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,25-Dihydroxyvitamin D3 to Inhibit Growth of DU 145 Human Prostate Cancer Cells by Blocking 24-Hydroxylase Activity1
Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, California 94305
Address all correspondence and requests for reprints to: David Feldman, M.D., Stanford University School of Medicine, Stanford, California 94305-5103. E-mail: feldman{at}cmgm.stanford.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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,25-Dihydroxyvitamin D3
[1,25-(OH)2D3] inhibits the proliferation of
many cancer cells in culture, but not the aggressive human prostate
cancer cell line DU 145. We postulated that the
1,25-(OH)2D3-resistant phenotype in DU 145
cells might result from the high levels of expression of
25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) induced by
treatment with 1,25-(OH)2D3. As this P450
enzyme initiates 1,25-(OH)2D3 catabolism, we
presumed that a high level of enzyme induction could limit the
effectiveness of the 1,25-(OH)2D3
antiproliferative action. To examine this hypothesis we explored
combination therapy with liarozole fumarate (R85,246), an imidazole
derivative currently in trials for prostate cancer therapy. As
imidizole derivatives are known to inhibit P450 enzymes, we postulated
that this drug would inhibit 24-hydroxylase activity, increasing the
1,25-(OH)2D3 half-life, thereby enhancing
1,25-(OH)2D3 antiproliferative effects on DU
145 cells. Cell growth was assessed by measurement of viable cells
using the MTS assay. When used alone, neither
1,25-(OH)2D3 (1–10 nM) nor
liarozole (1–10 µM) inhibited DU 145 cell growth.
However, when added together, 1,25-(OH)2D3 (10
nM)/liarozole (1 µM) inhibited growth 65%
after 4 days of culture. We used a TLC method to assess 24-hydroxylase
activity and demonstrated that liarozole (1–100 µM)
inhibited this P450 enzyme in a dose-dependent manner. Moreover,
liarozole treatment caused a significant increase in
1,25-(OH)2D3 half-life from 11 to 31 h. In
addition, 1,25-(OH)2D3 can cause homologous
up-regulation of the vitamin D receptor (VDR), and in the presence of
liarozole, this effect was amplified, thus enhancing
1,25-(OH)2D3 activity. Western blot analyses
demonstrated that DU 145 cells treated with
1,25-(OH)2D3/liarozole showed greater VDR
up-regulation than cells treated with either drug alone. In summary,
our data demonstrate that liarozole augments the ability of
1,25-(OH)2D3 to inhibit DU 145 cell growth. The
mechanism appears to be due to inhibition of 24-hydroxylase activity,
leading to increased 1,25-(OH)2D3 half-life and
augmentation of homologous up-regulation of VDR. We raise the
possibility that combination therapy using
1,25-(OH)2D3 and liarozole or other inhibitors
of 24-hydroxylase, both in nontoxic doses, might serve as an effective
treatment for prostate cancer. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,25-dihydroxyvitamin D3
[1,25-(OH)2D3], the active metabolite of
vitamin D, is to maintain calcium homeostasis in the body (1). Recent
findings indicate that 1,25-(OH)2D3 is also
involved in regulating cellular proliferation and differentiation in
various target tissues that possess vitamin D receptors (VDR) (1, 2, 3, 4).
1,25-(OH)2D3 and less calcemic analogs have
been shown to inhibit cell growth in both human prostate carcinoma cell
lines (5, 6, 7, 8, 9, 10, 11) and primary cultures of normal and prostate cancers (12).
However, 1,25-(OH)2D3 showed only minimal
inhibition of cell proliferation of DU 145, a human prostate cancer
cell line derived from a brain metastasis, despite the presence of
substantial amounts of VDR in this cell type (5, 7). The mechanism for
the relative unresponsiveness of DU 145 to the antiproliferative action
of 1,25-(OH)2D3 is not known. DU 145 cells have been shown to express high levels of 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) after treatment with 1,25-(OH)2D3 (5, 7). LNCaP cells can be induced to express low levels of 24-hydroxylase activity [12.6 ± 3.1 x 10-9 µmol/2 x 106 cells·30 min of 24,25(OH)2D3 produced] and are substantially growth inhibited by 1,25-(OH)2D3, whereas DU 145 cells can be induced to express very high levels of 24-hydroxylase activity (96.7 ± 39.5 x 10-9 µmol/2 x 106 cells·30 min) and are minimally growth inhibited (5, 7). As this P450 enzyme initiates the 1,25-(OH)2D3 inactivation pathway (1), we (8) and others (7, 13) have considered the possibility that rapid breakdown of 1,25-(OH)2D3 by 24-hydroxylase might be the cause of the resistant phenotype in DU 145 cells. In this study, we examine the premise that combination treatment with 1,25-(OH)2D3 and an inhibitor of 24-hydroxylase might render DU 145 cells more sensitive to the antiproliferative action of 1,25-(OH)2D3.
Combination therapy is often used to enhance the anticancer activity of various agents. Ketoconazole, liarozole, and other inhibitors of P450 enzymes may exhibit anticancer properties via several pathways, including actions on critical enzyme pathways (13, 14). In this study, we examined the possibility that combination treatment with 1,25-(OH)2D3 and liarozole, an imidazole derivative with antiprostate cancer properties (15, 16), might result in enhanced growth inhibition of DU 145 cells. Liarozole is known to inhibit several cytochrome P-450 enzymes, including retinoic acid 4-hydroxylase and aromatase (15, 17, 18). It is suspected that the former activity prolongs the half-life of retinoic acid and thereby increases the antiproliferative activity of endogenous retinoic acid when liarozole is administered to patients with prostate cancer (15, 16, 18). Here we show that 1,25-(OH)2D3 and liarozole interact synergistically to inhibit DU 145 cell growth. Our data demonstrate, for the first time, the ability of liarozole to directly inhibit 24-hydroxylase activity. The mechanism of liarozole action on DU 145 cells appears to be via inhibition of 24-hydroxylase, which causes a dual effect to prolong 1,25-(OH)2D3 half-life and to enhance up-regulation of VDR levels. Additional mechanisms may also play a role.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell culture
The DU 145 human prostate carcinoma cell line was obtained from
the American Type Culture Collection (Manassas, VA). Cells
were routinely cultured in RPMI 1640 medium supplemented with 5% FBS
and antibiotics at 37 C in a humidified atmosphere of 5%
CO2.
Assay of cell growth
Cell growth was assessed by measurement of viable cells using
the MTS assay. DU 145 cells were trypsinized and seeded at a density of
approximately 2,000 cells/well in 96-well tissue culture plates
(Falcon, Lincoln Park, NJ) in 200 µl culture medium. The cells were
allowed to attach for 24 h, and the medium was replaced with fresh
medium containing 5% FBS. Cells were then treated with vehicle
(ethanol), 1,25-(OH)2D3, and/or liarozole.
Triplicate wells were used for each experimental condition. The medium
containing vehicle or test compounds was renewed every 2 days during
the course of the experiment. After the appropriate incubation period,
the cells were processed by replacing them with fresh RPMI 1640 medium
containing MTS reagent (100 µl medium plus 20 µl MTS reagent/well).
The plates were incubated at 37 C in a humidified atmosphere of 5%
CO2 for approximately 3–4 h. The absorbance at 490 nm was
read using an automatic plate reader (Emax Precision Microplate Reader,
Molecular Devices, Menlo Park, CA) and was linear up to
the highest cell concentration tested (40,000 cells/well).
Induction of 24-hydroxylase activity
24-Hydroxylase enzyme activity was assayed in a cell suspension
system slightly modified from the method previously described (19). A
100-mm2 confluent DU 145 culture, growing under standard
conditions, was treated for various times (0.5, 3, 6, 16, and 20
h) with either vehicle (ethanol) or 10 nM
1,25-(OH)2D3. Cells were then rinsed with 10 ml
PBS and incubated with 10 ml culture medium at 37 C in a humidified
atmosphere of 5% CO2 for approximately 30 min to remove
1,25-(OH)2D3. Cells were then trypsinized and
resuspended at 106 cells/200 µl RPMI 1640 containing 10
mM HEPES with 1% FBS. The cells were incubated for 30 min
at 37 C with 1.0 nM [3H]25-OHD3
and 1.0 µM 25-(OH)D3. The reaction was
terminated by the addition of 750 µl methanol-chloroform (2:1) and 20
µl 24,25-(OH)2D3. The metabolites were
extracted three times with 200 µl chloroform. The organic extracts
were combined, dried with a Speed-Vac (Savant Instruments, Farmingdale,
NY) and dissolved in a 90:10 mixture of hexane-isopropanol. The
production of [3H]24,25-(OH)2D3
was quantitated by TLC on silica gel/aluminum foil plates developed in
methylene chloride-ethyl acetate (1:1) run with authentic standards.
The TLC strips were cut into 14 fractions and placed individually in
minicounting vials. This TLC system produced good separation of
[3H]25-(OH)2D3 from
[3H]24,25-(OH)2D3.
Inhibition of 24-hydroxylase activity
Time-course studies indicate that induction of 24-hydroxylase
activity could be detected at 3 h by 10 nM
1,25-(OH)2D3 treatment with a plateau at
approximately 20 h. Therefore, the conditions selected for
studying the inhibition of 24-hydroxylase activity by liarozole were
20-h induction, 106 cells, 1 nM
[3H]25-(OH)D3, and 30-min incubation with
various concentrations of liarozole (1, 10, 50, and 100
µM).
Determination of
1,25-(OH)2D3
half-life
The half-life of 1,25-(OH)2D3 in DU 145
cells was determined by measuring the residual unmetabolized
[3H]1,25-(OH)2D3 in the
conditioned medium at various time points after addition. Confluent DU
145 cells were treated for various times with
[3H]1,25-(OH)2D3 in the presence
or absence of liarozole. Two hundred microliters of conditioned medium
were mixed with 750 µl methanol-chloroform (2:1), and the metabolites
were extracted with 200 µl chloroform. Chloroform extraction was
repeated three times. The organic extracts were dried with a Speed-Vac
and dissolved in a 90:10 mixture of hexane-isopropanol. The
disappearance of [3H]1,25-(OH)2D3
and the production of
[3H]1,24,25-(OH)3D3 were
quantitated by a TLC system using methylene chloride-ethyl acetate
(1:3). After 145 min of development, the TLC strips were dried and
fractionated by cutting regions identified as
1,25-(OH)2D3 and
1,24,25-(OH)3D3 by comigration of authentic
standards. This TLC system gave good separation between
[3H]1,25-(OH)2D3 and
[3H]1,24,25-(OH)3D3. The Rf value
for 1,25-(OH)2D3 was 0.667, and that for
1,24,25-(OH)3D3 was 0.333.
Western blot analysis of vitamin D receptor (VDR)
Cell monolayers grown in RPMI 1640 supplemented with 5%
charcoal-stripped serum in 100-mm dishes were incubated with
ethanol vehicle, 1,25-(OH)2D3 (0.1, 1, and 10
nM), and/or liarozole (10 µM) for 4 days.
After 4 days of incubation, cells were harvested, and Western blot
analysis was performed as described previously using anti-VDR
monoclonal antibody (9A7) (20). The experiment was repeated twice with
similar results.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, A and B). The growth of DU 145 cells
was not significantly inhibited by the lower concentrations of 1 and 10
nM; however, at the highest concentration (100
nM), there was a slight growth inhibition of approximately
20% on day 6. Similarly, as shown in Fig. 1, C and D, liarozole failed
to inhibit the proliferation of DU 145 cells at 1 and 10
µM, but 100 µM resulted in 50% growth
inhibition at 4 days and 60% growth inhibition at 6 days. However, 100
µM liarozole is a toxic dose and when administered to
patients at these concentrations it causes hypervitaminosis A.
Neither 10 nM 1,25-(OH)2D3 nor 1
µM liarozole had any antiproliferative effect when used
alone. However as shown in Fig. 1, E and F, the combination treatment
caused 60% growth inhibition. These data indicate that
1,25-(OH)2D3 and liarozole interact
synergistically to inhibit DU 145 cell growth.
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). The level of 24-hydroxylase
activity in DU 145 cells is much higher than that in other cell types,
particularly compared with LNCaP cells, which are substantially
inhibited by 1,25-(OH)2D3 alone (5, 7).
Liarozole had no intrinsic ability to induce 24-hydroxylase activity.
However, liarozole can inhibit 24-hydroxylase activity. After treating
cells with 10 nM 1,25-(OH)2D3 for
20 h to induce 24-hydroxylase activity, we examined the abilities
of various concentrations of liarozole to inhibit enzyme activity by
blocking the conversion of [3H]25-OHD3 to
24,25-(OH)2D3. As shown in Fig. 3, liarozole (1, 10, 50, and 100
µM) was able to directly inhibit 24-hydroxylase activity
in a dose-dependent manner, such that 10 µM liarozole
resulted in approximately 80% inhibition of enzyme activity compared
with the activity of the induced cells in the absence of liarozole.
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10 h) compared
with that of cells treated with the combination (30 h; Fig. 4). Therefore, these data are consistent
with the observation that liarozole directly inhibits 24-hydroxylase
activity, thereby prolonging 1,25-(OH)2D3
half-life. This finding provides one possible mechanism for the
synergistic growth inhibitory effect of combination therapy with
1,25-(OH)2D3 and liarozole.
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, 1,25-(OH)2D3
alone resulted in a slight up-regulation of the VDR protein level
(2-fold). Liarozole alone had no significant effect on VDR abundance.
However, the combination of 1,25-(OH)2D3 and
liarozole resulted in a 1,25-(OH)2D3
dose-dependent increase in the VDR protein level. This effect was
observed most profoundly after a combination treatment with 10
nM 1,25-(OH)2D3 and 10
µM liarozole. This combination, as shown in Fig. 5B, resulted in a 5-fold increase in VDR abundance. Our data suggest that
an increase in the VDR protein level may serve as a second and related
mechanism, added to the prolonged 1,25-(OH)2D3
half-life, that contributes to the synergistic effect of
1,25-(OH)2D3 and liarozole inhibition of DU 145
cell growth.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As discussed earlier, at concentrations that are nontoxic, neither liarozole nor 1,25-(OH)2D3 alone substantially inhibited cell growth. Yet the combination of 1 µM liarozole and 10 nM 1,25-(OH)2D3 resulted in significant synergistic antiproliferative effects. Furthermore, this synergy is observed at a pharmacologically relevant concentration for both compounds. Based on this observation, we explored the possible mechanisms behind this synergy. We discovered that liarozole directly inhibited 24-hydroxylase activity in addition to inhibiting the already known P-450 enzymes, such as 4-hydroxylase and aromatase (15, 17, 18). As 24-hydroxylase is the initial enzyme for inactivating 1,25-(OH)2D3, we measured 1,25-(OH)2D3 half-life, and indeed, it was prolonged from 11 to 31 h. Therefore, by preventing rapid inactivation of 1,25-(OH)2D3 and prolonging the exposure time of cells to active hormone, DU 145 cells were able to respond to its antiproliferative effect. This provided the first possible mechanism for the synergistic activity of the 1,25-(OH)2D3/liarozole combination.
It is known that receptor regulation is an important mechanism for modulating target cell responsiveness to hormone (20, 23, 24). We explored the possibility that homologous up-regulation of the VDR would be enhanced in the presence of liarozole. Western blot analysis demonstrated a 5-fold increase in VDR protein level when cells were treated with 10 nM 1,25-(OH)2D3 and 10 µM liarozole compared with that after treatment with 1,25-(OH)2D3 alone. DU 145 cells treated with 1,25-(OH)2D3 alone only demonstrated a slight up-regulation of the VDR protein level. The possible explanation for this observation is that 1,25-(OH)2D3 is a potent stimulus of 24-hydroxylase activity; therefore, this would induce rapid degradation of 1,25-(OH)2D3, causing only a transient homologous up-regulation of VDR in DU 145 cells. Augmentation of VDR up-regulation has previously been reported using ketoconazole to inhibit 24-hydroxylase in a similar manner (25, 26). Enhanced VDR up-regulation is the second contributing mechanism explaining the liarozole synergistic interaction with 1,25-(OH)2D3. The increase in both ligand and receptor is a plausible mechanism for the enhanced antiproliferative activity of the 1,25-(OH)2D3/liarozole combination therapy in DU 145 cells. It is of interest that analogs of 1,25-(OH)2D3 designed to prevent 24-hydroxylation, such as 19-nor-25,26-hexafluoro-1,25-(OH)2D3, inhibit DU145 cell proliferation (9).
Our data suggest that DU 145 cells are more responsive to the antiproliferative effect of 1,25-(OH)2D3 when both its hormone and receptor are increased. Although the presence of VDR is essential for 1,25-(OH)2D3 activity (27), the level of VDR abundance in different prostate cancer cell lines by itself is not necessarily predictive of the amplitude of hormonal response (5, 28). However, in a given cell, increased abundance of receptor does appear to predict the extent of hormonal responsiveness, and increased or decreased receptor levels are usually correlated with increased and decreased responsiveness, respectively (20, 23, 24).
It should be noted that Zhao et al. have shown that combination therapy with either ketoconazole or liarozole and 1,25-(OH)2D3 or its analogs is cell type specific (13). That finding supports the concept that differences in cellular metabolism can at least partially explain the different potencies of various vitamin D analogs and differences in antiproliferative activity between different cancer cells. The fact that some cells are substantially growth inhibited by 1,25-(OH)2D3 alone (LNCaP and primary cultures) and other cells are not (DU 145) depends on a combination of factors, including, but not limited to, VDR abundance and inducible 24-hydroxylase activity (5, 7, 28). Liarozole in combination with 1,25-(OH)2D3 improves both parameters; by increasing VDR abundance and inhibiting 24-hydroxylase activity, it allows the otherwise resistant DU 145 cell to be growth arrested by 1,25-(OH)2D3. In preliminary experiments, liarozole also augmented the growth inhibitory activity of 1,25-(OH)2D3 in PC-3 and LNCaP cells, but to a much lesser extent (data not shown) than shown here for DU145 cells. The smaller augmentation was probably due to the greater antiproliferative activity of 1,25-(OH)2D3 alone in these cells (5) as well as the lesser induction of 24-hydroxylase in these cell lines (7), making the liarozole action to inhibit 24-hydroxylase less essential for 1,25-(OH)2D3-mediated growth inhibition.
Another possible mechanism for the enhanced antiproliferative effect in the presence of liarozole is its ability to inhibit retinoid metabolism, leading to increased retinoid levels (15, 18, 29). Retinoids have been shown to inhibit various cancer cell lines, including prostate cancer (30), and to be synergistic with 1,25-(OH)2D3 in inhibiting prostate cancer cell growth (10, 31). In fact, the beneficial effect of liarozole in patients with prostate cancer is attributed to this activity (15, 18, 29). We investigated the possibility that this activity might be contributing to the growth inhibition in our experiments. We treated DU 145 cells with a combination of 1,25-(OH)2D3 and increasing concentrations of retinoic acid to mimic the liarozole effect. We observed only a slight enhancement of growth inhibition (data not shown). As liarozole alone had no antiproliferative activity, and retinoids were not added in our standard combination experiments, we believe that the inhibition of retinoid metabolism does not substantially contribute to the effects that we have seen in cultured cells. However, in patients, the ability of liarozole to inhibit retinoid metabolism would be expected to further enhance the synergistic activity that we have demonstrated.
The mechanism(s) by which 1,25-(OH)2D3 inhibits the growth of prostate cancer cells is complex, multifactorial, and different in different cell lines. Several investigators have reported that treatment with 1,25-(OH)2D3 causes LNCaP cells to accumulate in the G1 phase of the cell cycle (10, 11). 1,25-(OH)2D3 also elicits a reduction of cyclin-dependent kinase 2 activity and an increase in the level of hypophosphorylated retinoblastoma (Rb) protein, which is a critical regulator of the G1/S checkpoint (11). Interestingly, DU 145 cells lack functional Rb protein. However, ectopic expression of functional Rb in DU 145 cells was not sufficient to restore the growth response to 1,25-(OH)2D3 (32). Others have found that growth inhibition of prostate cancer cells by a potent vitamin D analog involves the induction of p21waf1, p27kip1, and E-cadherin (9). In addition, we have demonstrated that 1,25-(OH)2D3 significantly regulates androgen receptor gene expression, which contributes to the regulation of LNCaP cell growth (33). Therefore, the mechanism by which 1,25-(OH)2D3 inhibits cell proliferation involves multiple signaling pathways and differs in various prostate cancer cell lines.
In summary, our data suggest that liarozole directly inhibits 24-hydroxylase activity, thereby effectively prolonging the 1,25-(OH)2D3 half-life. The increase in the 1,25-(OH)2D3 half-life resulted in enhanced up-regulation of VDR protein levels. We believe that this combination of increased 1,25-(OH)2D3 hormone levels as well as augmented VDR abundance represents the principal mechanism for the synergistic effect of 1,25-(OH)2D3 and liarozole in our experiments. However, additional mechanisms may play a role in the synergistic effect of this combination in DU 145 cells. In conclusion, the novel combination of liarozole and 1,25-(OH)2D3 therapy may serve as an effective treatment regimen for prostate cancer patients.
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Acknowledgments |
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Footnotes |
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Received June 17, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,25-dihydroxyvitamin D3 in
seven human prostatic carcinoma cell lines. Clin Cancer Res 1:997–1003[Abstract]
,25-dihydroxyvitamin D3 in
human prostate cancer cell line LNCaP involves reduction of
cyclin-dependent kinase 2 activity and persistent G1 accumulation.
Endocrinology 139:1197–1207,25-dihydroxyvitamin D3 (analogs) by cytochrome P450
enzyme inhibitors is compound- and cell-type specific. J Steroid
Biochem Mol Biol 57:197–202[CrossRef][Medline]
,25-dihydroxyvitamin D3 in the human prostatic
carcinoma cell line ALVA-31. J Steroid Biochem Mol Biol 58:277–288[CrossRef][Medline]
,25-Dihydroxyvitamin D3 actions in LNCaP human prostate
cancer cells are androgen-dependent. Endocrinology 138:3290–3298This article has been cited by other articles:
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D. Feldman, X.-Y. Zhao, and A. V. Krishnan Editorial/Mini-Review: Vitamin D and Prostate Cancer Endocrinology, January 1, 2000; 141(1): 5 - 9. [Full Text] [PDF]
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S. E. Blutt, T. J. McDonnell, T. C. Polek, and N. L. Weigel Calcitriol-Induced Apoptosis in LNCaP Cells Is Blocked By Overexpression of Bcl-2 Endocrinology, January 1, 2000; 141(1): 10 - 17. [Abstract] [Full Text] [PDF]
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M. Guzey, S. Takayama, and J. C. Reed BAG1L Enhances Trans-activation Function of the Vitamin D Receptor J. Biol. Chem., December 22, 2000; 275(52): 40749 - 40756. [Abstract] [Full Text] [PDF]
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