from manual counts of 3–5
random fields of all of the cancer cell lines and the MCF-10
nontransformed cells. The increases in the percentage of MDA-MB-231
cells attributable to preincubation prior to exposure to chemotherapy
were statistically significant over those of nonpretreated cells but
represented substantial underestimates of the true percentages of cell
death. This was because of the loss of adherence of dying cells that
were preferentially lost with the multiple washing steps required for
the staining procedure. These data confirm the >10-fold potentiation
of the effects of chemotherapy by pretreatment with
1,25(OH)2D3 and ATRA and
demonstrate that the cell death observed was attributable to apoptosis.
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demonstrates that preincubation of MCF-7 cells with 1 x 10-8 M
1,25(OH)2D3 or ATRA caused
an increase in the phosphorylation of Bcl-2 at 0.01, 0.1, and 1.0
µM paclitaxel with ATRA pretreatment and 0.1 and 1.0
µM paclitaxel with
1,25(OH)2D3 pretreatment.
These data suggest that at least part of the observed effect may be
secondary to a potentiation of the ability of paclitaxel to
phosphorylate Bcl-2.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Pretreatment of these cancer cells with 10-9
M 1,25(OH)2D3
and ATRA also potentiated the effects of these chemotherapy agents on
decreasing colony formation in tissue culture. The effects of the
hormones and the chemotherapy drugs were synergistic in all of the
cells, in at least some of the concentration ranges of chemotherapy
drugs tested, and were additive under other conditions. The effects
were once again greater with paclitaxel than with Adriamycin. The
ED50 of the chemotherapy drugs for inhibition of
colony formation and the concentration of hormones required to affect
sensitization were 10-fold lower that the values needed to affect
cell death. This is probably attributable to the factors that affect
colony formation. Clonogenic potential is affected by modulating the
capacity of the cells to proliferate as well as to survive, and both
the hormones and the chemotherapy agents affect both proliferation and
cell death.
The effects of retinoids and vitamin D3 on the
proliferation of MCF-7 and T-47D, two ER-positive cell lines, are
greater than on MDA-MB-231 cells that are ER negative. Modulation of
proliferation by retinoic acid requires the expression of RAR
(39
, 40)
and RARß (7)
. RARß is lost in
ER-negative cells, whereas ER-positive cells have elevated RAR
levels (40)
. Nevertheless, both
1,25(OH)2D3 and ATRA
inhibited colony formation and sensitized MDA-MB-231 cells to the
effects of chemotherapy agents. These effects were likely attributable
to the effects on survival by these hormones. This is because, in
contrast to proliferation, cell death can be induced by activating all
RARs, including RAR (17)
, a receptor expressed by all
of the cancer cell lines tested. Although VDR was present in all of the
cells, a physiologically meaningful heterodimer between VDR and RAR
can form (25)
, which may modulate the effects of
1,25(OH)2D3. Such
heterodimers were less likely in MDA-MB-231 cells. This could account
for the lack of synergy between
1,25(OH)2D3 and ATRA on the
inhibition of colony formation in MDA-MB-231 cells shown in Fig. 2
,
whereas synergy was observed in both MCF-7 and T-47D cells. The effects
of 1,25(OH)2D3 and ATRA on
inducing cell death after a 3-day incubation were minimal, however,
when compared with their effects on potentiating chemotherapy-induced
cell death. The real advantage of these compounds comes from their
potential use as sensitizers of cell death. Similar effects were
demonstrated in a squamous cell carcinoma cell line pretreated with the
1,25(OH)2-16-ene-23-yne-D3
analogue prior to cisplatin therapy (41)
.
As alluded to above, the effects observed with paclitaxel were greater than those obtained with Adriamycin. We investigated one potential mechanism that may cause a sensitizing effect by ATRA in MCF-7 cells treated with paclitaxel, that of the effects on Bcl-2. In addition to acting in its well-defined role as a chemotherapy agent through stabilization of microtubules, paclitaxel induces the phosphorylation and thereby the inactivation of Bcl-2 (42) . In this report, we present data that demonstrate, for the first time, that both 1,25(OH)2D3 and ATRA potentiate the ability of paclitaxel to phosphorylate Bcl-2. The mechanism of Bcl-2 phosphorylation by paclitaxel has been shown to be mediated through Raf-1 by direct phosphorylation by cytoplasmic Raf-1 (35) . Both 1,25(OH)2D3 and ATRA have been shown to activate the mitogen-activated protein kinase pathway (37 , 38) , but the mechanism of potentiation of paclitaxel-induced Bcl-2 phosphorylation by these compounds remains undefined and the subject of further investigation. What roles other mechanisms play in potentiation and whether the accentuation of the ability of paclitaxel to mediate phosphorylation of Bcl-2 is physiologically significant remain to be determined (43) .
The sensitization of breast cancer cells to the killing effects of chemotherapy agents and the relative insensitivity of nontransformed mammary epithelial cells may provide a useful therapeutic modality in the treatment of breast cancer.
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FOOTNOTES |
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1 Partially supported by Grant DAMD17-94-J-4463
(to R. W.) and grants from the New Jersey State Commission on Cancer
Research (to Q. W. and R. W.). 
2 To whom requests for reprints should be
addressed, at University of Medicine and Dentistry of New Jersey-New
Jersey Medical School, Division of Medical Oncology/Hematology, MSB
I-594, 185 South Orange Avenue, Newark, NJ 07103. Phone:
(973) 972-4871; Fax: (973) 972-2384.
3 The abbreviations used are: ATRA,
all-trans retinoic acid;
1,25(OH)2D3, 1,25-dihydroxyvitamin
D3; CDK, cyclin-dependent kinase; ER, estrogen receptor;
RAR, retinoic acid receptor; RXR, retinoid X receptor; VDR, vitamin D
receptor; TUNEL, terminal deoxynucleotidyl transferase-mediated nick
end labeling.
Received 10/15/99. Accepted 2/ 1/00.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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with retinoid inhibition of growth of estrogen receptor-positive MCF-7 mammary carcinoma cells. Cancer Res., 55: 4446-4451, 1995. 1 isoform is induced by estradiol and confers retinoic acid sensitivity in human breast cancer cells. Mol. Cell. Endocrinol., 109: 77-86, 1995.[Medline]
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