Kurkuma+ Schwarzer Pfeffer
Kurkuma, eines der wichtigsten Mittel in der ayurvedischen Medizin, ist das stärkste natürliche entzündungshemmende Mittel, das man heute kennt.
In seinem sehr gut recherchiertem und sehr empfehlenswerten "Anti Krebs Buch" beschreibt David Servan Schreiber, dass Kurkuma auch zum programmierten Zelltod
von Krebszellen (Apoptose) beiträgt und dass es das Zellwachstum hemmt. In Laborversuchen erhöhte es die Wirksamkeit der Chemotherapie.
Inder, die durch den hohen Curryverzehr im Durchschnitt 1,5-2g Kurkuma pro Tag (1/4 – ½ Teelöffel) konsumieren, haben 8x weniger Lungenkrebs, 9x weniger Dickdarmkrebs, 5x weniger Brustkrebs und 10x weniger Nierenkrebs als gleichaltrige Menschen im Westen. Und das, obwohl sie zahlreichen krebseregenden Stoffen
in der Umwelt ausgesetzt sind, oft in einem viel schlimmeren Ausmaß als die Menschen im Westen.
Da Kurkuma in medizinischen Texten aus Indien, China, Tibet und dem mittleren Osten seit über 2000 Jahren erwähnt wird, hat einer der am meisten zitierten Krebsforscher, Prof. Dr. Aggarwal vom M.D. Anderson Cancer Center in Houston, die Wirkungen von Kurkuma intensiv erforscht. In 2005 führte er den Nachweis, dass es bei Mäusen, denen man Brustkrebszellen übertragen hatte, auf Tumoren wirkte, die auf eine Chemotherapie mit Taxol nicht mehr reagierten. Bei diesen Mäusen verringerte die Gabe verzehrsüblicher Dosen von Kurkuma auf eindrucksvolle Weise die Ausbreitung von Metastasen. Daraufhin wurden drei klinische Versuche mit Kurkuma gestartet. Die drei Studien laufen gegenwärtig und die Ergebnisse sind noch nicht bekannt.
Hauptsächlich ist es das Molekül Curcumin, das diese Wirkungen auslöst. Wenn es jedoch nicht, wie dies bei der Curry-Gewürzmischung schon immer der Fall war, mit schwarzem Pfeffer vermischt wird, kann der Verdauungsapparat es nur sehr schlecht aufnehmen. Schwarzer Pfeffer erhöht die Kurkuma-Absorption um das 2000-Fache.
Die außerordentliche Wirksamkeit von Kurkuma rührt zu einem großen Teil daher, dass es in der Lage ist, mit dem schwarzen Ritter des Krebses, dem NF-Kappa B, zu interagieren. Dieses schützt normalerweise die Krebszellen vor den Selbstverteidigungsmechanismen des Körpers.
Die pharmazeutische Industrie sucht nach neuen nicht toxischen Molekülen, die in der Lage sind, diesen gefährlichen Verbündeten der Krebszellen zu bekämpfen.
Schon die bisherigen Forschungsergebnisse zeigen deutlich, dass Kurkuma ein Machtvoller Gegenspieler von NF-Kappa B ist, und im Verlauf der 2000 Jahre, die es
in der indischen Küche zum Einsatz kommt, hat es seine absolute Unschädlichkeit bewiesen.
Man kann es sehr gut an gekochte Gemüse, Suppen oder Salatsoßen geben.
Rezept:
Achtung: damit Kurkuma vom Körper aufgenommen werden kann, muss es mit schwarzem Pfeffer (nicht einfach irgendeinem Pfeffer) vermischt werden. Idealerweise sollte es in Öl gelöst werden (bevorzugt Olivenöl oder Leinöl).
Empfohlene Einnahme: ein halber Teelöffel Kurkumapulver mit einer guten Prise (5%) schwarzem Pfeffer und einem Teelöfel Oliven- oder Leinöl vermischt im Mund einspeicheln und schlucken.
Wer das braucht, kann für den Geschmack noch etwas Honig oder Agavendicksaft zufügen.
Eine umfassende Abhandlung von Walter Häge über die medizinischen Wirkungen von Kurkuma (insbesondere bei Krebserkrankungen) finden Sie
[Jayaraj Ravindran/Sahdeo Prasad/Bharat B. Aggarwal]
Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells
Selectively?
Cancer is a hyperproliferative disorder that is usually treated by
chemotherapeutic agents that are toxic not only to tumor cells but also to
normal cells, so these agents produce major side effects. In addition, these
agents are highly expensive and thus not affordable for most. Moreover, such
agents cannot be used for cancer prevention. Traditional medicines are
generally free of the deleterious side effects and usually inexpensive.
Curcumin, a component of turmeric (Curcuma longa), is one such agent that is
safe, affordable, and efficacious. How curcumin kills tumor cells is the focus
of this review. We show that curcumin modulates growth of tumor cells through
regulation of multiple cell signaling pathways including cell proliferation
pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP,
c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway
(p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and
protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills
tumor cells, and not normal cells, is also described in detail.
KEY WORDS: apoptosis, cancer, curcumin, molecular targets, signalling
pathways.
There are 4 types of cancers:
a. carcinoma: arise from the epithelial sheet
that covers the surfaces, e.g., skin, colon, etc. Approximately 90% of all
human cancers are carcinomas;
b. sarcoma: these include cancer of the
connective tissues such as muscle, bone, cartilage, and fibrous tissue.
Approximately 2% of all cancers are sarcomas;
c. leukaemia
d. lymphoma: they originate from blood forming
cells and from cells of the immune system, respectively. Approx. 8% of all
cancers are leukemia and lymphomas.
Based on metastatic potential, there are two classifications of cancers:
a. benign tumors or adenomas: when neoplastic
growth remains clustered as a single mass,
b. malignant tumor or adenocarcinoma: when
tumor invades normal tissue and spreads throughout the body.
It is estimated that human body consists of 10–13 trillion cells. Almost
all of these cells get turned over within approximately 100 days, thus
suggesting an apoptosis/cell death rate of 100–130 billion cells each day. What
is the mechanism of this mode of cell death in normal cells is unclear.
Cancer cells distinct from normal cells in 6 different ways and these
characteristics are shared by all cancers.
self sufficiency in growth signals,
insensitivity to growth inhibitory signals,
evasion of apoptosis,
limitless replicative potential,
sustained angiogenesis,
tissue invasion,
metastasis.
The ability of tumor cell populations to expand in number is determined
not only by the rate of cell proliferation but also by the rate of cell death.
Apoptosis is a major source of cell death, thus agents that trigger
apoptosis/cell death, could be the most promising candidates as therapeutic for
cancer.
Why certain types of cancers are more prevalent in some countries than
others is not clear but lifestyle (diet) is known to play major role.
Among the potential dietary contributors to this disparity is turmeric
(Curcuma longa), a spice that is consumed frequently by people from southeast
Asia, a continent
with low incidence of most cancers.
Powder of turmeric is extensively used in Ayurveda, Unani, and Siddha
medicine as a home remedy for various diseases. This powder, curcumin
(diferuloylmethane)
a yellow-colored polyphenol, first isolated in 1815, crystallized in
1870, and identified as 1,6-heptadiene-3,5-
dione-1,7-bis(4-hydroxy-3-methoxyphenyl)-(1E,6E). Curcumin analoges which made
by mother nature and man have been described. In addition, besides
diferuloylmethane or curcumin, turmeric contains minor fractions such as
demethoxycurcumin (curcumin II), bisdemethoxycurcumin (curcumin III), and the
recently identified cyclocurcumin. All these analoges suggest that while
hydroxyl groups in curcumin are required for its antioxidant activity, its
methoxy groups are essential for its antiinflammatory and antiproliferative
activity. Various molecular targets modulated by this agent include
transcription factors, growth factors and their receptors, cytokines, enzymes,
and genes regulating cell proliferation and apoptosis.
The anticarcinogenic properties of curcumin in animals have been
demonstrated by its inhibition of tumor initiation and tumor promotion. Studies
of curcumin have shown that it influences structurally unrelated membrane
proteins across several signaling pathways. A recent report suggests that
curcumin inserts deep into the cellular membrane in a transbilayer orientation,
anchored by hydrogen bonding to the phosphate group of lipids, thus inducing
negative curvature in the bilayer. The promotion of negative curvature by
curcumin may have a direct effect on apoptosis by increasing the permeabilizing
activity of the apoptotic protein tBid. Curcumin has been shown to suppress
multiple signaling pathways and inhibit cell proliferation, invasion,
metastasis, and angiogenesis. The chemopreventive action of curcumin might be
due to its ability to induce apoptosis by several pathways. Curcumin directly
or indirectly controls different gene or gene products involved in cell death
pathways as discussed here
MODES OF CELL DEATH
There are two major pathways of cell death, apoptosis (death by suicide)
and necrosis (death by injury). Apoptosis is also known as programmed cell
death and involves a series of biochemical events leading to characteristic
cell morphology and death. Necrosis is caused by external factors, such as
infection, toxins, or trauma. Additional cell death mechanisms, such as
autophagy, entosis, paraptosis, and anoikis, have been defined more recently. A
brief review of these modes of cell death will serve as background for our discussion
of the modes and mediators of curcumin-induced cell death.
Apoptosis
Apoptosis is a normal physiological process that is required for the
maintenance of cell homeostasis. The cellular changes involved in this process
are both morphological and biochemical, including disintegration of the
cytoskeleton and subsequent cell shrinkage, chromatin condensation, and
activation of specific proteases, called caspases. Apoptosis can be initiated
by a variety of internal and external stimuli, including receptor ligation and
toxic insults. Apoptosis not only plays a crucial role in tissue development
and homeostasis, but is also involved in a wide range of pathological
conditions. Apoptotic cell death is accompanied by a series of complex
biochemical events and definite morphologic changes, which include cell
shrinkage, chromatin condensation, DNA fragmentation, membrane budding, and the
appearance of membrane-associated apoptotic bodies. Failure to accurately
undergo apoptosis can cause severe anomalies, ranging from autoimmune disease
to cancer.
Necrosis
Necrosis typically occurs as a result of mechanical or toxic cell
injury. Necrotic cells are distinguished from apoptotic cells in that they
undergo stages such as cell swelling, plasma membrane rupture, organelle breakdown,
and ultimately lysis, allowing release of the cytoplasmic contents and hence
induction of an inflammatory response.
Autophagy
Autophagy or autophagocytosis is a cellular degradation process
involving the degradation of a cell's own components through the lysosomal
action. It is a tightly regulated cell-degradation mechanism that plays a
normal part in cell growth, development, and homeostasis, helping to maintain a
balance between the cellular products. This process involves dynamic membrane
rearrangements under a range of physiological conditions. It plays a role in
cellular maintenance and development, and has been implicated in a number of
genetic diseases.
Entosis
Entosis is a nonapoptotic cell death process that occurs in human tumors
and that is provoked by loss of attachment to matrix. This cell death mechanism
is initiated by an unusual process involving the invasion of one live cell into
another, followed by the degradation of internalized cells by lysosomal
enzymes. This cell death process and apoptosis can both result in the
internalization of one cell inside of another; the mechanisms responsible for
cell internalization are highly distinguishable. Unlike the phagocytic
ingestion of apoptotic cells, cell internalization in suspension is not
associated with caspase activation nor driven by phosphatidylserine exposure.
Paraptosis
Paraptosis, an alternative, nonapoptotic cell death program that may be
induced by the insulin-like growth factor I receptor (among other inducers), is
mediated by mitogen-activated protein kinases (MAPKs). Caspases are not
activated in this process, nor are caspase inhibitors effective in blocking
cell death (23). It is reported that TAJ/TROY, a member of the tumor necrosis
factor receptor superfamily that induces nonapoptotic cell death by paraptosis,
is accompanied by phosphatidylserine externalization and loss of the
mitochondrial transmembrane potential and is independent of caspase activation.
Anoikis
One form of detachment-induced death is an apoptotic program termed
anoikis that has been characterized in suspension cell cultures (25,26). Cell
death induced by detachment from extracellular matrix functions as a luminal
clearing mechanism during development and also may function as a barrier to the
development of carcinomas, which display luminal filling as a hallmark.
MECHANISMS OF CELL DEATH BY CURCUMIN
Curcumin has a diverse range of molecular targets, supporting the
concept that it acts upon numerous biochemical and molecular cascades. Curcumin
physically binds to
as many as 33 different proteins, including thioredoxin reductase,
cyclooxygenase-2, (COX2), protein kinase C, 5-lipoxygenase (5-LOX), and
tubulin. Various molecular targets modulated by this agent include
transcription factors, growth factors and their receptors, cytokines, enzymes,
and genes regulating cell proliferation, and apoptosis. Curcumin has been shown
to inhibit the proliferation and survival of almost all types of tumor cells.
Accumulating evidence suggests that the mode of curcumin-induced cell death is
mediated both by the activation of cell death pathways and by the inhibition of
growth/proliferation pathways. Many studies indicate the selective role of
curcumin towards cancer cells than normal cells. We could identify more than 40
biomolecules that are involved in cell death induced by curcumin.
The mechanistic relationship among different signal transduction
pathways, whether acting alone or together, leading to apoptosis is described.
Because curcumin mediates
Modulation of various cell death pathways by curcumin. Targets
up-regulated by curcumin are in a blue box, those down-regulated are in a
yellow box, and those unaffected are in a white box. AP-1 activator protein-1,
AMPK 5' adenosine monophosphate-activated ...
Caspase Activation
Caspases, or cysteine-aspartic acid proteases, are a family of cysteine
proteases that play essential roles in apoptosis, necrosis, and inflammation.
There are numerous reports that suggests the involvement of caspases in
curcumin-induced apoptosis. Curcumin causes DNA damage and endoplasmic
reticulum (ER) stress and mitochondrial-dependent-induced apoptosis through the
activation of caspase-3. Combined curcumin and TRAIL treatment enhanced
accumulation of hypo-diploid U87MG cells in sub G1 cell cycle phase and induced
the cleavage of procaspases-3, -8, -9, and release of cytochrome c from
mitochondria. Earlier reports suggest that curcumin activates caspases-3 and -8
but not caspase-9, supporting the rationale that apoptosis occurs via a
membrane-mediated mechanism. Both a caspase-8 and broad-based caspase
inhibitor, but not a caspase-9 specific inhibitor, suppressed curcumin-induced
cell death. Curcumin induces apoptosis through mitochondrial pathway involving
caspase-8, BID cleavage, cytochrome c release, and caspase-3 activation in
HL-60 cells.
Induction of Death Receptors
Death receptors are cell surface receptors that transmit apoptotic
signals initiated by specific ligands such as Fas ligand, TNF-α, and TRAIL. These receptors play a crucial
role in apoptosis and can activate a caspase cascade within seconds of ligand
binding. Induction of apoptosis via this mechanism is therefore very rapid.
Studies showed that curcumin inhibited the expression of Bcl-2, Bcl-xL,
survivin, and XIAP, and induced the expressions Bax, Bak, PUMA, Bim, and Noxa
and death receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Curcumin is a potent
enhancer of TRAIL-induced apoptosis through upregulation of DR5 expression.
Both treatment with DR5/Fc chimeric protein and silencing of DR5 expression
using small interfering RNA (siRNA) attenuated curcumin plus TRAIL-induced
apoptosis, showing that DR5 plays a critical role in this mode of cell death.
Curcumin also induced the expression of a potential proapoptotic gene, C/EBP
homologous protein (CHOP), both at its mRNA and protein levels. It has also
been reported that curcumin significantly induces death receptor 5 (DR5)
expression both at the mRNA and protein levels, accompanying the generation of
the reactive oxygen species (ROS).
Fas Receptor Aggregation
Fas receptor is the ligand for Fas-activated apoptosis. Binding of the
ligand promotes receptor clustering, DISC formation and the activation of the
caspase cascade. In addition, the Fas receptor is generally thought only to
activate apoptosis and does not play an important role in other aspects of cell
signaling like the TNF receptor. Curcumin induces Fas receptor aggregation in a
FasL-independent manner, and low-temperature incubation, previously shown to
inhibit receptor aggregation, prevented curcumin-induced cell death. Apoptosis
in nasopharyngeal carcinoma cell line NCE induced by curcumin was found to
up-regulate the Fas receptor gene as well as the protein in a dose-dependent
manner. Curcumin is able to inhibit the proliferation of CA46 cells and induce
apoptosis by down-regulating the expression of c-myc, Bcl-2, and mutant-type
p53, and up-regulating the expression of Fas. Curcumin induced the modulation
of cell cycle and apoptosis in gastric and colon cancer cells and stimulated
the activity of caspase-8, which initiates Fas signaling pathway of apoptosis.
Induction of p53/p21 Pathway
The transcription factor p53 has been reported to play a very important
role in apoptosis. As a tumor suppressor, p53 is responsible for protecting
cells from tumorigenic alterations. Mutational inactivation of p53 is
frequently observed in various human cancers. Studies on cell death on p21(+/+)
and p21(−/−) HCT-116 cells treated with curcumin showed an
associated reduction in pro-caspase-3 and PARP-1 cleavage, which are indicative
of apoptosis, and concluded that curcumin-induced apoptosis in HCT-116 colon
cancer cells does not depend on p21 status. The inhibition of p21 WAF1/CIP1 by
siRNA blocks curcumin-induced apoptosis, thus establishing a link between cell
cycle and apoptosis. Results of Liu et al. demonstrated that ING4 expression
was almost undetectable in U251 cells, but significantly up-regulated during
cell cycle arrest induced by curcumin, and p53 expression was up-regulated followed
by induction of p21 WAF1/CIP1 and ING4. Experiments using p53-null as well as
dominant-negative and wild-type p53-transfected cells have established that
curcumin induces apoptosis in carcinoma cells via a p53-dependent pathway. The
studies showed that curcumin selectively increases p53 expression at G2 phase
of carcinoma cells and releases cytochrome c from mitochondria, which is an
essential requirement for apoptosis.
Release of Apoptosis-Inducing Factor
Apoptosis-inducing factor (AIF) is a mitochondrial apoptogenic protease
that up on an apoptotic stimulus translocates from mitochondria to cytosol and
further to the nucleus, where it triggers chromatin condensation and
large-scale DNA fragmentation. Curcumin-mediated apoptosis in HeLa, SiHa, and Ca
Ski cells appears to be due to upregulation of proapoptotic Bax, AIF, release
of cytochrome c and down-regulation of antiapoptotic Bcl-2, Bcl-xL. It was
shown for the first time by Thayyullathil et al. that curcumin-induced rapid
reactive oxygen species (ROS) generation causes the release of AIF from the
mitochondria to the cytosol and nucleus, hence, leading to caspase
3-independent apoptosis. It is also reported that curcumin-induced release of
cytochrome c, a second mitochondria-derived activator of caspase (Smac) and
AIF, was also blocked in Bax−/− cells.
Cell Cycle Regulation
The cell cycle is set of events, resulting in cell growth and division
into two daughter cells. The stages are G1-S-G2-M. The G1 stage is "GAP
1". The S stage is "Synthesis", this is the stage when DNA
replication occurs. The G2 stage is "GAP 2". The M stage is
"mitosis", and is when nuclear and cytoplasmic division occurs.
Curcumin was found to induce G0/G1 and/or G2/M phase cell cycle arrest,
up-regulate CDKIs, p21WAF1/CIP1, p27KIP1, and p53, and slightly down-regulate
cyclin B1 and cdc2 in ECV304 cells. The cyclin D1 proto-oncogene is an
important regulator of G1 to S phase transition in numerous cell types from
diverse tissues. A study has demonstrated that curcumin induces apoptosis in
the G2 phase of the cell cycle in deregulated cyclin D1-expressing mammary
epithelial carcinoma cells, leaving its normal cells unaffected. Curcumin
induced the expression of cyclin-dependent kinase (CDK) inhibitors p16(/INK4a),
p21 WAF1/CIP1, and p27(/KIP1), and inhibited the expression of cyclin E and
cyclin D1, and hyperphosphorylation of retinoblastoma (Rb) protein. Curcumin
induces the degradation of cyclin E expression through the ubiquitin-dependent
pathway and up-regulates cyclin-dependent kinase inhibitors p21 and p27 in
multiple human tumor cell lines. In human mantle cell lymphoma, curcumin causes
cell cycle arrest at the G1/S phase of the cell cycle and induces apoptosis.
Curcumin enhances the expression of tumor cyclin-dependent kinase (CDK)
inhibitors p21 and p27 as well as tumor suppressor protein p53 but suppressed
the expression of retinoblastoma protein and also induced the accumulation of
cells in G1 phase of the cell cycle in multiple human tumor cell lines. A
recent report shows the activation of ATM/Chk1 by curcumin leads to G2/M cell
cycle arrest and apoptosis in pancreatic cancer cells.
Inhibition of PI3K-AKT Activation
Akt (protein kinase B), a serine/threonine kinase, is a critical enzyme
in signal transduction pathways involved in cell proliferation, apoptosis and
angiogenesis. Studies showed that curcumin concentration- and time-dependently
inhibited the phosphorylation of Akt, mTOR, and their downstream substrates in
human prostate cancer PC-3 cells, and this inhibitory effect acts downstream of
phosphatidylinositol 3-kinase and phosphatidylinositol-dependent kinase 1.
Curcumin causes dose-dependent apoptosis and DNA fragmentation of Caki cells,
which is preceded by the sequential dephosphorylation of Akt, down-regulation of
the antiapoptotic Bcl-2, Bcl-xL, and IAP proteins, release of cytochrome c and
activation of caspase 3. Curcumin-induced effects have been shown to be
associated with the suppression of NF-κB and IKK activities but independent of the
B-Raf/MEK/ERK and Akt pathways in melanoma cell lines.
Inhibition of mTOR
mTOR is a large (>250 kDa) class IV PI-3 kinase family member with
protein kinase activity. mTOR forms a complex with the 12-kDa cytosolic
protein, FKBP-12, and rapamycin and functions to arrest the cell cycle in the
G1 phase. mTOR regulates Akt activity, a crucial downstream effector in the
PI-3K–PTEN pathway, which controls cell proliferation and survival. Targeting
this function of mTOR may also have therapeutic potential. For example,
curcumin was shown to inhibit the Akt/mammalian target of rapamycin/p70
ribosomal protein S6 kinase pathway and activate the
extracellular-signal-regulated kinases (ERK) 1/2, thereby inducing autophagy.
Down-Regulation of Androgen Receptors
Various studies evaluated the role of curcumin in cell growth and
activation of signal transduction pathways in both androgen-dependent and
-independent prostate cancer cell lines. The results showed that curcumin
down-regulated transactivation and expression of AR, AP-1, NF-κB, and CBP. These studies showed
that curcumin has enormous potential as an anticancer agent against prostate
cancer. Curcumin enhanced the apoptosis-inducing potential of TRAIL in
androgen-unresponsive PC-3 cells and sensitized androgen-responsive
TRAIL-resistant LNCaP cells.
Inhibition of Growth Factors and
their Receptors
Growth factors play a critical role in the proliferation of tumor cells.
EGF, HER2, FGF, VEGF, PDGF, insulin growth factor (IGF)-1, and others have been
associated with cell proliferation. The suppression of these growth factors or
their receptors results in suppression of tumor growth. For example, the
inhibition of EGFR expression and decreased ERK1/2 activity decreased survival
and enhanced induction of apoptosis in lung and pancreatic adenocarcinoma
cells. Curcumin inhibited EGF-stimulated phosphorylation of EGFR in MDA-MB-468
cells and phosphorylation of ERK 1 and -2, as well as ERK activity and levels
of nuclear c-fos in MDA-MB-468 and HBL100 cells. Recently it was reported that
curcumin inhibits 253JB-V and KU7 bladder cancer cell growth, which could be
attributed to induction of apoptosis and decreased expression of the
proapoptotic protein survivin and VEGF and VEGFR1.
Inhibition of AMP-Activated Protein
Kinase (AMPK)
AMP-activated protein kinase is a heterotrimeric serine/threonine
protein kinase comprising a catalytic subunit (α) and two regulatory subunits (β and γ). Curcumin strongly activates AMPK in a
p38-dependent manner in CaOV3 ovarian cancer cells, thus inducing cell death.
Stimulation of AMPK by curcumin down-regulated peroxisome
proliferator-activated receptor-gamma (PPAR-γ) in 3T3-L1 adipocytes and decreased COX2
expression in MCF-7 cells, which in turn affects the proliferation rate.
Inhibition of COX2 and
5 LOX
Cyclooxygenase-2 (COX), also known as prostaglandin (PG) H2 synthase, is
the rate-limiting enzyme in the conversion of arachidonic acid into PGs. The
two known forms of COX are referred to as COX1 and COX2. Overexpression of COX2
has been frequently observed in colon tumors, and COX2 plays a major role in
colon carcinogenesis Curcumin was found to modulate both the expression and the
activity of these enzymes. A number of studies were carried out to establish
the role of curcumin in mediating COX2 and 5 LOX. In human colon epithelial
cells, curcumin inhibits COX2 induction by the colon tumor promoters tumor
necrosis factor alpha and fecapentaene-12, thus inhibiting proliferation and
inducing apoptosis. Curcumin has been shown to regulate the eicosanoid pathway
involving COX and LOX. The details of how 5LOX and COX2 are regulated by
curcumin are not fully established; however, we do know that curcumin regulates
LOX and COX2 predominately at the transcriptional level and, to a certain
extent, the posttranslational level. There is a report that the inhibition of
COX2 and Wnt/EGFR/NF-κB-signaling pathways induces apoptosis in colon cancer cells.
Inhibition of Ornithine
Decarboxylase
A recent study has shown that a chemopreventive effect of curcumin could
be due to the hyperproduction of ROS, which would in turn induce apoptosis in
tumor cells. The study found that enzyme activity and protein expression of
ornithine decarboxylase (ODC) were reduced during curcumin treatment.
Overexpression of ODC in human promyelocytic leukemia HL-60 parental cells
could reduce curcumin-induced apoptosis, which would lead to loss of
mitochondrial membrane potential, through reducing intracellular ROS. Moreover,
ODC over expression prevented cytochrome c release and the activation of
caspase-9 and caspase-3 following curcumin treatment. An earlier study showed
the effects of curcumin on renal carcinoma. In the study, Fe-NTA, a known
complete renal carcinogen, which generates ROS in vivo, was given
intraperitoneally to mice, and curcumin was tested for its ability to inhibit
oxidative stress and the ODC activity and histopathological changes in the
kidney. ODC activity in the kidney was significantly increased but remained at
normal levels in curcumin-pretreated mice.
Inhibition of Acidic
Sphingomyelinase
Curcumin's apoptosis-inducing effects in colon cancer cell lines are
accompanied by ceramide generation. This increase occurs through de novo
synthesis, as much as the increase in ceramide could be attenuated by
pre-incubation of the cells with myriocin, and no changes were observed in
sphingomyelin levels or in either acidic or neutral sphingomyelinase
activities. However, the inhibition of ROS using N-acetylcysteine led to an
inhibition of JNK activation. Hence, the study concluded that curcumin induces
apoptosis via a ROS-associated mechanism that converges on JNK activation, and
to a lesser extent via a parallel ceramide-associated pathway. Curcumin reduced
the hydrolytic capacity of the cells against choline-labeled sphingomyelin,
associated with a mild increase in cellular sphingomyelin in the cells.
Curcumin also inhibited acid sphingomyelinase an effect that may account for
its antiproliferative effects against colon cancer cells.
Inhibition of Phospholipase D
The enzymatic activity of phospholipase D (PLD) is known to be essential
for cell survival and protection from apoptosis. During apoptosis, a small
fraction of PLD1 is cleaved by caspases in a p53-independent manner and NF-PLD1
amplifies apoptotic signaling through inhibition of the remaining PLD1 activity
(217). In a cell-free system, curcumin inhibited several types of
phospholipases, most effectively PLD. It also inhibited
12-O-tetradecanoylphorbol-13-acetate-induced PLD activation in intact J774.1
cells in a dose-dependent manner.
Activation of Thioredoxin Reductase
The thioredoxin reductase (TrxR) isoenzymes, TrxR1 in cytosol or nucleus
and TrxR2 in mitochondria, are essential mammalian selenocysteine
(Sec)-containing flavoenzymes with a -Gly-Cys-Sec-Gly active site. TrxRs are
the only enzymes catalyzing the NADPH-dependent reduction of the active site
disulfide in thioredoxins (Trxs), which play essential roles in substrate
reductions, defense against oxidative stress, and redox regulation by thiol
redox control. Trx can scavenge reactive oxygen species (ROS) and directly
inhibits proapoptotic proteins such as apoptosis signal-regulating kinase 1
(ASK1). There are a number of inhibitors with chemotherapy applications that
target either Trx or TrxR to induce apoptosis in cancer cells. A study has
shown that rat TrxR1 activity in Trx-dependent disulfide reduction was
inhibited by curcumin. Different curcumin analogs were also investigated for
their inhibitory effects on thioredoxin reductase (TrxR). Most of them were more
potent TrxR inhibitors than natural curcumin.
Inhibition of STAT3 Activation
Signal transducers and activators of transcription (STATs) play
important roles in numerous cellular events, including differentiation,
inflammation, and the immune response. Furthermore, constitutive STAT
activation can be observed in a high number of tumors. Curcumin is incorporated
into H-RS cells and inhibits both NF-κB and STAT3 activation, leading to decreased
expression of proteins involved in cell proliferation and apoptosis, e.g.,
Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1, survivin, c-myc, and cyclin D1. Curcumin
treatment induced a decrease of nuclear STAT3, -5a, and -5b, without affecting
either STAT1 or the phosphorylation state of STAT1, -3 or -5 in the K562 cell
line. Most interestingly, the decrease of nuclear STAT5a and -5b after curcumin
treatment was accompanied by an increase of truncated STAT5 isoforms,
indicating that curcumin is able to induce the cleavage of STAT5 into its
dominant-negative variants lacking the STAT5 C-terminal region. The
constitutive phosphorylation of STAT3 found in certain multiple myeloma cells
was abrogated by treatment with curcumin, and inhibition of STAT3 by curcumin
leads to the induction of apoptosis.
Activation of c-Jun Kinase
In vitro experiments indicated that inhibition of c-Jun/AP-1 binding to
its cognate motif by curcumin may be responsible for the inhibition of
c-Jun/AP-1-mediated gene expression. Curcumin, a natural inhibitor of JNK
signaling, protected the HT22 cells from glutamate-induced death at nanomolar
concentrations. Curcumin time- and
dose-dependent induction of apoptosis was accompanied by sustained
phosphorylation and activation of c-jun N-terminal kinase (JNK) and p38 MAPK as
well as
inhibition of constitutive NF-κB transcriptional activity.
Induction of DNA Fragmentation
Curcumin inhibits activation of Vgamma9Vdelta2 T cells by
phosphoantigens and induces apoptosis involving apoptosis-inducing factor and
large-scale DNA fragmentation. This cytotoxicity was associated with increased
annexin V reactivity, nuclear expression of active caspase-3, cleavage of
poly(ADP-ribose) polymerase, translocation of apoptosis-inducing factor to the
nucleus, and morphological evidence of nuclear disintegration. Curcumin
activates the apoptotic pathway in human renal Caki cells. Treatment of Caki
cells with 50 μM
curcumin resulted in the activation of caspase 3, cleavage of phospholipase C-γ1, and DNA fragmentation. Curcumin
treatment protected cells from UVC-induced oligonucleosomal DNA degradation.
Experiments using recombinant DFF activated with caspase-3 showed that curcumin
inhibits plasmid DNA and chromatin degradation although it does not prevent
activation of DFF40/CAD endonuclease after its release from the inhibitor.
Curcumin-treated Jurkat cells exhibited DNA splitting into high- but not
low-molecular-weight fragments. These cells retained their high mitochondrial
Delta psi, and the content of Ca2+ in endoplasmic reticulum stores remained at
the level typical for untreated cells.
Direct DNA Damage
Drug- or radiation-induced injury to DNA may produce deviations in DNA’s
normal double helical conformation. These changes include structural
distortions that interfere with replication and transcription, as well as point
mutations that disrupt base pairing and exert damaging effects on future
generations through changes in DNA sequence. If the damage is minor, it can
often be repaired (DNA repair). If the damage is extensive, it can induce
apoptosis. Curcumin induces such DNA damage to both the mitochondrial and
nuclear genomes in human hepatoma G2 cells. The study demonstrated
dose-dependent damage in both the mitochondrial and nuclear genomes and the
greater extent of the mitochondrial damage. The mechanism underlies the
elevation in ROS and lipid peroxidation generated by curcumin. Studies with
mouse–rat hybrid retina ganglion cell line N18 cells showed a dose- and
time-dependent increase in DNA damage with curcumin treatment, which was
confirmed by comet assay as well as agarose gel electrophoresis.
Intracellular [Ca (2±)](i) Depletion
Curcumin induced a marked depletion of [Ca(2+)](i) in Caki cells bathed
with both Ca(2+)-containing and -free solutions. This indicates that curcumin
acts as a stimulator of intracellular Ca(2+) uptake into mitochondria via
uniporter pathway and may involve the execution of apoptosis. Reports suggest
that curcumin may induce the expression of the HSP70 gene through the initial
depletion of intracellular Ca(+2), followed by the suppression of p53 gene function
in the target cells.
Mitochondrial Activation
Mitochondria play a pivotal role in the process of apoptosis. The
intrinsic pathway of apoptosis involves the activation of proapoptotic members
of the Bcl-2 family that exert their function through mitochondria. Role of
mitochondria is well established in a curcumin-induced apoptosis. Curcumin
induces the release of cytochrome c from mitochondria, causing activation of
caspase 3 and concomitant PARP cleavage, which is the hallmark of
caspase-dependent apoptosis (28). Curcumin-induced rapid ROS generation causes
the release of AIF from the mitochondria to the cytosol and nucleus, hence
leading to caspase 3-independent apoptosis (69). HepG2 cells exposed to
curcumin for 1 h showed a transient elevation of mitochondrial membrane
potential (MMP), followed by cytochrome c release into the cytosol and
disruption of MMP after 6 h exposure to curcumin. These results suggest that
mitochondrial hyperpolarization is a prerequisite for curcumin-induced
apoptosis and that mtDNA damage is the initial event triggering a chain of
events leading to apoptosis in HepG2 cells . A study on curcumin protection of
PC12 cells against MPP (+)-induced apoptosis suggested that the cytoprotective
effects of curcumin might be mediated by the Bcl-2-mitochondria-ROS-iNOS
pathway. Curcumin induced an increase in rat liver mitochondrial membrane
permeability, resulting in swelling, loss of membrane potential and inhibition
of ATP synthesis. These effects were mediated by the opening of the permeability
transition pore. Curcumin targets proliferative cells more efficiently than
differentiated cells and induces apoptosis via mitochondrial pathways. Addition
of curcumin to neuro 2a cells induces a rapid decrease in mitochondrial
membrane potential and the release of cytochrome c into cytosol, followed by
activation of caspase-9 and caspase-3.
Binding and Inhibition of Glyoxalase
Glyoxalases (Glo1 and Glo2) are involved in the glycolytic pathway by
detoxifying the reactive methylglyoxal (MGO) into d-lactate in a two-step
reaction using glutathione (GSH) as cofactor. Inhibitors of glyoxalases are
considered antiinflammatory and anti-tumor agents. Curcumin inhibits Glo1,
resulting in non-tolerable levels of MGO and GSH. As a result, various
metabolic pathways are disturbed, so that for example, cellular ATP and GSH
content are depleted. The depletion of cellular ATP and GSH may in turn
decrease cell survival.
Suppression of Antiapoptotic
Proteins
The inhibitors of apoptosis (IAP) proteins are a recently discovered
class of caspase inhibitors that selectively bind and inhibit caspase-3, -7,
and -9; these inhibitors have great potential in the treatment of malignancy.
Curcumin is reported to inhibit the expression of these caspases inhibitors
both in vitro and in vivo. Other antiapoptotic proteins that are inhibited by
curcumin include Bcl-2, Bcl-xL, X-linked inhibitors of apoptosis (XIAP), and
survivin. Curcumin sensitizes prostate cancer cells to TRAIL by inhibiting
Akt-regulated NF-κB
and NF-kappaB-dependent antiapoptotic Bcl-2, Bcl-xL, and XIAP. Curcumin-induced
apoptosis in human androgen-independent (DU145) and -dependent (LNCaP) prostate
cancer cell lines and HL-60 cells, which correlated with down-regulation of the
expression of Bcl-2 and Bcl-xL
Binding to Microtubules
Curcumin may inhibit cancer cell proliferation by perturbing microtubule
assembly dynamics. At higher inhibitory concentrations (>10 μM), curcumin induced significant depolymerization
of interphase microtubules and mitotic spindle microtubules of HeLa and MCF-7
cells. However, at low inhibitory concentrations there were minimal effects on
cellular microtubules. It disrupted microtubule assembly in vitro, reduced
GTPase activity, and induced tubulin aggregation. In one study,
curcumin-down-regulated Taxol induced phosphorylation of the serine/threonine
kinase Akt, a survival signal which in many instances is regulated by
NF-kappaB, but tubulin polymerization and cyclin-dependent kinase Cdc2
activation induced by Taxol was not affected by curcumin.
Proteasome Activation
It has been reported that curcumin-induced apoptosis is mediated through
the impairment of ubiquitin proteasome system (UPS). Curcumin disrupts UPS
function by directly inhibiting the enzyme activity of the proteasome's 20S
core catalytic component. The direct inhibition of proteasome activity also
causes an increase in half-life of IκBα that ultimately leads to the down-regulation
of NF-κB
activation, thus activating the apoptotic pathway. Exposure of mouse neuro 2a
cells to curcumin causes a dose-dependent decrease in proteasome activity and
an increase in ubiquitinated proteins. Curcumin targets proliferative cells
more efficiently than differentiated cells and induces apoptosis via
mitochondrial pathways.
Pro- and Antioxidant Mechanisms
Studies have shown that curcumin mediates its apoptotic and
antiinflammatory activities through modulation of the redox status of the cell.
TNF-mediated NF-κB
activation was inhibited by curcumin; and glutathione reversed the inhibition.
Glutathione also counteracted the inhibitory effects of curcumin on TNF-induced
NF-κB-regulated
antiapoptotic (Bcl-2, Bcl-xL, IAP1), proliferative (cyclin D1), and
proinflammatory (COX2, iNOS, and MMP-9) gene products. Reports suggest that
curcumin modifies TrxR by shifting the enzyme from an antioxidant to a
prooxidant. Low concentrations of curcumin may protect hepatocytes by reducing
lipid peroxidation and cytochrome c release. Conversely, higher concentrations
provoke glutathione depletion, caspase-3 activation, and hepatocytotoxicity.
Curcumin pretreatment significantly decreased ROS and resulted in survival of
copper-injured BRL cells, possibly by anti-oxidation and inhibition of p-JNK expression.
Curcumin induces apoptosis via ROS generation in malignant cells, but not in
normal cells. In Jurkat cells, curcumin prevents glutathione decrease, thus
protecting cells against caspase-3 activation and oligonucleosomal DNA
fragmentation. In normal cells, curcumin induces apoptosis in a
glutathione-independent pathway.
Autophagy
Autophagy is a response of cancer cells to various anticancer therapies.
It is designated programmed cell death type II and characterized by the
formation of autophagic vacuoles in the cytoplasm. In one study, curcumin
induced G2/M arrest and nonapoptotic autophagic cell death in U87-MG and
U373-MG malignant glioma cells. It inhibited the Akt/mTOR/p70S6K pathway and
activated the ERK1/2 pathway, resulting in induction of autophagy. In the
subcutaneous xenograft model of U87-MG cells, curcumin inhibited tumor growth
significantly (P < 0.05) and induced autophagy. It inhibited the
Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase pathway and
activated the extracellular-signal-regulated kinases and induced autophagy.
Inhibition of NF-κB
The transcription factor NF-κB is constitutively expressed in almost all
cancer types and suppresses apoptosis in a wide variety of tumors. The
constitutive expression of NF-κB has been reported in human cancer cell lines in culture,
carcinogen-induced mouse mammary tumors, and biopsies from cancer patients.
There are various reports that curcumin inhibits the activation of NF-κB by inducers such as TNF, H2O2.
phorbol ester, cigarette smoke condensate, interleukin (IL)-1,
12-O-tetradecanoylphorbol-13-acetate (TPA), and anticancer drugs. Curcumin
inhibits the activation of NF-κB and the expression of various oncogenes regulated by NF-κB, including c-jun, c-fos, c-myc, NIK,
MAPKs, ERK, ELK, PI3K, Akt, CDKs, and iNOS. Curcumin prevents the entry of NF-κB into the nucleus, thereby
decreasing the expression of cell cycle regulatory proteins and survival
factors such as Bcl-2 and survivin. Curcumin arrested the cell cycle by
preventing the expression of cyclin D1, cdk-1, and cdc-25.
In hepatic cancer HA22T/VGH cell line, curcumin inhibited constitutively
activated NF-κB
and NF-κB
regulated gene products such as apoptosis proteins (IAPs) and other target
genes. It inhibits TNF-induced NF-κB-regulated gene products involved in cellular
proliferation (COX2, cyclin D1, and c-myc), antiapoptosis (IAP1, IAP2, XIAP,
Bcl-2, and Bcl-xL;. Curcumin could prevent tumor-induced thymic atrophy by
restoring the activity of NF-κB. Further investigations suggest that neutralization of tumor-induced
oxidative stress and restoration of NF-κB activity along with the reduction of the TNF-α signaling pathway can be the
mechanism behind curcumin-mediated thymic protection. Curcumin down-regulated
NF-κB in human
multiple myeloma cells, leading to the suppression of proliferation and
induction of apoptosis.
Inhibition of Wnt/beta-catenin
Signaling
The Wnt/beta-catenin signaling pathway plays a major role in
development, tissue homeostasis, and regeneration. The deregulation of this
pathway is found in various human cancers. Numerous reports suggest that
curcumin is a good inhibitor of b-catenin/Tcf signaling in gastric, colon, and
intestinal cancer cells. It has been reported
that inhibition of Wnt-2 had synergistic effects on suppressing Wnt
signaling and inducing apoptosis, suggesting that aberrant canonical
Wnt/beta-catenin signaling in colorectal cancer can be regulated at multiple
levels. Thus, the proapoptotic effects of curcumin could be mediated through
this pathway
Activation of Nrf2
Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive
basic leucine zipper transcription factor that is involved in the
transcriptional regulation of many antioxidant genes. The Nrf2/antioxidant
response element (ARE) signaling pathway plays a key role in activating
cellular antioxidants, including heme oxygenase-1 HO-1), NADPH quinone
oxidoreductase-1 (NQO1), and glutathione. Curcumin treatment results in ROS
generation, activation of Nrf2 and MAP kinases and the inhibition of
phosphatase activity in hepatocytes, and when curcumin is not administered in
toxic doses, these multiple pathways converge to induce HO-1. Another study
further suggests that curcumin has the ability to induce HO-1 expression, presumably
through Nrf2-dependent ARE activation in rat vascular smooth muscle cells and
human aortic smooth muscle cells, and provide evidence that the
antiproliferative effect of curcumin is considerably linked to its ability to
induce HO-1 expression.
Inhibition of hTERT
Another possible activity of curcumin able to induce cell death
processes is the inhibition of hTERT, the active subunit of telomerase.
Increasing concentrations of curcumin caused a decrease in the level of hTERT
mRNA in MCF-7 cells. hTERT is activated in cancer cells and prevents telomere
shortening and thus the activation of apoptotic processes. The inhibition of
hTERT is an additional mechanism by which curcumin can induce cell death in
cancer cells.
EFFECT OF CURCUMIN ON NORMAL CELLS
Curcumin has been shown to have differential effects on normal cells
such as endothelial cells, lymphocytes, hepatocytes, fibroblasts, thymocytes,
and mammary epithelial cells. Why curcumin kills tumor cells and not normal
cells is not fully understood, but several reasons have been suggested. First,
absorption and Fluoreszenz
spectroscopic methods
showed that cellular uptake of curcumin is higher in tumor cells than in normal
cells. The studies also showed that curcumin was maximally distributed in the
cell membrane and the nucleus. Second, the glutathione levels in tumor cells
tend to be lower than normal cells, thus enhancing the sensitivity of tumor
cells to curcumin. Third, most tumor cells, but not normal cells, express constitutively
active NF-κB and
mediate their survival. Curcumin can suppress the survival and proliferation of
tumor cells by suppressing NF-κB-regulated gene products. Apart from this, human epidermal
keratinocytes have been shown to undergo apoptosis when exposed to curcumin
through the inhibition of AP-1. Low concentrations of curcumin may protect
hepatocytes by reducing lipid peroxidation and cytochrome c release.
Conversely, higher concentrations provoke glutathione depletion, caspase-3
activation, and hepatocytotoxicity. Interestingly, curcumin had no effect on
normal rat hepatocytes, which showed no superoxide generation and therefore no
cell death. Primary cultures of human dermal fibroblasts were less sensitive to
lower doses of curcumin. Studies have shown that curcumin causes fibroblast
apoptosis and that this could be inhibited by co-administration of antioxidants
N-acetyl-l-cysteine , biliverdin or bilirubin, suggesting that ROS are
involved. In endothelial cells, curcumin inhibited MAP kinase activity and
enhanced TNF-induced apoptosis. Studies suggests that curcumin induces the
apoptosis in human retinal endothelial cells by the regulation of intracellular
ROS generation, VEGF expression and release, and VEGF-mediated PKC-beta II
translocation. Curcumin can induce cell death in both quiescent and
proliferating normal human lymphocytes, without oligonucleosomal DNA
degradation, which is considered a main hallmark of apoptotic cell death.
Curcumin induces cell death in lymphocytes that can be classified as
apoptosis-like cell death.
CONCLUSION
Overall, our review shows that curcumin can kill a wide variety of tumor
cell types through diverse mechanisms. Because of numerous mechanisms of cell
death employed by curcumin, it is possible that cells may not develop
resistance to curcumin-induced cell death. Furthermore, its ability to kill
tumor cells and not normal cells makes curcumin an attractive candidate for
drug development. Although numerous animal studies and clinical trials have
been done, additional studies are needed to gain the full benefit from
curcumin.
Vorwort/Suchen Zeichen/Abkürzungen Impressum