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Experimental Therapeutics, Preclinical Pharmacology |
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461 [L. A. M., H. M. M., D. L. R., C-P. H. Y., S. B. H.]; Laboratory of Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, New York, New York 10021 [D. M., T. R. R. P., S. J. D.]; and Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323 [M. D. K., H. A., A. B. S.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The low aqueous solubility of Taxol and the development of
clinical drug resistance have led to a search for new compounds that
may have a greater or comparable efficacy relative to Taxol. Ideally,
the new agents would be more soluble in aqueous solvents and would be
poor substrates for P-glycoprotein, a known mediator of Taxol
resistance (9)
. Several promising antimicrotubule drugs
with unique structures unrelated to that of Taxol have been reported to
have similar mechanisms of action as Taxol (Fig. 1)
. Discodermolide was isolated from a
marine sponge and reported to induce the assembly of microtubules
in vitro more rapidly than Taxol and cause mitotic arrest
and microtubule bundling (10, 11, 12)
. Discodermolide has been
predicted to be 100-fold more soluble than Taxol and to have a reduced
affinity for P-glycoprotein (13)
. Epothilones A and B,
which were isolated from a Myxobacterium fermentation
broth, were also found to induce tubulin polymerization, arrest cells
in mitosis, and cause the formation of microtubule bundles (14
, 15) . Epothilone B was reported to be more potent than Taxol and
epothilone A in promoting microtubule assembly in vitro
(15)
. The epothilones are 30 times more water soluble than
Taxol (16)
. Structure-activity studies with the
epothilones have demonstrated that the acyl region (C1-C8) is essential
for Taxol-like activity (17)
. In addition, the epothilones
retained sensitivity in P-glycoprotein-expressing cells that were
resistant to Taxol (15)
. Recently, a fourth microtubule
stabilizing agent, eleutherobin, was isolated from a marine soft coral
and shown to have activity comparable to that of Taxol
(18)
. Structure-activity analysis of eleutherobin
analogues concluded that the C8 urocanic acid moiety is required for
Taxol-like activity (19)
. Eleutherobin displayed
cross-resistance in multidrug resistant cell lines, an effect
that was reversible by verapamil, suggesting that eleutherobin is a
substrate of P-glycoprotein (19
, 20)
. Although there are
no clinical data available to date on the therapeutic activity of these
new antimitotic agents, it is their distinct chemical structures and
improved aqueous solubility that will influence their therapeutic
activity, based on the pharmacokinetics, bioavailability, and
metabolism of each drug.
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The present study examined the effects of the three new classes of antimicrotubule agents on a Taxol-resistant human non-small cell lung carcinoma cell line, A549-T12. Although isolated as a Taxol-resistant cell line, it was later found that these cells required low concentrations of Taxol (2–6 nM) for normal growth. The mechanism of resistance/dependence has not yet been determined; however, it is known that these cells do not express P-glycoprotein and do have alterations in their ß-tubulin isotype expression (30) . The primary objectives of this study were to compare and contrast the cytotoxic profiles of these three new classes of antimitotic agents in Taxol-sensitive and -resistant cell lines and to investigate their ability to substitute for Taxol in the A549-T12 cell line. The results obtained led to an extensive evaluation of the interaction between Taxol and discodermolide in four human cancer cell lines using the CI3 method.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Culture.
The drug-sensitive mouse macrophage-like cell line J774.2 and its
Taxol-resistant cell line, J7-T3-1.6, were maintained as described
previously (36)
. J7-T3-1.6 cells were grown in the
presence of 1.6 µM Taxol. Drug-sensitive and
vinblastine-resistant human ovarian carcinoma cell lines SKOV3 and
SKVLB were from Dr. V. Ling (British Columbia Cancer Research Center,
Vancouver, Canada) and were maintained as described previously
(19)
. SKVLB cells were grown in the presence of 1
µM vinblastine. Both J7-T3-1.6 and SKVLB cells
overexpress P-glycoprotein. The Taxol-resistant human non-small
cell lung carcinoma cell line A549-T12 was derived from the
drug-sensitive A549 cell line, and both cell lines were maintained as
described previously (30)
. The A549-T12 cell line was
grown in the presence of 12 nM Taxol. The human breast
carcinoma cell lines MCF-7 and MDA-MB-231 were both maintained in
Improved Modified Eagle Medium containing 10% heat-inactivated
fetal bovine serum and 1% penicillin/streptomycin.
Cytotoxicity Assays.
Cells were seeded at a density of 1 x 104
(A549) or 3 x 104 cells/ml (A549-T12) in
triplicate 6-well plates and allowed to attach for 24 h. After
incubation with the indicated drug concentrations for 72 h,
adherent cells were trypsinized and counted (Coulter counter model
ZF0031; Coulter Corp., Miami, FL), and the IC50
was determined. The SKOV3 and SKVLB cell lines were assayed in a
similar manner. Cells were seeded in triplicate at a density of 6 x 103 (SKOV3) or 12 x
103 cells/ml (SKVLB) in 6-well plates and
incubated with drug for 6 days. An accurate IC50
could only be derived after a 6-day incubation period due to the high
resistance of these cell lines. J774.2 and J7-T3-1.6 cells were plated
at a density of 2 x 104 cells/well in
96-well plates and allowed to attach overnight. Serial dilutions of
each drug were added, and the cells were incubated for 72 h.
The IC50 was determined using the CellTiter 96
AQueous nonradioactive cell proliferation assay
(Promega, Madison, WI), which correlates with the number of
live cells. Different methods to determine IC50
values were used, depending on the most accurate method for that set of
cell lines.
For the drug combination assay, A549-T12 cells were seeded at a density of 4 x 104 cells/ml in 96-well plates in the absence or presence of various Taxol concentrations plus serial dilutions of the test drug in triplicate. After a 72-h incubation, the plates were assayed using the colorimetric proliferation assay. To sustain the growth of A549-T12 cells in the absence of Taxol, cells were seeded at the higher densities described above.
Methylene Blue Assay.
Cells were seeded into 24-well plates at a density of 400 (A549) or 500
cells/well (A549-T12) and treated with different concentrations of
Taxol. After 8–11 days of growth, the medium was removed, and cells
were stained with 0.5% methylene blue (Sigma) in 50% ethanol for 20
min and then rinsed with distilled water.
Indirect Immunofluorescence.
A549-T12 cells, which were grown to subconfluence on glass coverslips
in the absence of drug or in the presence of different drugs at the
indicated concentrations, were prepared for immunofluorescence
microscopy as described previously (8)
, with the following
modifications: (a) nonspecific binding was blocked using
10% normal goat serum in PBS for 30 min at 37°C; (b)
cells were incubated with a monoclonal antibody to 
-tubulin (Sigma;
1:100 dilution; 5% normal goat serum in PBS) and then incubated with a
Cy3-conjugated antimouse IgG secondary antibody (Amersham, Arlington
Heights, IL; 1:1000 dilution); and (c) slides were analyzed
using a Zeiss Axioskop microscope (rhodamine filter) at x63
magnification.
Flow Cytometry.
For the drug substitution experiments, A549-T12 cells were seeded at a
density of 3 x 104 cells/ml in
75-cm2 flasks and treated with various drugs at
the indicated concentrations. After 48 h, both adherent and
nonadherent cells were harvested, fixed in 70% ethanol for at least 20
min, permeabilized with 0.1% Triton X-100 in PBS for 3 min, and
stained for 30 min at 37°C with 10 µg/ml propidium iodide (Sigma)
in a PBS solution containing 1 µg/ml RNase A (Boehringer Mannheim,
Indianapolis, IN). Cell cycle analysis was performed using the Becton
Dickinson FACScan and the CellQuest program. For the drug combination
studies, A549 cells were seeded at a density of 3 x
104 cells/ml in 75-cm2
flasks and grown in the presence of either Taxol, discodermolide, or
both at their equipotent ratios of 1:5, respectively, for
24 h. The cells were then prepared as described above.
Multiple Drug Effect Analysis.
Cells were seeded in triplicate into either 96-well or 24-well plates,
and after adherence, the different drugs were added (alone or in
combination) for 72 h (96 h for MDA-MB-231 cells). Tenfold serial
dilutions were performed for both single drugs and the combinations to
obtain good dosage ranges. The doses evaluated were all based on the
IC50 values of each individual drug, and combined
drug regimens were evaluated at their equipotent ratios,
i.e., equivalent to the ratio of their
IC50. Dose-response curves were determined from
cell survival data obtained using the colorimetric cell proliferation
assay (Promega) or cell counts. The CI method of Chou and Talalay
(37)
was used to analyze the nature of the interaction
between Taxol and either discodermolide or epothilone B using
Calcusyn software (Biosoft, Cambridge, United Kingdom). In summary, the
interaction of the two drugs was quantified by determining a CI at
various levels of cytotoxicity or cell kill. CI values of less than or
greater than 1 indicate synergism or antagonism, respectively, whereas
a value of 1 indicates additivity. The CIs were calculated using both
the mutually nonexclusive assumption (dissimilar mechanism of action of
both drugs) and the mutually exclusive assumption (similar mechanism of
action of both drugs). Each data point represented is the mean ±
SE of at least three independent experiments, each of which was
performed in triplicate. One-sample t tests and Wilcoxon
signed rank tests (two-tailed) were used to determine whether the means
and medians, respectively, of the CI values were significantly
different from 1.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The J7-T3-1.6 cell line, which was
selected with Taxol and overexpresses P-glycoprotein, displayed
significant cross-resistance to vinblastine and low resistance to
epothilone A, epothilone B, and discodermolide. Because of the
insensitivity of J7-T3-1.6 cells to eleutherobin, it was not possible
to accurately determine its cross-resistance in this cell line. A human
ovarian carcinoma cell line, SKOV3, displayed the highest sensitivity
to epothilone B and vinblastine, with decreased but similar responses
to Taxol, epothilone A, discodermolide, and eleutherobin. The
resistance pattern for the vinblastine-resistant SKVLB cells, which
also overexpress P-glycoprotein, indicated low-level cross-resistance
to epothilone A, epothilone B, and discodermolide. However, definite
cross-resistance to eleutherobin was exhibited. Experiments examining
the steady-state accumulation of [3H]Taxol
indicated that eleutherobin, in contrast to the epothilones and
discodermolide, was a substrate for P-glycoprotein (data not shown).
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. At 6
nM, Taxol was cytotoxic in A549 cells; however, A549-T12
cells grew normally in 6 nM Taxol. Epothilone A,
eleutherobin, and discodermolide displayed comparable activities in
A549 cells, whereas epothilone B was more potent (Table 2)
. The A549-T12 cell line exhibited
cross-resistance to epothilone A, epothilone B, and eleutherobin but no
cross-resistance to discodermolide, vinblastine, or colchicine. In the
absence of 2 nM Taxol, A549-T12 cells were 20-fold less
sensitive to discodermolide (Fig. 3)
.
When Taxol was titrated with a range of discodermolide concentrations,
the potency of discodermolide was maximal in the presence of 2
nM Taxol (Fig. 3)
. At concentrations of Taxol above 2
nM, the combination of discodermolide and Taxol
became significantly cytotoxic. Of the drugs evaluated in this study,
this effect was seen only with the combination of Taxol and
discodermolide.
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In contrast, A549-T12 cells exhibited a normal microtubule
cytoskeleton in the presence of Taxol, epothilone A, epothilone
B, and eleutherobin (Fig. 4, A–D)
, indicating that the
epothilones and eleutherobin were able to replace Taxol in this cell
line. The different concentrations of the various drugs used reflect
their distinct cytotoxic potencies. Neither discodermolide nor
vinblastine was able to substitute for Taxol in A549-T12 cells (Fig. 4, F and H)
. At higher concentrations of
discodermolide (
12 nM), the microtubules became
arranged in bundle-like formations at the periphery of the cell (Fig. 4G)
, an effect that was not observed with higher doses of
the other drugs tested (data not shown).
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. When Taxol was removed,
the resistant cells became blocked at the
G2-M-phase transition (Fig. 5E)
. In
the presence of epothilone A, epothilone B, or eleutherobin, the
A549-T12 cells also exhibited a normal cell cycle profile (Fig. 5, B–D)
. In contrast, the addition of discodermolide (2 or 6
nM) did not prevent the development of a
G2-M-phase block in the resistant cell line (Fig. 5, F and G)
. These data corroborate the
immunofluorescence results and show that discodermolide is unable to
substitute for Taxol in A549-T12 cells. At lower concentrations of
discodermolide (0.001–1 nM), the cells also
displayed a G2-M-phase block. At higher
concentrations of discodermolide (12–24 nM),
there was a substantial increase in the hypodiploid population,
resulting in the loss of the cell cycle profile (Fig. 5H)
.
A549-T12 cells also demonstrated a mitotic block in the presence of
vinblastine (data not shown).
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Taxol and Discodermolide Are a Synergistic Drug Combination in
Various Human Carcinoma Cell Lines.
To extend the observation made in A549-T12 cells that the cytotoxicity
of discodermolide was potentiated in the presence of Taxol (Fig. 3)
and
to fully evaluate the nature of the interaction of Taxol with
discodermolide, we analyzed the combination of both drugs using flow
cytometry and multiple drug effect analysis. Flow cytometric analysis
revealed an increase in the hypodiploid population of A549
drug-sensitive cells when the cells were exposed concurrently to
nanomolar concentrations of Taxol and discodermolide (up to 5
nM Taxol/25 nM discodermolide; Fig. 6
). At these concentrations, there was no
subsequent rise in the number of cells in the
G2-M phase of the cell cycle. Only at high
concentrations of both Taxol and discodermolide (10 nM
Taxol/50 nM discodermolide) was there a concomitant
increase in the number of cells in the mitotic phase (data not shown).
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summarizes the multiple drug effect
analysis of four human cancer cell lines, which is represented as
fractional cell growth inhibition (fA) as a function of the
CI. Because it could not be determined whether the interactions
between the various classes of microtubule-binding agents were mutually
exclusive or nonexclusive, the CI values were routinely calculated
using both methods, which gave almost identical results in all
experiments. The data presented here summarize the CI values based on
the more conservative assumption of mutual nonexclusion. CI values for
the combination of concurrent Taxol with discodermolide were
significantly less than 1 in all four cell lines, indicating a
synergistic drug interaction. In all cell lines tested, this
interaction was effective over a 3–4-fold log concentration of either
drug. We also evaluated the effects of sequential drug exposure, in
which either Taxol or discodermolide was administered alone for 24 h before administration of the second drug. Sequencing of the drugs
also resulted in the same magnitude of synergism as concurrent exposure
and was independent of drug schedule (data not shown). Conversely,
additive interactions were observed in all four cell lines after
concurrent exposure to both Taxol and epothilone B, indicating that the
synergism observed between Taxol and discodermolide was not shared by
other microtubule-polymerizing agents.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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During the past few years, new natural products from diverse sources and with distinct chemical structures have emerged. Despite their structural diversity, a model has been proposed that depicts a common pharmacophore linking these agents (38) . The epothilones, eleutherobin, and discodermolide all have mechanisms of action with definite similarities to those of Taxol. In our in vitro microtubule polymerization assay, Taxol, the epothilones, eleutherobin, and discodermolide all enhance the assembly of stable microtubules in the absence of GTP, which is normally required for normal in vitro microtubule assembly.
Here we report a comprehensive analysis of the cross-resistant profiles of the epothilones, eleutherobin, and discodermolide in Taxol-sensitive and -resistant cell lines, which have different mechanisms of resistance. The data indicate little, if any, cross-resistance of the epothilones and discodermolide in Taxol-resistant cell lines that overproduce P-glycoprotein. These data are consistent with the results obtained from the Taxol accumulation study in a Taxol-resistant murine cell line in which the epothilones and discodermolide were unable to reverse the reduction in Taxol accumulation, reinforcing the finding that they are not substrates for P-glycoprotein.
Our study has taken advantage of an interesting cell line, A549-T12, that was isolated in our laboratory as a Taxol-resistant cell line and is maintained in 12 nM Taxol. A549-T12 cells are approximately 9-fold resistant to Taxol and do not overproduce P-glycoprotein. On further examination, it was observed that the cells grew poorly, if at all, in the absence of Taxol. We report that after 48 h in the absence of Taxol, the microtubule cytoskeleton of A549-T12 cells is diminished, and the cells undergo a mitotic block; however, the addition of Taxol after 48 h reverses these abnormalities. It appears that the cells have modified their normal biochemistry to survive in the presence of the drug to such an extent that they have become dependent on the drug for normal growth. A possible mechanism for this phenomenon may be the selection of a variant form of tubulin whose microtubules are normally unstable but thrive in the presence of low concentrations of Taxol. Taxol-requiring Chinese hamster ovary cell lines have been described previously (39) .
The availability of the A549-T12 cell line has allowed us to distinguish discodermolide from the other antimitotic compounds described in this study. The epothilones and eleutherobin demonstrated cross-resistance in A549-T12 cells and could substitute for Taxol, reversing the G2-M-phase block that is induced after Taxol withdrawal. This is in contrast to what we observed with discodermolide, which did not exhibit cross-resistance and is unable to substitute for Taxol. In fact, it is clear that in A549-T12 cells, low concentrations of Taxol are required for discodermolide to exert its maximum cytotoxic effects, thereby suggesting that the cellular substrate for discodermolide is a microtubule whose conformation has been modified by Taxol. A previous report has alluded to the requirement of an intact microtubule cytoskeleton for discodermolide binding to occur in cells (11) . Vinblastine, like Taxol, is an antimitotic agent whose cellular target is also the tubulin/microtubule system. In contrast to Taxol, its major binding site is the tubulin dimer, and in vitro, the drug promotes microtubule depolymerization (40) . Although vinblastine is an excellent substrate for P-glycoprotein, and we observed high cross-resistance in the cell lines overproducing P-glycoprotein, there is no cross-resistance in the A549-T12 cell line. The cross-resistance data with the various antimitotic agents in A549-T12 cells are intriguing and require a thorough understanding of the mechanisms of resistance and dependence in the A549-T12 cell line.
Median effect analysis using the CI method of Chou and Talalay (37) confirmed a synergistic interaction between Taxol and discodermolide. In contrast, the combination of discodermolide and epothilone B was additive, indicating that there is a specific relationship between Taxol and discodermolide resulting in synergistic cytotoxicity. We have also shown that low concentrations of Taxol and discodermolide caused an increase in the hypodiploid population of cells without a corresponding increase in the G2-M-phase cell population. We therefore speculate that the synergism observed is probably due to the potentiation of apoptosis by this drug combination, although the precise mechanism remains to be determined.
Previous work has shown a schedule-dependent synergistic interaction between Taxol and vinblastine, both of which bind to separate distinct targets on the tubulin macromolecule (41) . Here we describe synergy between Taxol and discodermolide, two drugs that apparently bind to the same or overlapping sites on ß-tubulin (11) . It is uncommon for two drugs that bind to identical sites on the same target to synergize when administered concurrently or in sequence. More often, this type of drug combination results in additivity (similar to what we observe with Taxol and epothilone B) or antagonism because both drugs cannot bind the same site simultaneously. In A549-T12 cells, discodermolide does not exhibit cross-resistance, unlike the epothilones and eleutherobin. Furthermore, it has been reported that epothilone A-resistant ovarian carcinoma cells that do not express P-glycoprotein exhibit cross-resistance to Taxol, baccatin, and taxotere but do not exhibit cross-resistance to discodermolide (42) .4 Taken together, these findings imply that the Taxol and discodermolide binding sites may be overlapping rather than identical.
Alternatively, the mechanism of synergy may be completely unrelated to
the tubulin-binding properties of discodermolide, which was originally
described in the literature as an immunosuppressant (43)
.
In addition, discodermolide has been shown to modulate the expression
of interleukin 2 receptors, which in turn regulate Fas-induced and
nuclear factor 
B-induced apoptosis, suggesting a hypothetical
mechanism by which the synergy we have observed with Taxol and
discodermolide could potentiate apoptosis (44)
.
At the present time, there is no information available on the antitumor activity of these new drugs in human tumors, and it will be of great interest to compare them with Taxol. Our data suggest that Taxol and discodermolide may represent a synergistic drug combination that merits exploration.
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FOOTNOTES |
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1 Supported in part by USPHS Grants CA 39821 and
CA 77263 (both to S. B. H.) and by Cancer Core Support Grant CA
13330; by GM-29028 (to A. B. S.); and by AI16943 and CA 28824 (both
to S. J. D.). L. A. M. was supported in part by the National
Institute of General Medical Services Training Program in
Pharmacological Sciences Grant 5T32 GM07260. 
2 To whom requests for reprints should be
addressed, at Department of Molecular Pharmacology, Albert Einstein
College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Phone:
(718) 430-2163; Fax: (718) 430-8922; E-mail: shorwitz{at}aecom.yu.edu
3 The abbreviation used is: CI, combination
index.
4 P. Giannakakou, personal communication.
Received 8/23/99; revised 12/14/99; accepted 12/20/99.
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A. Goncalves, D. Braguer, K. Kamath, L. Martello, C. Briand, S. Horwitz, L. Wilson, and M. A. Jordan Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics PNAS, September 13, 2001; (2001) 191388598. [Abstract] [Full Text] [PDF]
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C.-P. H. Yang and S. B. Horwitz Taxol Mediates Serine Phosphorylation of the 66-kDa Shc Isoform Cancer Res., September 1, 2000; 60(18): 5171 - 5178. [Abstract] [Full Text]
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P. Giannakakou and T. Fojo Discodermolide: Just Another Microtubule-stabilizing Agent? No! A Lesson in Synergy Clin. Cancer Res., May 1, 2000; 6(5): 1613 - 1615. [Full Text]
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A. Goncalves, D. Braguer, K. Kamath, L. Martello, C. Briand, S. Horwitz, L. Wilson, and M. A. Jordan Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics PNAS, September 25, 2001; 98(20): 11737 - 11742. [Abstract] [Full Text] [PDF]
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, no Taxol; •, 2 nM Taxol.
