| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics |
Department of Biochemistry and Molecular Biology, College of Pharmacy [J-W. H., S. H. A., S. H. P., S. Y. W., G-U. B., D-W. S., H-K. K., H-W. L.], and Department of Genetic Engineering, College of Life Science and Natural Resources [S. H.], Sungkyunkwan University, Suwon 440-746; Department of Pharmacology, College of Medicine, Konyang University, Nonsan 320-711 [H. Y. L.]; and School of Agricultural Biotechnology, Seoul National University, Suwon 441-744 [Y-W. L.], Korea
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
|---|
Experiments searching for detransforming activity with oncogene-transformed cells led to the identification of various natural and synthetic compounds, such as NaB (32) , trapoxin (33) , trichostatin A (34) , depudecin (35) , FR901228 (36) , oxamflatin (37) , and MS-27-275 (38) . In addition to their ability to revert the cell morphology of various oncogene-transformed cells or cancer cells to apparently normal cells, these compounds have also been shown to exhibit HDAC-inhibitory activity and cell cycle arrest, leading to the suggestion that the morphological reversion of transformed cells was the result of their HDAC inhibitory activity. Although the precise mechanism has not been elucidated, the inhibitory effects of these compounds on cell cycle appears to be the result of selective induction of endogenous genes that play significant roles in G1-S progression of the cell cycle (37) . Therefore, HDAC inhibitors have been considered to be a novel class of cancer treatment agent.
Apicidin is a novel cyclic tetrapeptide with a potent broad spectrum of antiprotozoal activity against apicomplexan parasites (39) , and its structure is related to trapoxin, a potent HDAC inhibitor. Therefore, the antiparasitic activity of apicidin appears to be attributable to inhibition of apicomplexan HDAC at low nanomolar concentrations. Indeed, the potent HDAC-inhibitory activity of apicidin prompted us to evaluate apicidin as a potential antiproliferative agent. Here, we report characteristic features of apicidin and its strong antiproliferation efficacy.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
|---|
Cell Culture and Preparation of Cell Extracts.
HeLa, a human cervix cancer cell line; v-ras-transformed
NIH3T3, a mouse fibroblast cell line; Colon 3.1-M26, a mouse colon
carcinoma cell line; MG63, a human osteosarcoma cell line; and MCF-7, a
human breast cancer cell line, were cultured in DMEM (Life
Technologies, Inc.), supplemented with 10% fetal bovine serum (HyClone
Laboratories, Logan, UT), and 1% penicillin/streptomycin (Life
Technologies, Inc.). A2058, a human melanoma cell line; AGS, a human
gastric adenocarcinoma cell line; HBL-100, a human breast cancer cell
line; and CCD-18Co, a human normal colon cell line, were cultured in
RPMI 1640 (Life Technologies, Inc.), 10% fetal bovine serum, and 1%
penicillin/streptomycin. HeLa cells were incubated with 0.01, 0.1, 0.5,
1, and 2 µg/ml apicidin or 1 mM NaB (Sigma
Chemical Co., St. Louis, MO) in culture medium for 24 h. In some
experiments, proliferating HeLa cells were treated with 1 µg/ml
apicidin or 1 mM NaB for 24 h. At this time
point, the medium was removed, cells were washed thoroughly with PBS,
and medium with no apicidin or NaB was added back. Cells were then
incubated further until the end of the 24-, 48-, and 150-h periods. The
controls were prepared by incubating cells for the corresponding period
in complete medium containing DMSO instead of the agents. After
stimulation, cells were rinsed twice with ice-cold wash buffer
containing 50 mM Tris-HCl (pH 7.5), 120
mM NaCl, 20 mM NaF, 1
mM EDTA, 5 mM EGTA, 15
mM sodium PPi, 30
mM p-nitrophenyl phosphate, 1
mM benzamidine, and 0.1 mM
phenylmethylsulfonyl fluoride, and were then extracted in the same
buffer containing 1% NP40. Cells were collected with a plastic
scraper, homogenized, and cleared by centrifugation at 4°C for 15 min
at 15,000 x g. The protein concentration was
measured by the Bradford method, with BSA as the standard. Aliquots of
the supernatants were frozen in liquid nitrogen and stored at -70°C.
Cell Growth Inhibition Assay.
To examine the effect of apicidin on the proliferation of mouse and
human cancer cell lines, cell growth inhibition was assessed with the
SRB protein dye assay 48 h after cell seeding at 1 x 105 cells/well in 6-well plates in
complete growth medium (41)
. In brief, exponentially
growing cells were treated with 0.01, 0.1, 0.5, 1, and 2 µg/ml
apicidin for 48 h, and the culture medium was removed. The cells
were then fixed by incubating with 1 ml of 10% trichloroacetic acid at
4°C for 1 h, followed by five washes with distilled water. After
complete air-drying of the plate, 0.4% SRB solution in 1% glacial
acetic acid was added at room temperature for 30 min to stain the
cells. Subsequently, the plate was washed five times with 1% glacial
acetic acid and allowed to air-dry overnight. Tris-HCl (1 ml, 10
mM) was then added to each well to dissolve the SRB bound
to cellular protein; the SRB absorbance was then measured at 490
nm on an EL 808 ultra microplate reader (Bio-Tek Instruments, Inc.,
Winooski, VT). The absorbance is proportional to the number of cells
attached to the culture plate. Therefore, the results of SRB represent
the antiproliferative effect of apicidin on mouse and human cancer cell
lines.
HDAC Assay.
The mammalian HDAC was partially purified from HeLa cells
(42)
and assayed for HDAC activity as described previously
(43)
by incubation with
[3H]acetyl-labeled histones as the substrate
for 20 min at 37°C. The released [3H]acetic
acid was extracted with ethyl acetate, quantitated by scintillation
counting, and used as a measure of HDAC activity.
Immunoblotting.
HeLa cells were incubated with 0.01, 0.1, 0.5, 1, and 2 µg/ml
apicidin or 1 mM NaB in culture medium for 24 h. Cell
lysates were boiled in Laemmli sample buffer for 3 min, and 30 µg of
each total protein were subjected to SDS-PAGE on 15% slab gels
for the analysis of gelsolin, cyclin D1, CDK2,
p21WAF1/Cip1, HDAC1, and p53, except for pRb,
which was run on a 7.5% slab gel. Proteins were transferred to
polyvinylidene difluoride membranes, and membranes were blocked for 30
min in PBS containing 0.1% Tween 20 (PBS-T) and 5% (w/v) dry skim
milk powder, and incubated overnight with antigelsolin (Transduction
Laboratories), -cyclin D1 (Upstate Biotechnology Inc.), -CDK2 (Upstate
Biotechnology), -p21WAF1/Cip1 (Santa Cruz
Biotechnologies, Inc.), -HDAC1 (Upstate Biotechnology), -p53 (Upstate
Biotechnology), and -pRb (PharMingen) antisera. The membranes were then
washed with PBS-T and incubated for 2 h with an antirabbit or an
antimouse secondary antibody. Bound antibodies were detected with the
enhanced amplified alkaline phosphatase immunoblot system (Bio-Rad).
Histone Isolation and Immunodetection of Acetylated Histone H4.
HeLa cells were incubated with 0.01, 0.1, 0.5, 1, and 2 µg/ml
apicidin or 0.1% DMSO in culture medium. After 24 h, cells were
trypsinized, and histones were isolated by the established techniques
(32)
. Each histone sample (50 µg) was dialyzed
and concentrated, using a Microcon-3 (Amicon, Inc), against 0.1
M acetic acid and distilled water, respectively, and the
samples were resuspended in Laemmli sample buffer for 3 min and
subjected to 10–20% Tricine SDS-PAGE for the determination of
acetylated histone H4. Acetylated histone H4 was detected by
anti-acetyl histone H4 antiserum (Upstate Biotechnology) at 1:2000
dilution in 5% dry skim milk powder in PBS-T and visualized as
described above.
Analysis of DNA Synthesis and Cell Cycle.
DNA synthesis was measured by [3H]thymidine
incorporation assay as described previously (44)
. HeLa
cells were plated at 20,000 cells/well in 24-well plates in complete
growth medium and incubated for 24 h. The medium was removed, and
the cells were cultured for an additional 16 h with 1 µg/ml
apicidin. Two hundred fifty nl of 1 mCi/ml
methyl-[3H]thymidine (Amersham
Pharmacia Biotech) were added to each well, and the cells were
incubated for an additional 8 h. The cells were fixed and washed
twice with ice-cold trichloroacetic acid (10%). The precipitated
material was solubilized with 0.2 N NaOH, and the incorporated
radioactivity was counted by liquid scintillation; results are
expressed as percentage of the maximal
[3H]thymidine incorporated in the presence of
0.1% DMSO alone. To analyze the effect of apicidin on cell cycle
progression, the DNA content profile of a given population was
determined by flow cytometry according to the method described by
Noguchi and Browne (45)
. Briefly, after fixation with 70%
ethanol and treatment with 0.25 µg/ml RNase, nuclei were stained with
50 µg/ml propidium iodide, and the relative DNA content was measured
using a BRYTE HS system (Bio-Rad Laboratories) and a ModFit LT (Verity
Software House, Inc., Topsham, ME).
|
RESULTS AND DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
|---|
, cell growth was inhibited to various degrees in the presence of
apicidin, having half-maximum effects between 1.8 and 0.1 µg/ml.
Apicidin showed a marked antiproliferative effect against AGS, a human
stomach cancer cell, and v-ras-transformed NIH3T3 cells
(IC50 < 0.2 µg/ml), and a moderate effect
against MG63, a human osteosarcoma cell line, MCF7, a human breast
cancer cell, and ZR-75-1, a human breast carcinoma cell
(IC50 > 1 µg/ml). However, the growth of the
cancer cell lines tested was more sensitive to apicidin than the normal
cell line, CCD-18Co (a normal human colon cell line), for which the
IC50 value of apicidin was 2.36 µg/ml. The
results indicate that apicidin has a broad spectrum of
antiproliferative activity toward various cancer cell lines. To further
analyze the antiproliferative effect of apicidin, its effect on the
cell cycle progression was next investigated. Thus, HeLa cells, an
epithelium-like carcinoma cell line from human cervix, were
treated with various concentrations of apicidin for 24 h and were
incubated with [3H]thymidine for the last
8 h. Treatment of asynchronous HeLa cell cultures with apicidin
resulted in a dose-dependent inhibition of
[3H]thymidine incorporation, with 50%
inhibition at 1 µg/ml and maximal inhibition at 2 µg/ml, indicating
significant inhibition of G1-S progression (Fig. 1A)
. Further analysis of the effect of apicidin on the
distribution of cell population showed effects similar to the above
result (Fig. 1B)
. Apicidin treatment increased the number of
cells at G0-G1 from 45% to
70%, whereas the cells at S phase decreased from 35% to 8%,
indicating inhibition of the cell cycle at
G0-G1. Taken together, the
results indicate that the antiproliferative activity of apicidin might
be attributed to cell cycle arrest at G1 phase in
HeLa cells.
|
|
, HeLa cells have an oval or polygonal appearance in the absence of
apicidin; however, they were dramatically changed to an elongated shape
with filamentous protrusions after treatment with increasing
concentrations of apicidin (up to 2 µg/ml). The production of
filamentous protrusions increased in a dose-dependent manner. The
changes produced by NaB, another HDAC inhibitor, on the morphology of
HeLa cells were in appearance similar to those of apicidin,
indicating that morphological reversion in HeLa cells by apicidin could
result from the inhibition of HDAC. In addition, the morphological
change seemed to require de novo protein and RNA synthesis
because cycloheximide and actinomycin D significantly inhibited the
detransforming activity of apicidin (Fig. 2)
. The requirements of
de novo protein and RNA synthesis for morphological changes
induced by apicidin are very similar to those of oxamflatin
(37)
. v-ras-transformed NIH3T3 cells also
reverted from a spindle-like to a normal morphology after treatment
with apicidin, similar to that observed with depudecin (Ref.
35
; data not shown). The broad spectrum of detransforming
activity of apicidin implies possible roles in stress fiber formation
and cell growth control.
|
, HDAC activity was inhibited in a concentration-dependent
manner, with 50% inhibition at 0.003 µg/ml (5
nM) and maximal inhibition at 0.025 µg/ml (40
nM). The IC50 of apicidin
is lower than those of NaB (119 µM; Ref.
37
), oxamflatin (15.7 nM; Ref.
37
), depudecin (4.7 µM; Ref.
35
), and MS-27-275 (2 µM; Ref.
38
), indicating that the novel cyclic tetrapeptide has
potent HDAC inhibitory activity.
|
.
Proliferating HeLa cells had low levels of acetylated histone H4 in the
absence of apicidin. However, the acetylation of histone H4 was
increased in a dose-dependent manner, reaching maximum at 0.5 µg/ml
of apicidin. Taken together, the in vivo effect of apicidin on nuclear histone acetylation is very closely correlated with the in vitro effect of apicidin on HDAC activity, indicating that the induction of histone hyperacetylation by apicidin most likely results from inhibition of histone deacetylase. Although transient histone H4 acetylation by HDAC inhibitors, including NaB and trichostatin A (47) , was observed in human keratinocytes, the histone hyperacetylation in HeLa cells by apicidin was persistent up to 48 h (data not shown).
Changes of Endogenous Gene Expression by Apicidin.
Apicidin caused not only morphological changes (Fig. 2)
but also cell
cycle arrest (Fig. 1)
, similar to other inhibitors [trichostatin A
(34)
, trapoxin (33)
, FR901228
(36)
, and oxamflatin (37)
]. Specifically,
morphological changes of HeLa cells by apicidin required de
novo protein and RNA synthesis (Fig. 2)
, indicating the
involvement of proteins in the alteration of cellular shape and
cytoskeletal architecture. We therefore examined the effect of apicidin
on the expressions of gelsolin, a Ca2+-dependent
actin filament-severing and capping protein (48)
that
controls the length of actin filaments and cell shape and motility
(49)
. The expression of gelsolin in HeLa cells was
obviously up-regulated by apicidin, which occurred at concentration of
0.5 µg/ml, and no further induction was observed at higher
concentrations, indicating a threshold effect (Fig. 4)
. This effect was very similar to the effect on morphology
(compare Fig. 4
with Fig. 2
), suggesting that the increase in gelsolin
produced by apicidin could be responsible for the apicidin-mediated
detransforming activity. This suggestion is supported by the
observations that HDAC inhibitor-induced morphological changes were
suppressed by microinjection of antigelsolin antibodies
(50)
and that malignant transformation was correlated with
decreased expression of gelsolin (51
, 52)
.
|
, apicidin was found to inhibit
G1-S progression in the cell cycle of HeLa cells.
Because acetylation and deacetylation of histone have been shown to
play an important role in the regulation of gene expression in
eukaryotic cells (9, 10, 11
, 17 , 26, 27, 28)
, cell cycle arrest at
G1 phase by apicidin might be attributable to
alteration of the expression of genes important to
G1-S progression. To test this possibility, we
determined the levels of cyclin D1, CDK2,
p21WAF1/Cip1, HDAC1, and p53, as well as the
phosphorylation of Rb by immunoblot analysis. The protein levels of
cyclin D1, CDK2, HDAC1, p53, and Rb were not affected by the addition
of apicidin for 24 h (Fig. 4)
. On the other hand, the expression
of p21WAF1/Cip1, a CDK inhibitor, was markedly
up-regulated by apicidin at 0.5 µg/ml but did not appear to be
further induced at higher concentrations, as observed in the expression
of gelsolin by apicidin (Fig. 4)
. In addition, Rb was
hyperphosphorylated in the absence of apicidin as monitored by its
slower migration in immunoblots of one-dimensional SDS-PAGE; apicidin
treatment, however, caused the collapse of the slower migration of a
family of bands into a single band, indicating dephosphorylation of Rb
protein. Induction of p21WAF1/Cip1 by apicidin
was well correlated with a decrease in Rb phosphorylation.
p21WAF1/Cip1 expression is usually controlled at
the transcriptional level by both p53-dependent and -independent
mechanisms (53)
. In HeLa cells,
p21WAF1/Cip1 appeared to be expressed by a
p53-independent mechanism because expression of p53 was not paralleled
by that of p21WAF1/Cip1. The
G1 arrest of HeLa cells may be caused by
induction of p21WAF1/Cip1, which binds to CDKs
and inhibits their activity, leading to hypophosphorylation of Rb
protein. This hypothesis is supported by similar results obtained with
other HDAC inhibitors such as oxamflatin (37)
and trapoxin
(54)
.
Irreversible Effect of Apicidin on HDAC, Expression of
p21WAF1/Cip1 and Gelsolin, Growth Arrest, and Morphological
Reversion.
Although trapoxin and trichostatin A exerted almost the same biological
effect on the cell cycle and differentiation, their modes of inhibition
appear to be different: trichostatin A inhibits HDAC irreversibly, and
trapoxin reversibly (33
, 55)
. These observations prompted
us to examine the effect of withdrawal of apicidin on morphological
reversion, expression of p21WAF1/Cip1 and
gelsolin, growth arrest, and HDAC activity. HeLa cells were treated
with apicidin for 24 h. Apicidin was then withdrawn by exchanging
culture medium with fresh medium with no apicidin, and the cells were
then allowed to grow further for various times. Morphological reversion
of HeLa cells to a characteristically elongated cell with filamentous
protrusions had not occurred by 24 h after the withdrawal
of apicidin and was sustained until 7 days (Fig. 5)
. In contrast, after withdrawal of NaB, HeLa cells reverted to a shape
with an oval or polygonal appearance, as before the addition of
apicidin (Fig. 5)
.
|
, withdrawal of NaB from the reaction mixture by
dialysis resulted in a gradual recovery of HDAC activity during
dialysis, with 
70% of the initial enzyme activity recovered.
However, when cells were treated with apicidin, the enzyme activity was
never recovered even after 1 day of dialysis. Consistent with these
data, histone H4 extracted from nuclei was found to be significantly
hyperacetylated up to 7 days after the removal of apicidin (Fig. 6A)
, whereas hyperacetylation of histone H4 was markedly
decreased shortly after the withdrawal of NaB (Fig. 6A)
.
These results suggest that the effect of apicidin on morphological
changes and HDAC activity in vitro and in vivo is
irreversible and that the morphological change and inhibition of HDAC
are closely associated. However, it appears that the reversibility was
not absolute: 7 days after the removal of apicidin,
p21WAF1/Cip1 levels reverted to those observed in
the absence of apicidin, whereas gelsolin apparently did not revert, as
determined by immunoblot analysis (Fig. 6A)
. Cyclin D1
concentrations, which were not affected by apicidin (Fig. 4)
,
remained unaltered under any experimental condition (Fig. 6A)
. The number of cells, however, appeared to have
increased, as observed microscopically, 7 days after apicidin was
removed, although the elongated cell shape with filamentous protrusions
remained unaltered (Fig. 5)
. We thus determined the cell number through
7 days after withdrawal of apicidin. Although the growth of cultures
from which apicidin was removed was significantly inhibited up to
48 h after withdrawal of apicidin, growth gradually recovered to
40% of that of the culture not treated with apicidin (Fig. 7)
. Consistent with these data, DNA synthesis was attenuated up to
48 h after apicidin was removed (Fig. 6C)
, whereas
withdrawal of NaB led to a rapid recovery of DNA synthesis, to 80%
of the initial DNA synthesis. Therefore, it seems possible that the
irreversible effect of apicidin might be attributed, in part, to the
slow dissociation rate of the enzyme-inhibitor complex, resulting in
apparent HDAC inhibition. Although the irreversible inhibitory effect
of apicidin on the development of intracellular apicomplexan parasites
in vitro has been observed previously (39)
, the
mechanism by which apicidin inhibits HDAC remains to be explored.
|
|
|
FOOTNOTES |
|---|
1 Supported by Research Grant KPRC-99-KA-1-3 from
Kyonggi Pharmaceutical Research Center. This work forms partial
fulfillment of requirement of the Ph.D. degree of S. H. A. at
Sungkyunkwan University, Seoul, Korea. 
2 These authors contributed equally to this
work.
3 To whom requests for reprints should be
addressed, at College of Pharmacy, Sungkyunkwan University, 300
Chonchon-dong, Changan-ku Suwon, 440-746, Kyunggi-do, Korea. Phone:
82-31-290-7702; Fax: 82-31-290-7722; E-mail: hylee{at}yurim.skku.ac.kr
4 The abbreviations used are: HAT, histone
acetyltransferase; HDAC, histone deacetylase; CDK, cyclin-dependent
kinase; NaB, sodium n-butyrate; SRB, sulforhodamine B.
Received 3/29/00. Accepted 8/28/00.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  J. S. You, J. K. Kang, D.-W. Seo, J. H. Park, J. W. Park, J. C. Lee, Y. J. Jeon, E. J. Cho, and J.-W. Han Depletion of Embryonic Stem Cell Signature by Histone Deacetylase Inhibitor in NCCIT Cells: Involvement of Nanog Suppression Cancer Res., July 15, 2009; 69(14): 5716 - 5725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-N. Kim, N. H. Kim, W. Lee, D.-W. Seo, and Y. K. Kim Histone Deacetylase Inhibitor Induction of P-Glycoprotein Transcription Requires Both Histone Deacetylase 1 Dissociation and Recruitment of CAAT/Enhancer Binding Protein {beta} and pCAF to the Promoter Region Mol. Cancer Res., May 1, 2009; 7(5): 735 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-C. Lin, J.-H. Lin, C.-W. Chou, Y.-F. Chang, S.-H. Yeh, and C.-C. Chen Statins Increase p21 through Inhibition of Histone Deacetylase Activity and Release of Promoter-Associated HDAC1/2 Cancer Res., April 1, 2008; 68(7): 2375 - 2383. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Di Renzo, M. L. Broccia, E. Giavini, and E. Menegola Relationship between Embryonic Histonic Hyperacetylation and Axial Skeletal Defects in Mouse Exposed to the Three HDAC Inhibitors Apicidin, MS-275, and Sodium Butyrate Toxicol. Sci., August 1, 2007; 98(2): 582 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Y. Archer, J. Johnson, H.-J. Kim, Q. Ma, H. Mou, V. Daesety, S. Meng, and R. A. Hodin The histone deacetylase inhibitor butyrate downregulates cyclin B1 gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells Am J Physiol Gastrointest Liver Physiol, October 1, 2005; 289(4): G696 - G703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Acharya, A. Sparreboom, J. Venitz, and W. D. Figg Rational Development of Histone Deacetylase Inhibitors as Anticancer Agents: A Review Mol. Pharmacol., October 1, 2005; 68(4): 917 - 932. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. N. Bhalla Epigenetic and Chromatin Modifiers As Targeted Therapy of Hematologic Malignancies J. Clin. Oncol., June 10, 2005; 23(17): 3971 - 3993. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Varshochi, F. Halim, A. Sunters, J. P. Alao, P. A. Madureira, S. M. Hart, S. Ali, D. M. Vigushin, R. C. Coombes, and E. W.-F. Lam ICI182,780 Induces p21Waf1 Gene Transcription through Releasing Histone Deacetylase 1 and Estrogen Receptor {alpha} from Sp1 Sites to Induce Cell Cycle Arrest in MCF-7 Breast Cancer Cell Line J. Biol. Chem., February 4, 2005; 280(5): 3185 - 3196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hu and N. H. Colburn Histone Deacetylase Inhibition Down-Regulates Cyclin D1 Transcription by Inhibiting Nuclear Factor-{kappa}B/p65 DNA Binding Mol. Cancer Res., February 1, 2005; 3(2): 100 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-H. Kim, J.-W. Park, J.-Y. Lee, and T. K. Kwon Sodium butyrate sensitizes TRAIL-mediated apoptosis by induction of transcription from the DR5 gene promoter through Sp1 sites in colon cancer cells Carcinogenesis, October 1, 2004; 25(10): 1813 - 1820. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Park, Y. Jung, T. Y. Kim, S. G. Kim, H.-S. Jong, J. W. Lee, D.-K. Kim, J.-S. Lee, N. K. Kim, T.-Y. Kim, et al. Class I Histone Deacetylase-Selective Novel Synthetic Inhibitors Potently Inhibit Human Tumor Proliferation Clin. Cancer Res., August 1, 2004; 10(15): 5271 - 5281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Maggio, R. R. Rosato, L. B. Kramer, Y. Dai, M. Rahmani, D. S. Paik, A. C. Czarnik, S. G. Payne, S. Spiegel, and S. Grant The Histone Deacetylase Inhibitor MS-275 Interacts Synergistically with Fludarabine to Induce Apoptosis in Human Leukemia Cells Cancer Res., April 1, 2004; 64(7): 2590 - 2600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Rosato, J. A. Almenara, C. Yu, and S. Grant Evidence of a Functional Role for p21WAF1/CIP1 Down-Regulation in Synergistic Antileukemic Interactions between the Histone Deacetylase Inhibitor Sodium Butyrate and Flavopiridol Mol. Pharmacol., March 1, 2004; 65(3): 571 - 581. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Atadja, L. Gao, P. Kwon, N. Trogani, H. Walker, M. Hsu, L. Yeleswarapu, N. Chandramouli, L. Perez, R. Versace, et al. Selective Growth Inhibition of Tumor Cells by a Novel Histone Deacetylase Inhibitor, NVP-LAQ824 Cancer Res., January 15, 2004; 64(2): 689 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-W. Cheong, S. Y. Chong, J. Y. Kim, J. I. Eom, H. K. Jeung, H. Y. Maeng, S. T. Lee, and Y. H. Min Induction of Apoptosis by Apicidin, a Histone Deacetylase Inhibitor, via the Activation of Mitochondria-Dependent Caspase Cascades in Human Bcr-Abl-Positive Leukemia Cells Clin. Cancer Res., October 15, 2003; 9(13): 5018 - 5027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Di Padova, T. Bruno, F. De Nicola, S. Iezzi, C. D'Angelo, R. Gallo, D. Nicosia, N. Corbi, A. Biroccio, A. Floridi, et al. Che-1 Arrests Human Colon Carcinoma Cell Proliferation by Displacing HDAC1 from the p21WAF1/CIP1 Promoter J. Biol. Chem., September 19, 2003; 278(38): 36496 - 36504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Rosato, J. A. Almenara, and S. Grant The Histone Deacetylase Inhibitor MS-275 Promotes Differentiation or Apoptosis in Human Leukemia Cells through a Process Regulated by Generation of Reactive Oxygen Species and Induction of p21CIP1/WAF1 1 Cancer Res., July 1, 2003; 63(13): 3637 - 3645. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Lagger, A. Doetzlhofer, B. Schuettengruber, E. Haidweger, E. Simboeck, J. Tischler, S. Chiocca, G. Suske, H. Rotheneder, E. Wintersberger, et al. The Tumor Suppressor p53 and Histone Deacetylase 1 Are Antagonistic Regulators of the Cyclin-Dependent Kinase Inhibitor p21/WAF1/CIP1 Gene Mol. Cell. Biol., April 15, 2003; 23(8): 2669 - 2679. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Witt, S. Monkemeyer, G. Ronndahl, B. Erdlenbruch, D. Reinhardt, K. Kanbach, and A. Pekrun Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin Blood, March 1, 2003; 101(5): 2001 - 2007. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fournel, M.-C. Trachy-Bourget, P. T. Yan, A. Kalita, C. Bonfils, C. Beaulieu, S. Frechette, S. Leit, E. Abou-Khalil, S.-H. Woo, et al. Sulfonamide Anilides, a Novel Class of Histone Deacetylase Inhibitors, Are Antiproliferative against Human Tumors Cancer Res., August 1, 2002; 62(15): 4325 - 4330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Taniura, H. Kamitani, T. Watanabe, and T. E. Eling Transcriptional Regulation of Cyclooxygenase-1 by Histone Deacetylase Inhibitors in Normal Human Astrocyte Cells J. Biol. Chem., May 3, 2002; 277(19): 16823 - 16830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Tsubaki, V. Hwa, S. M. Twigg, and R. G. Rosenfeld Differential Activation of the IGF Binding Protein-3 Promoter by Butyrate in Prostate Cancer Cells Endocrinology, May 1, 2002; 143(5): 1778 - 1788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kamitani, S. Taniura, K. Watanabe, M. Sakamoto, T. Watanabe, and T. Eling Histone acetylation may suppress human glioma cell proliferation when p21WAF/Cip1 and gelsolin are induced Neuro-oncol, April 1, 2002; 4(2): 95 - 101. [Abstract] [PDF]
|
|
|
|
|
|
J.-W. Han, S. H. Ahn, Y. K. Kim, G.-U. Bae, J. W. Yoon, S. Hong, H. Y. Lee, Y.-W. Lee, and H.-W. Lee Activation of p21WAF1/Cip1 Transcription through Sp1 Sites by Histone Deacetylase Inhibitor Apicidin. INVOLVEMENT OF PROTEIN KINASE C J. Biol. Chem., November 2, 2001; 276(45): 42084 - 42090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Kwon, S. H. Ahn, Y. K. Kim, G.-U. Bae, J. W. Yoon, S. Hong, H. Y. Lee, Y.-W. Lee, H.-W. Lee, and J.-W. Han Apicidin, a Histone Deacetylase Inhibitor, Induces Apoptosis and Fas/Fas Ligand Expression in Human Acute Promyelocytic Leukemia Cells J. Biol. Chem., January 11, 2002; 277(3): 2073 - 2080. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
) or not
treated (
) with 1 µg/ml apicidin for 24 h. At this time
point, media were removed (•), the cells were washed thoroughly with
PBS, and medium with no apicidin was added back. Cells were then
incubated further for the indicated times, after which the number of
cells was determined by SRB assay, as described in "Materials and
Methods." Data are the means of triplicate determinations from three
experiments; bars, SE.