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Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-05-1320.
NEOPLASIA
From the Cytokine Research Section, Department of
Bioimmunotherapy, The University of Texas MD Anderson Cancer Center,
Houston, TX; and Imgenex, San Diego, CA.
Because of the central role of the transcription factor
nuclear factor- Multiple myeloma (MM) is a B-cell malignancy
characterized by the latent accumulation in bone marrow of secretory
plasma cells with a low proliferative index and an extended life
span.1 MM accounts for 1% of all cancers and more than
10% of all hematologic cancers. Various agents used for the treatment
of myeloma include combinations of vincristine,
Bis-2-chloroethylnitrosourea (BCNU), melphalan,
cyclophosphamide, adriamycin, and prednisone or
dexamethasone.2 Usually, patients younger than 65 years
are treated with high-dose melphalan with autologous stem-cell support,
and older patients who cannot tolerate such intensive treatment receive
standard-dose oral melphalan and prednisone. Despite these treatments,
this malignancy remains incurable, with a complete remission rate of 5% and a median survival of 30 to 36 months.3,4
The dysregulation of the apoptotic mechanism in plasma cells is
considered a major underlying factor in the pathogenesis and subsequent
chemoresistance in MM. It is established that interleukin-6 (IL-6), produced in either an autocrine or a paracrine manner, has an essential role in the malignant progression of MM by regulating the growth and survival of tumor cells.5,6 The presence of IL-6 leads to constitutive activation of signal transducer and activator of transcription-3 (Stat3), which in turn results in expression of high levels of the antiapoptotic protein B-cell lymphoma-xL (Bcl-xL).7
Bcl-2 overexpression, another important characteristic of the majority
of MM cell lines,8 rescues these tumor cells from
glucocorticoid-induced apoptosis.4 Furthermore, treatment
of MM cells with tumor necrosis factor (TNF) activates nuclear
factor- One of the potential mechanisms by which MM cells could develop
resistance to apoptosis is through the activation of nuclear transcription factor NF- To identify a pharmacologically safe and effective agent with which to
block constitutive NF- Our results demonstrate that all MM cell lines expressed constitutively
active NF- Materials
The rabbit polyclonal antibodies to I Cell culture
Preparation of nuclear extracts for NF-  80°C. The nuclear pellet
was resuspended in 25 µL ice-cold nuclear extraction buffer. After 30 minutes of intermittent mixing, the extract was centrifuged, and
supernatants containing nuclear extracts were secured. The protein
content was measured by the Bradford method. If the nuclear
extracts were not used immediately, they were stored at
80°C.
Electrophoretic mobility shift assay for NF-  B activation was analyzed by electrophoretic mobility
shift assay (EMSA) as described previously.39 In
brief, 8 µg nuclear extracts prepared from curcumin-treated or
untreated cells were incubated with 32P end-labeled 45-mer
double-stranded NF-B oligonucleotide from human immunodeficiency
virus-1 long terminal repeat (5'-TTGTTACAAGGGACTTTCCGCT GGGGACTTTCCAG GGAGGCGTGG-3'; underlining indicates NF-B
binding site) for 15 minutes at 37°C, and the DNA-protein
complex was resolved in a 6.6% native polyacrylamide gel. The
radioactive bands from the dried gels were visualized and quantitated
by the PhosphorImager (Molecular Dynamics, Sunnyvale, CA) with the use of ImageQuant software (Molecular Dynamics).
Immunocytochemistry for NF- Western blot First, 30 to 50 µg cytoplasmic protein extracts, prepared as described,40 were resolved on 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel. After electrophoresis, the proteins were electrotransferred to a nitrocellulose membrane, blocked with 5% nonfat milk, and probed with antibodies against either IB , phospho-IB, Bcl-2,
Bcl-xL, or cyclin D1 (1:3000) for 1 hour. Thereafter, the
blot was washed, exposed to HRP-conjugated secondary antibodies for 1 hour, and finally detected by chemiluminescence (ECL; Amersham
Pharmacia Biotech, Arlington Heights, IL).
For detection of cleavage products of PARP, whole-cell extracts were prepared by lysing the curcumin-treated cells in lysis buffer (20 mM Tris [tris(hydroxymethyl)aminomethane chloride], pH 7.4; 250 mM NaCl; 2 mM EDTA [ethylenediaminetetraacetic acid], pH 8.0; 0.1% Triton-X100; 0.01 mg/mL aprotinin; 0.005 mg/mL leupeptin; 0.4 mM phenylmethanesulfonyl fluoride [PMSF]; and 4 mM NaVO4). Lysates were then spun at 14 000 rpm for 10 minutes to remove insoluble material. Lysates were resolved on 7.5% gel and probed with PARP antibodies. PARP was cleaved from the 116-kDa intact protein into 85-kDa and 40-kDa peptide products. To detect cleavage products of procaspase-7 and procaspase-9, whole-cell extracts were resolved on 10% gel and probed with appropriate antibodies. I B kinase assay was performed by a modified method as
described earlier.41 Briefly, 200 µg cytoplasmic
extracts were immunoprecipitated with 1 µg anti-IKK and
anti-IKK antibodies each, and the immune complexes so
formed were precipitated with 0.01 mL protein A/G-sepharose beads for
2 hours. The beads were washed first with lysis buffer and then with
the kinase assay buffer (50 mM HEPES
[N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid] pH 7.4, 20 mM MgCl2, and 2 mM
dithiothreitol (DTT)). The immune complex was then assayed for
the kinase activity with the use of kinase assay buffer containing 20 µCi (0.74 MBq)]  -P32-ATP, 10 µM
unlabeled ATP, and 2 µg glutathione S-transferase-IB per sample (1-54). After incubation at 30°C for 30 minutes, the
reaction was stopped by boiling the solution in 6 × SDS
sample buffer. Then, the reaction mixture was resolved on 12%
SDS-PAGE. The radioactive bands of the dried gel were visualized and
quantitated by PhosphorImager. To determine the total amount of IKK
complex in each sample, 60 µg cytoplasmic protein was resolved on a
7.5% acrylamide gel and then electrotransferred to a nitrocellulose
membrane; the membrane was blocked with 5% nonfat milk protein for 1 hour and then incubated with either anti-IKK or anti-IKK
antibodies for 1 hour. The membrane was then washed and treated with
HRP-conjugated secondary antimouse IgG antibody and finally detected by
chemiluminescence (Amersham Pharmacia Biotech).
MTT assay The antiproliferative effects of curcumin against different MM cell lines were determined by the MTT dye uptake method as described earlier.42 Briefly, the cells (5000 per well) were incubated in triplicate in a 96-well plate in the presence or absence of indicated test samples in a final volume of 0.1 mL for 24 hours at 37°C. Thereafter, 0.025 mL MTT solution (5 mg/mL in PBS) was added to each well. After a 2-hour incubation at 37°C, 0.1 mL extraction buffer (20% SDS, 50% dimethylformamide) was added; incubation was continued overnight at 37°C; and then the optical density (OD) at 590 nm was measured by means of a 96-well multiscanner autoreader (Dynatech MR 5000, Chantilly, VA), with the extraction buffer as blank. The following formula was used: Percentage cell viability = (OD of the experiment samples/OD of the control) × 100.Thymidine incorporation assay The antiproliferative effects of curcumin were also monitored by the thymidine incorporation method. For this, 5000 cells in 100 µL medium were cultured in triplicate in 96-well plates in the presence or absence of curcumin for 24 hours. At 6 hours before the completion of experiment, cells were pulsed with 0.5 µCi (0.0185 MBq) 3H-thymidine, and the uptake of 3H-thymidine was monitored by means of a Matrix-9600-counter (Packard
Instruments, Downers Grove, IL).
Flow cytometric analysis To determine the effect of curcumin on the cell cycle, MM cells were treated for different times, washed, and fixed with 70% ethanol. After incubation overnight at20°C, cells were washed with PBS
prior to staining with propidium iodide (PI), and then suspended in
staining buffer (10 µg/mL PI; 0.5% Tween-20; 0.1% RNase in
PBS). The cells were analyzed by means of a fluorescence-activated cell
sorted (FACS) Vantage flow cytometer that uses the CellQuest acquisition and analysis programs (Becton Dickinson, San Jose, CA).
Cells were gated to exclude cell debris, cell doublets, and cell clumps.
To determine the apoptosis, curcumin-treated cells were washed in phosphate-buffered saline, resuspended in 100 µL binding buffer containing fluorescein isothiocyanate (FITC)-conjugated annexin V and analyzed by flow cytometry. As curcumin also emits the fluorescence in the same range as FITC, unstained treated cells were also analyzed in parallel. Determination of IL-6 protein Cell-free supernatants were collected from untreated or curcumin-treated cultures of multiple myeloma cells. Aliquots of 100 µL were removed, and IL-6 contents were determined by enzyme-linked immunosorbent assay (ELISA) kit (BioSource International).
Human MM U266, RPMI 8226, MM.1, and MM.1R cell lines used in our
study are well characterized.34-37 We used them to
investigate the effect of curcumin on constitutively active NF- Curcumin suppresses constitutive NF- B status in 4 different MM cell
lines by EMSA. The results shown in Figure
1 indicate that all 4 cell lines
expressed constitutively active NF-B, resolved as an upper and a
lower band. We then investigated the effect of curcumin on
constitutively active NF-B. We first examined the dose of curcumin
required for complete suppression of NF-B. For this, all the MM cell
lines were treated with different concentrations of curcumin for 4 hours and then examined for NF-B by EMSA. Densitometric analysis of
the retarded radiolabeled probe showed a decrease in NF-B
DNA-binding activity. These results showed that 50 µM curcumin was
sufficient to fully suppress the constitutive NF-B activation in
U266 (Figure 1A), MM.1 (Figure 1B), MM.1R (Figure 1C), and RPMI 8226 (Figure 1D). We then examined the minimum duration of exposure to
curcumin required for suppression of NF-B. For this, cells were
incubated with 50 µM curcumin for different periods of time,
and the nuclear extracts were prepared and examined for NF-B by
EMSA. The results showed that curcumin down-regulated constitutive
NF-B in all 4 cell lines but with different kinetics. Complete down-regulation of NF-B occurred at 4 hours in U266 (Figure
1E), MM.1 (Figure 1F), and MM.1R (Figure 1G) cells, whereas it took 8 hours to down-regulate NF-B in RPMI 8226 cells (Figure 1H). Curcumin
down-regulated only the upper band and not the lower band of NF-B in
most cases. In the case of RPMI 8226 cells, both bands were
down-regulated.
Because NF- When NF-
Curcumin inhibits I B and subsequent release of NF-B (p65
to p50) requires prior phosphorylation at Ser32 and Ser36
residues.43 Therefore, to investigate whether the
inhibitory effect of curcumin is mediated through the alteration of
phosphorylation of IB, U266 cells were treated with curcumin, and
their protein extracts were checked for phospho-IB expression.
Results in Figure 3A show that untreated
U266 cells constitutively expressed Ser32-phosphorylated IB. Upon
curcumin treatment, the phosphorylated IB content decreased
rapidly.
Phosphorylation of I IKK has been shown to be regulated by several upstream
kinases.43,44 Whether curcumin inhibited IKK activity
directly or suppressed the activation of IKK was investigated. To
determine if curcumin acted as a direct inhibitor of IKK activity, the
IKK was immunoprecipitated from untreated U266 cells and then treated with different concentrations of curcumin for 30 minutes. After the
treatment, the samples were examined for IKK activity with the use of
GST-I Curcumin down-regulates the expression of NF- B, Bcl-2, Bcl-xL, and cyclin D1
have all been shown to be regulated by NF-B,17
we examined the effect of curcumin on the expression of these gene
products by immunoblotting. As depicted in Figure
4, all 4 gene products were expressed in
U266 cells. The treatment of cells with curcumin down-regulated the pools of IB (Figure 4A), Bcl-2 (Figure 4B), Bcl-xL
(Figure 4C), and cyclin D1 (Figure 4E) proteins in a time-dependent
manner, although the kinetics of suppression followed by each protein were different. Cyclin D1 showed the most abrupt and complete depletion
within 4 hours of curcumin. Bcl-2 also showed a complete decline, but
it achieved the lowest level by 8 hours. On the other hand, IB
and Bcl-xL showed only a partial decline.
Interleukin-6 is another NF- Curcumin suppresses the proliferation of MM cells Because NF-B has been implicated in cell survival and
proliferation,13,14 we examined the effect of curcumin on
proliferation of MM cell lines. U266, RPMI 8226, MM.1, and MM.1R cells
were cultured in the presence of different concentrations of curcumin, and the number of viable cells examined by trypan blue dye-exclusion method. Results in Figure 5 show that
curcumin at a concentration as low as 1 µM inhibited growth by 27%,
23%, 45%, and 51% in U266 (Figure 5A), RPMI 8226 (Figure 5B), MM.1
(Figure 5C), and MM.1R (Figure 5D), respectively. At 10 µM, curcumin
completely suppressed the growth in all cell lines. These results
indicate that curcumin suppresses the proliferation of all MM cell
lines tested, including MM.1R (the line resistant to
dexamethasone-induced apoptosis).
We also examined the antiproliferative effects of curcumin by thymidine
incorporation in U266 cells. Curcumin suppressed thymidine incorporation within 24 hours in a dose-dependent manner (Figure 6A). The MTT method (which indicates the
mitochondrial activity of the cells) showed that curcumin
suppressed the mitochondrial activity of U266 cells within 24 hours, and the suppression occurred in a dose-dependent manner (Figure
6B).
Curcumin induces apoptosis in MM cells We investigated whether suppression of NF-B in MM cells also
leads to apoptosis. The curcumin-induced apoptosis was
examined by the annexin V method. Annexin V binds to those
cells that express phosphatidylserine on the outer layer of the cell
membrane, a characteristic feature of cells entering apoptosis. This
allows for live cells (unstained with either fluorochrome) to be
discriminated from apoptotic cells (stained only with annexin
V).45 To check this, U266 cells were treated for 24 hours with different concentrations of curcumin and then stained with
annexin V-FITC. Results in Figure 6C show a dose-dependent increase in
cells positive for annexin V, indicating the onset of apoptosis in
curcumin-treated cells.
Another hallmark of apoptosis is activation of caspases. To determine
this, U266 cells were treated with curcumin for different periods of
time, and whole-cell extracts were prepared and analyzed for activation
of caspase-9 (an upstream caspase) and caspase-7 (a downstream caspase)
and for cleavage of PARP, a well-known substrate for caspase-3,
caspase-6, and caspase-7.46 Immunoblot analysis
of the extracts from cells treated with curcumin for different times
clearly showed a time-dependent activation of caspase-9 (Figure
7A), as indicated by the disappearance of
a 47-kDa band and the appearance of a 37-kDa band. Similarily, the Western blot analysis also showed an activation of caspase-7 (Figure 7B), as indicated by the disappearance of a 35-kDa band and the appearance of a 20-kDa band. Activation of downstream caspases led to
the cleavage of a 118-kDa PARP protein into an 89-kDa fragment, another hallmark of cells undergoing apoptosis (Figure 7C), whereas untreated cells did not show any PARP cleavage. Antibodies that recognize only the cleaved 89-kDa PARP species increased with an
increase in duration of curcumin treatment (Figure 7C lower panel).
These results clearly suggest that curcumin induced apoptosis in MM
cells.
To further demonstrate the activation of caspases by curcumin in situ, we also labeled the cells with a cell-permeable carboxyfluorescein analog of benzyloxycarbonylalanylaspartic acid fluoromethyl ketone (zVAD-FMK; a general caspase inhibitor) that irreversibly binds to the activated caspases and gives a green fluorescence in the same range as FITC. Untreated cells did not show any fluorescence, but curcumin-treated cells showed an intense fluorescence, indicating the presence of active caspases in these cells (Figure 7D). To determine whether caspase activation is needed for curcumin-induced PARP cleavage, U266 cells were treated with curcumin in the presence of caspase inhibitors Ac-DEVD-CHO (caspase-3 inhibitor) or Ac-YVAD-CHO (caspase-1 inhibitor) and analyzed for PARP cleavage. As shown in Figure 7E, caspase-3 inhibitor suppressed the curcumin-induced PARP cleavage whereas caspase-1 inhibitor did not. To further determine whether caspase activation is needed for the suppression of cell growth induced by curcumin, U266 cells were treated with caspase inhibitors Ac-DEVD-CHO or Ac-YVAD-CHO and then examined for curcumin-induced cytotoxicity by the MTT method. Results shown in Figure 7F demonstrate a dose-dependent protection of cells from curcumin-induced cytotoxicity by caspase-3 inhibitor but not by caspase-1 inhibitor. These results, thus suggest that caspase-3 activation is essential for curcumin-induced cytotoxicity. Curcumin arrests the cells at the G1/S phase of the cell cycle D-type cyclins are required for the progression of cells from the G1 phase of the cell cycle to S phase (DNA synthesis).47 Because we observed a rapid decline of cyclin D1 in curcumin-treated MM cells, we wished to determine the effect of curcumin on U266 cell cycle. Flow cytometric analysis of the DNA from curcumin-treated cells showed a significant increase in the percentage of cells in the G1 phase, from 61% to 70%, and a decrease in the percentage of cells in the S phase, from 20% to 9%, within 24 hours of curcumin (10 µM) treatment (Figure 8). These results clearly show that curcumin induces G1/S arrest of the cells.
NEMO-binding domain (NBD) peptide suppresses constitutive
NF- , IKK, and IKK (also called
NEMO). The amino-terminal -helical region of NEMO has been shown to interact with the C-terminal segment of IKK and
IKK.16 A small peptide from the C-terminus of IKK
and IKK NEMO has been shown to block this interaction. To make it
cell permeable, the NBD peptide was conjugated to a small sequence from
the antennapedia homeodomain. This peptide has been shown to
specifically suppress NF-B activation. The peptide without the
antennapedia homeodomain protein sequence was used as a control.
Our results to this point have shown that curcumin suppressed
constitutive NF-
Curcumin potentiates the cytotoxic effects of chemotherapeutic agents Because NF-B has been implicated in chemoresistance of
cells, we investigated the effects of curcumin on chemosensitivity. We
investigated the effect of curcumin on the cytotoxic effects of
vincristine and melphalan against various multiple myeloma cell lines.
These 2 chemotherapeutic agents showed variable cytotoxic effects in
different multiple myeloma cell lines when treated alone (Figure
10). MM.1 cells were clearly most
sensitive to both the drugs (Figure 10C). The presence of curcumin
enhanced the cytotoxic effects of both vincristine and melphalan
against all the multiple myeloma cell lines. For instance, U266 cells
were least sensitive to vincristine, but the presence of curcumin
enhanced the cytotoxicity from below 10% to greater than 70% (Figure
10A). When compared with MM.1 cells, dexamthasone-resistant MM.1R cells
were also found to be relatively resistant to both vincristine as well
as melphalan. The treatment of these chemoresistant cells with curcumin enhanced the cytotoxic effects of both the chemotherapeutic agents (Figure 10D). As a control, curcumin had minimal cytotoxic effect on
normal human peripheral blood mononuclear cells under these conditions
(data not shown). These results indicate that curcumin may sensitize
the multiple myeloma cells to the cytotoxic effects of vincristine
and melphalan.
Because of the central role of NF- Our results indicate that all 4 MM cell lines (U266, RPMI 8226, MM.1, and MM.1R) expressed constitutively active NF- We found that curcumin suppressed constitutive NF- We found that suppression of NF- The suppression of cell proliferation by curcumin in MM cells is in
agreement with our previous reports that curcumin-induced suppression
of NF- Several potential mechanisms could explain why NF- We also found that MM cells overexpress cyclin D1, another
NF- Suppression of NF- MM is an incurable, aggressive B-cell malignancy, and more than
90% of MM patients become chemoresistant. Several agents have been
tested in the search for more effective treatment of MM. Besides
curcumin, these include PS341 (a proteosome inhibitor) and thalidomide
(an inhibitor of TNF production).54,55 Nonspecific drug
toxicity is one of the major problems in drug development. Numerous studies have shown that curcumin is pharmacologically safe. It
was recently demonstrated in phase 1 clinical trials that humans can
tolerate up to 8 g curcumin per day when it is taken
orally.33 Additionally, curcumin has been shown to
down-regulate the expression of ICAM-1, VCAM-1, and ELAM-1, all
NF-
Submitted May 06, 2002; accepted August 26, 2002.
Prepublished online as Blood First Edition Paper, September 5, 2002; DOI 10.1182/blood-2002-05-1320.
Supported by the Clayton Foundation for Research (B.B.A.) and by Leukemia-Lymphoma Society grant 6153-02 (N.D.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Bharat B. Aggarwal, Cytokine Research Section, Department of Bioimmunotherapy, Box 143, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: aggarwal{at}mdanderson.org.
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  B. Sung, A. B. Kunnumakkara, G. Sethi, P. Anand, S. Guha, and B. B. Aggarwal Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model Mol. Cancer Ther., April 1, 2009; 8(4): 959 - 970. [Abstract] [Full Text] [PDF]
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 S.-A. Park, H.-K. Na, E.-H. Kim, Y.-N. Cha, and Y.-J. Surh 4-Hydroxyestradiol Induces Anchorage-Independent Growth of Human Mammary Epithelial Cells via Activation of I{kappa}B Kinase: Potential Role of Reactive Oxygen Species Cancer Res., March 15, 2009; 69(6): 2416 - 2424. [Abstract] [Full Text] [PDF]
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 M. Miller, S. Chen, J. Woodliff, and S. Kansra Curcumin (Diferuloylmethane) Inhibits Cell Proliferation, Induces Apoptosis, and Decreases Hormone Levels and Secretion in Pituitary Tumor Cells Endocrinology, August 1, 2008; 149(8): 4158 - 4167. [Abstract] [Full Text] [PDF]
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G. Sethi, K. S. Ahn, B. Sung, and B. B. Aggarwal Pinitol targets nuclear factor-{kappa}B activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion, and angiogenesis Mol. Cancer Ther., June 1, 2008; 7(6): 1604 - 1614. [Abstract] [Full Text] [PDF]
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 B. Sung, M. K. Pandey, K. S. Ahn, T. Yi, M. M. Chaturvedi, M. Liu, and B. B. Aggarwal Anacardic acid (6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-{kappa}B-regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhibitory subunit of nuclear factor-{kappa}B{alpha} kinase, leading to potentiation of apoptosis Blood, May 15, 2008; 111(10): 4880 - 4891. [Abstract] [Full Text] [PDF]
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 B. E. Bachmeier, I. V. Mohrenz, V. Mirisola, E. Schleicher, F. Romeo, C. Hohneke, M. Jochum, A. G. Nerlich, and U. Pfeffer Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NF{kappa}B Carcinogenesis, April 1, 2008; 29(4): 779 - 789. [Abstract] [Full Text] [PDF]
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 G. Sethi, B. Sung, and B. B. Aggarwal Nuclear Factor-{kappa}B Activation: From Bench to Bedside Experimental Biology and Medicine, January 1, 2008; 233(1): 21 - 31. [Abstract] [Full Text] [PDF]
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 M. Romagnoli, G. Desplanques, S. Maiga, S. Legouill, M. Dreano, R. Bataille, and S. Barille-Nion Canonical Nuclear Factor {kappa}B Pathway Inhibition Blocks Myeloma Cell Growth and Induces Apoptosis in Strong Synergy with TRAIL Clin. Cancer Res., October 15, 2007; 13(20): 6010 - 6018. [Abstract] [Full Text] [PDF]
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K. S. Ahn, G. Sethi, T.-H. Chao, S. T. C. Neuteboom, M. M. Chaturvedi, M. A. Palladino, A. Younes, and B. B. Aggarwal Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-{kappa}B regulated gene products Blood, October 1, 2007; 110(7): 2286 - 2295. [Abstract] [Full Text] [PDF]
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 H. Aoki, Y. Takada, S. Kondo, R. Sawaya, B. B. Aggarwal, and Y. Kondo Evidence That Curcumin Suppresses the Growth of Malignant Gliomas in Vitro and in Vivo through Induction of Autophagy: Role of Akt and Extracellular Signal-Regulated Kinase Signaling Pathways Mol. Pharmacol., July 1, 2007; 72(1): 29 - 39. [Abstract] [Full Text] [PDF]
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 M. K. Pandey, S. K. Sandur, B. Sung, G. Sethi, A. B. Kunnumakkara, and B. B. Aggarwal Butein, a Tetrahydroxychalcone, Inhibits Nuclear Factor (NF)-{kappa}B and NF-{kappa}B-regulated Gene Expression through Direct Inhibition of I{kappa}B{alpha} Kinase beta on Cysteine 179 Residue J. Biol. Chem., June 15, 2007; 282(24): 17340 - 17350. [Abstract] [Full Text] [PDF]
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G. Sethi, K. S. Ahn, M. K. Pandey, and B. B. Aggarwal Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-{kappa}B-regulated gene products and TAK1-mediated NF-{kappa}B activation Blood, April 1, 2007; 109(7): 2727 - 2735. [Abstract] [Full Text] [PDF]
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A. Bhardwaj, G. Sethi, S. Vadhan-Raj,, C. Bueso-Ramos, Y. Takada, U. Gaur, A. S. Nair, S. Shishodia, and B. B. Aggarwal Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-{kappa}B-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells Blood, March 15, 2007; 109(6): 2293 - 2302. [Abstract] [Full Text] [PDF]
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D.-M. Hwang, J. K. Kundu, J.-W. Shin, J.-C. Lee, H. J. Lee, and Y.-J. Surh cis-9,trans-11-Conjugated linoleic acid down-regulates phorbol ester-induced NF-{kappa}B activation and subsequent COX-2 expression in hairless mouse skin by targeting I{kappa}B kinase and PI3K-Akt Carcinogenesis, February 1, 2007; 28(2): 363 - 371. [Abstract] [Full Text] [PDF]
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K. S. Ahn, G. Sethi, K. Krishnan, and B. B. Aggarwal {gamma}-Tocotrienol Inhibits Nuclear Factor-{kappa}B Signaling Pathway through Inhibition of Receptor-interacting Protein and TAK1 Leading to Suppression of Antiapoptotic Gene Products and Potentiation of Apoptosis J. Biol. Chem., January 5, 2007; 282(1): 809 - 820. [Abstract] [Full Text] [PDF]
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S. Bhattacharyya, D. Mandal, G. S. Sen, S. Pal, S. Banerjee, L. Lahiry, J. H. Finke, C. S. Tannenbaum, T. Das, and G. Sa Tumor-Induced Oxidative Stress Perturbs Nuclear Factor-{kappa}B Activity-Augmenting Tumor Necrosis Factor-{alpha}-Mediated T-Cell Death: Protection by Curcumin Cancer Res., January 1, 2007; 67(1): 362 - 370. [Abstract] [Full Text] [PDF]
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 C. Morais, B. Pat, G. Gobe, D. W. Johnson, and H. Healy Pyrrolidine dithiocarbamate exerts anti-proliferative and pro-apoptotic effects in renal cell carcinoma cell lines Nephrol. Dial. Transplant., December 1, 2006; 21(12): 3377 - 3388. [Abstract] [Full Text] [PDF]
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O. Kwon, K. A Kim, S. O. Kim, R. Ha, W. K. Oh, M. S. Kim, H. S. Kim, G. D. Kim, J. W. Kim, M. Jung, et al. NF-{kappa}B inhibition increases chemosensitivity to trichostatin A-induced cell death of Ki-Ras-transformed human prostate epithelial cells Carcinogenesis, November 1, 2006; 27(11): 2258 - 2268. [Abstract] [Full Text] [PDF]
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A. Ciucci, P. Gianferretti, R. Piva, T. Guyot, T. J. Snape, S. M. Roberts, and M. G. Santoro Induction of Apoptosis in Estrogen Receptor-Negative Breast Cancer Cells by Natural and Synthetic Cyclopentenones: Role of the I{kappa}B Kinase/Nuclear Factor-{kappa}B Pathway Mol. Pharmacol., November 1, 2006; 70(5): 1812 - 1821. [Abstract] [Full Text] [PDF]
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 I Strickland and S Ghosh Use of cell permeable NBD peptides for suppression of inflammation Ann Rheum Dis, November 1, 2006; 65(suppl_3): iii75 - iii82. [Abstract] [Full Text] [PDF]
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 A. S. Nair, S. Shishodia, K. S. Ahn, A. B. Kunnumakkara, G. Sethi, and B. B. Aggarwal Deguelin, an Akt Inhibitor, Suppresses I{kappa}B{alpha} Kinase Activation Leading to Suppression of NF-{kappa}B-Regulated Gene Expression, Potentiation of Apoptosis, and Inhibition of Cellular Invasion J. Immunol., October 15, 2006; 177(8): 5612 - 5622. [Abstract] [Full Text] [PDF]
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 K. S. Ahn, G. Sethi, S. Shishodia, B. Sung, J. L. Arbiser, and B. B. Aggarwal Honokiol Potentiates Apoptosis, Suppresses Osteoclastogenesis, and Inhibits Invasion through Modulation of Nuclear Factor-{kappa}B Activation Pathway Mol. Cancer Res., September 1, 2006; 4(9): 621 - 633. [Abstract] [Full Text] [PDF]
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K. Wolanin, A. Magalska, G. Mosieniak, R. Klinger, S. McKenna, S. Vejda, E. Sikora, and K. Piwocka Curcumin Affects Components of the Chromosomal Passenger Complex and Induces Mitotic Catastrophe in Apoptosis-Resistant Bcr-Abl-Expressing Cells Mol. Cancer Res., July 1, 2006; 4(7): 457 - 469. [Abstract] [Full Text] [PDF]
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J. K. Kundu, Y. K. Shin, S. H. Kim, and Y.-J. Surh Resveratrol inhibits phorbol ester-induced expression of COX-2 and activation of NF-{kappa}B in mouse skin by blocking I{kappa}B kinase activity Carcinogenesis, July 1, 2006; 27(7): 1465 - 1474. [Abstract] [Full Text] [PDF]
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G. P. Collett and F. C. Campbell Overexpression of p65/RelA potentiates curcumin-induced apoptosis in HCT116 human colon cancer cells Carcinogenesis, June 1, 2006; 27(6): 1285 - 1291. [Abstract] [Full Text] [PDF]
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S. Olivier, P. Close, E. Castermans, L. de Leval, S. Tabruyn, A. Chariot, M. Malaise, M.-P. Merville, V. Bours, and N. Franchimont Raloxifene-Induced Myeloma Cell Apoptosis: A Study of Nuclear Factor-{kappa}B Inhibition and Gene Expression Signature Mol. Pharmacol., May 1, 2006; 69(5): 1615 - 1623. [Abstract] [Full Text] [PDF]
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S. Shishodia, G. Sethi, M. Konopleva, M. Andreeff, and B. B. Aggarwal A Synthetic Triterpenoid, CDDO-Me, Inhibits I{kappa}B{alpha} Kinase and Enhances Apoptosis Induced by TNF and Chemotherapeutic Agents through Down-Regulation of Expression of Nuclear Factor {kappa}B-Regulated Gene Products in Human Leukemic Cells Clin. Cancer Res., March 15, 2006; 12(6): 1828 - 1838. [Abstract] [Full Text] [PDF]
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 D. R. Yance Jr and S. M. Sagar Targeting Angiogenesis With Integrative Cancer Therapies Integr Cancer Ther, March 1, 2006; 5(1): 9 - 29. [Abstract] [PDF]
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Y. Takada, H. Ichikawa, V. Badmaev, and B. B. Aggarwal Acetyl-11-Keto-beta-Boswellic Acid Potentiates Apoptosis, Inhibits Invasion, and Abolishes Osteoclastogenesis by Suppressing NF-{kappa}B and NF-{kappa}B-Regulated Gene Expression. J. Immunol., March 1, 2006; 176(5): 3127 - 3140. [Abstract] [Full Text] [PDF]
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 W.G. Cao, M. Morin, V. Sengers, C. Metz, T. Roger, R. Maheux, and A. Akoum Tumour necrosis factor-{alpha} up-regulates macrophage migration inhibitory factor expression in endometrial stromal cells via the nuclear transcription factor NF-{kappa}B Hum. Reprod., February 1, 2006; 21(2): 421 - 428. [Abstract] [Full Text] [PDF]
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H. Ichikawa and B. B. Aggarwal Guggulsterone Inhibits Osteoclastogenesis Induced by Receptor Activator of Nuclear Factor-{kappa}B Ligand and by Tumor Cells by Suppressing Nuclear Factor-{kappa}B Activation Clin. Cancer Res., January 15, 2006; 12(2): 662 - 668. [Abstract] [Full Text] [PDF]
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G. Shen, C. Xu, R. Hu, M. R. Jain, A. Gopalkrishnan, S. Nair, M.-T. Huang, J. Y. Chan, and A.-N. T. Kong Modulation of nuclear factor E2-related factor 2-mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin Mol. Cancer Ther., January 1, 2006; 5(1): 39 - 51. [Abstract] [Full Text] [PDF]
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 Y.-J. Surh, J. K. Kundu, H.-K. Na, and J.-S. Lee Redox-Sensitive Transcription Factors as Prime Targets for Chemoprevention with Anti-Inflammatory and Antioxidative Phytochemicals J. Nutr., December 1, 2005; 135(12): 2993S - 3001S. [Abstract] [Full Text] [PDF]
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R. K. Thomas, M. L. Sos, T. Zander, O. Mani, A. Popov, D. Berenbrinker, S. Smola-Hess, J. L. Schultze, and J. Wolf Inhibition of Nuclear Translocation of Nuclear Factor-{kappa}B Despite Lack of Functional I{kappa}B{alpha} Protein Overcomes Multiple Defects in Apoptosis Signaling in Human B-Cell Malignancies Clin. Cancer Res., November 15, 2005; 11(22): 8186 - 8194. [Abstract] [Full Text] [PDF]
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B. B. Aggarwal, S. Shishodia, Y. Takada, S. Banerjee, R. A. Newman, C. E. Bueso-Ramos, and J. E. Price Curcumin Suppresses the Paclitaxel-Induced Nuclear Factor-{kappa}B Pathway in Breast Cancer Cells and Inhibits Lung Metastasis of Human Breast Cancer in Nude Mice Clin. Cancer Res., October 15, 2005; 11(20): 7490 - 7498. [Abstract] [Full Text] [PDF]
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A. Hachem and R. B. Gartenhaus Oncogenes as molecular targets in lymphoma Blood, September 15, 2005; 106(6): 1911 - 1923. [Full Text] [PDF]
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 W.-G. Cao, M. Morin, C. Metz, R. Maheux, and A. Akoum Stimulation of Macrophage Migration Inhibitory Factor Expression in Endometrial Stromal Cells by Interleukin 1, beta Involving the Nuclear Transcription Factor NF{kappa}B Biol Reprod, September 1, 2005; 73(3): 565 - 570. [Abstract] [Full Text] [PDF]
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B. Y. Kim, K. A. Kim, O. Kwon, S. O. Kim, M. S. Kim, B. S. Kim, W. K. Oh, G. D. Kim, M. Jung, and J. S. Ahn NF-{kappa}B inhibition radiosensitizes Ki-Ras-transformed cells to ionizing radiation Carcinogenesis, August 1, 2005; 26(8): 1395 - 1403. [Abstract] [Full Text] [PDF]
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L. S. Mangashetti, S. M. Khapli, and M. R. Wani IL-4 Inhibits Bone-Resorbing Activity of Mature Osteoclasts by Affecting NF-{kappa}B and Ca2+ Signaling J. Immunol., July 15, 2005; 175(2): 917 - 925. [Abstract] [Full Text] [PDF]
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Y. Takada, M. Andreeff, and B. B. Aggarwal Indole-3-carbinol suppresses NF-{kappa}B and I{kappa}B{alpha} kinase activation, causing inhibition of expression of NF-{kappa}B-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells Blood, July 15, 2005; 106(2): 641 - 649. [Abstract] [Full Text] [PDF]
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H. Tatetsu, Y. Okuno, M. Nakamura, F. Matsuno, T. Sonoki, I. Taniguchi, S. Uneda, K. Umezawa, H. Mitsuya, and H. Hata Dehydroxymethylepoxyquinomicin, a novel nuclear factor-{kappa}B inhibitor, induces apoptosis in multiple myeloma cells in an I{kappa}B{alpha}-independent manner Mol. Cancer Ther., July 1, 2005; 4(7): 1114 - 1120. [Abstract] [Full Text] [PDF]
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G.-Y. Kim, K.-H. Kim, S.-H. Lee, M.-S. Yoon, H.-J. Lee, D.-O. Moon, C.-M. Lee, S.-C. Ahn, Y. C. Park, and Y.-M. Park Curcumin Inhibits Immunostimulatory Function of Dendritic Cells: MAPKs and Translocation of NF-{kappa}B as Potential Targets J. Immunol., June 15, 2005; 174(12): 8116 - 8124. [Abstract] [Full Text] [PDF]
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K. Ito, T. Nakazato, M. J. Xian, T. Yamada, N. Hozumi, A. Murakami, H. Ohigashi, Y. Ikeda, and M. Kizaki 1'-Acetoxychavicol Acetate Is a Novel Nuclear Factor {kappa}B Inhibitor with Significant Activity against Multiple Myeloma In vitro and In vivo Cancer Res., May 15, 2005; 65(10): 4417 - 4424. [Abstract] [Full Text] [PDF]
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Z. Ma, K.-i. Otsuyama, S. Liu, S. Abroun, H. Ishikawa, N. Tsuyama, M. Obata, F.-J. Li, X. Zheng, Y. Maki, et al. Baicalein, a component of Scutellaria radix from Huang-Lian-Jie-Du-Tang (HLJDT), leads to suppression of proliferation and induction of apoptosis in human myeloma cells Blood, April 15, 2005; 105(8): 3312 - 3318. [Abstract] [Full Text] [PDF]
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T. Sanda, S. Iida, H. Ogura, K. Asamitsu, T. Murata, K. B. Bacon, R. Ueda, and T. Okamoto Growth Inhibition of Multiple Myeloma Cells by a Novel I{kappa}B Kinase Inhibitor Clin. Cancer Res., March 1, 2005; 11(5): 1974 - 1982. [Abstract] [Full Text] [PDF]
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T. Syrovets, J. E. Gschwend, B. Buchele, Y. Laumonnier, W. Zugmaier, F. Genze, and T. Simmet Inhibition of I{kappa}B Kinase Activity by Acetyl-boswellic Acids Promotes Apoptosis in Androgen-independent PC-3 Prostate Cancer Cells in Vitro and in Vivo J. Biol. Chem., February 18, 2005; 280(7): 6170 - 6180. [Abstract] [Full Text] [PDF]
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R. Piva, P. Gianferretti, A. Ciucci, R. Taulli, G. Belardo, and M. G. Santoro 15-Deoxy-{Delta}12,14-prostaglandin J2 induces apoptosis in human malignant B cells: an effect associated with inhibition of NF-{kappa}B activity and down-regulation of antiapoptotic proteins Blood, February 15, 2005; 105(4): 1750 - 1758. [Abstract] [Full Text] [PDF]
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N. W.C.J. van de Donk, H. M. Lokhorst, E. H.J. Nijhuis, M. M.J. Kamphuis, and A. C. Bloem Geranylgeranylated Proteins are Involved in the Regulation of Myeloma Cell Growth Clin. Cancer Res., January 15, 2005; 11(2): 429 - 439. [Abstract] [Full Text] [PDF]
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T. Syrovets, B. Buchele, C. Krauss, Y. Laumonnier, and T. Simmet Acetyl-Boswellic Acids Inhibit Lipopolysaccharide-Mediated TNF-{alpha} Induction in Monocytes by Direct Interaction with I{kappa}B Kinases J. Immunol., January 1, 2005; 174(1): 498 - 506. [Abstract] [Full Text] [PDF]
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S. Shishodia and B. B. Aggarwal Guggulsterone Inhibits NF-{kappa}B and I{kappa}B{alpha} Kinase Activation, Suppresses Expression of Anti-apoptotic Gene Products, and Enhances Apoptosis J. Biol. Chem., November 5, 2004; 279(45): 47148 - 47158. [Abstract] [Full Text] [PDF]
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G. P. Collett and F. C. Campbell Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells Carcinogenesis, November 1, 2004; 25(11): 2183 - 2189. [Abstract] [Full Text] [PDF]
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Y. Takada, X. Fang, Md. S. Jamaluddin, D. D. Boyd, and B. B. Aggarwal Genetic Deletion of Glycogen Synthase Kinase-3{beta} Abrogates Activation of I{kappa}B{alpha} Kinase, JNK, Akt, and p44/p42 MAPK but Potentiates Apoptosis Induced by Tumor Necrosis Factor J. Biol. Chem., September 17, 2004; 279(38): 39541 - 39554. [Abstract] [Full Text] [PDF]
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S. Shishodia and B. B. Aggarwal Cyclooxygenase (COX)-2 Inhibitor Celecoxib Abrogates Activation of Cigarette Smoke-Induced Nuclear Factor (NF)-{kappa}B by Suppressing Activation of I-{kappa}B {alpha} Kinase in Human Non-Small Cell Lung Carcinoma: Correlation with Suppression of Cyclin D1, COX-2, and Matrix Metalloproteinase-9 Cancer Res., July 15, 2004; 64(14): 5004 - 5012. [Abstract] [Full Text] [PDF]
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D. Deeb, H. Jiang, X. Gao, M. S. Hafner, H. Wong, G. Divine, R. A. Chapman, S. A. Dulchavsky, and S. C. Gautam Curcumin sensitizes prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L by inhibiting nuclear factor-{kappa}B through suppression of I{kappa}B{alpha} phosphorylation Mol. Cancer Ther., July 1, 2004; 3(7): 803 - 812. [Abstract] [Full Text] [PDF]
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A. C. Bharti, Y. Takada, and B. B. Aggarwal Curcumin (Diferuloylmethane) Inhibits Receptor Activator of NF-{kappa}B Ligand-Induced NF-{kappa}B Activation in Osteoclast Precursors and Suppresses Osteoclastogenesis J. Immunol., May 15, 2004; 172(10): 5940 - 5947. [Abstract] [Full Text] [PDF]
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B. Zheng, G. V. Georgakis, Y. Li, A. Bharti, D. McConkey, B. B. Aggarwal, and A. Younes Induction of Cell Cycle Arrest and Apoptosis by the Proteasome Inhibitor PS-341 in Hodgkin Disease Cell Lines Is Independent of Inhibitor of Nuclear Factor-{kappa}B Mutations or Activation of the CD30, CD40, and RANK Receptors Clin. Cancer Res., May 1, 2004; 10(9): 3207 - 3215. [Abstract] [Full Text] [PDF]
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A. C. Bharti, S. Shishodia, J. M. Reuben, D. Weber, R. Alexanian, S. Raj-Vadhan, Z. Estrov, M. Talpaz, and B. B. Aggarwal Nuclear factor-{kappa}B and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis Blood, April 15, 2004; 103(8): 3175 - 3184. [Abstract] [Full Text] [PDF]
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Y. Dai, X.-Y. Pei, M. Rahmani, D. H. Conrad, P. Dent, and S. Grant Interruption of the NF-{kappa}B pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells Blood, April 1, 2004; 103(7): 2761 - 2770. [Abstract] [Full Text] [PDF]
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N. R. Jana, P. Dikshit, A. Goswami, and N. Nukina Inhibition of Proteasomal Function by Curcumin Induces Apoptosis through Mitochondrial Pathway J. Biol. Chem., March 19, 2004; 279(12): 11680 - 11685. [Abstract] [Full Text] [PDF]
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A. C. Bharti, Y. Takada, S. Shishodia, and B. B. Aggarwal Evidence That Receptor Activator of Nuclear Factor (NF)-{kappa}B Ligand Can Suppress Cell Proliferation and Induce Apoptosis through Activation of a NF-{kappa}B-independent and TRAF6-dependent Mechanism J. Biol. Chem., February 13, 2004; 279(7): 6065 - 6076. [Abstract] [Full Text] [PDF]
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N. J. Donato, J. Y. Wu, J. Stapley, H. Lin, R. Arlinghaus, B. Aggarwal, S. Shishodin, M. Albitar, K. Hayes, H. Kantarjian, et al. Imatinib Mesylate Resistance Through BCR-ABL Independence in Chronic Myelogenous Leukemia Cancer Res., January 15, 2004; 64(2): 672 - 677. [Abstract] [Full Text] [PDF]
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A. C. Bharti, N. Donato, and B. B. Aggarwal Curcumin (Diferuloylmethane) Inhibits Constitutive and IL-6-Inducible STAT3 Phosphorylation in Human Multiple Myeloma Cells J. Immunol., October 1, 2003; 171(7): 3863 - 3871. [Abstract] [Full Text] [PDF]
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Y. Takada and B. B. Aggarwal Betulinic Acid Suppresses Carcinogen-Induced NF-{kappa}B Activation Through Inhibition of I{kappa}B{alpha} Kinase and p65 Phosphorylation: Abrogation of Cyclooxygenase-2 and Matrix Metalloprotease-9 J. Immunol., September 15, 2003; 171(6): 3278 - 3286. [Abstract] [Full Text] [PDF]
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T. M. Mitchell and R. Z. Orlowski Correspondence re: Somasundaram et al., Dietary Curcumin Inhibits Chemotherapy-induced Apoptosis in Models of Human Breast Cancer. Cancer Res., 62: 3868-3875, 2002. Cancer Res., August 15, 2003; 63(16): 5165 - 5167. [Full Text] [PDF]
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S. Shishodia, S. Majumdar, S. Banerjee, and B. B. Aggarwal Ursolic Acid Inhibits Nuclear Factor-{kappa}B Activation Induced by Carcinogenic Agents through Suppression of I{kappa}B{alpha} Kinase and p65 Phosphorylation: Correlation with Down-Regulation of Cyclooxygenase 2, Matrix Metalloproteinase 9, and Cyclin D1 Cancer Res., August 1, 2003; 63(15): 4375 - 4383. [Abstract] [Full Text] [PDF]
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S. Shishodia, P. Potdar, C. G. Gairola, and B. B. Aggarwal Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-{kappa}B activation through inhibition of I{kappa}B{alpha} kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1 Carcinogenesis, July 1, 2003; 24(7): 1269 - 1279. [Abstract] [Full Text] [PDF]
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Y. Takada, A. Mukhopadhyay, G. C. Kundu, G. H. Mahabeleshwar, S. Singh, and B. B. Aggarwal Hydrogen Peroxide Activates NF-{kappa}B through Tyrosine Phosphorylation of I{kappa}B{alpha} and Serine Phosphorylation of p65: EVIDENCE FOR THE INVOLVEMENT OF I{kappa}B{alpha} KINASE AND Syk PROTEIN-TYROSINE KINASE J. Biol. Chem., June 20, 2003; 278(26): 24233 - 24241. [Abstract] [Full Text] [PDF]
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| Copyright © 2003 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
B and I
kinase in human
multiple myeloma cells, leading to suppression of proliferation and
induction of apoptosis
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Abstract
Introduction
