Luteolin is a potent anticancer agent that could halt a wide spectrum of
tumors and cancer cells
Molecular targets of luteolin in cancer
Introduction
Compounds of natural origin could lead
to new, innovative therapeutic agents for cancer. Several promising new
anticancer agents have been developed and used in the clinic on the basis of
their selective molecular targets (Rengarajan et
al., 2014). Yet, the progress of modern technology enables us to design and
synthesize drug molecules for specific molecular targets. Therefore, we can
shift our attention from chemically synthetic drugs to purely natural ones (Ortholand and
Ganesan, 2004; Montaser and
Luesch, 2011). Luteolin (3,4,5,7-tetrahydroxy flavone) is a natural flavonoid
present in several plants. Vegetables and fruits rich in luteolin include
carrots, broccoli, onion leaves, parsley, celery, sweet bell peppers, and
chrysanthemum flowers (Miean and Mohamed,
2001; Sun et al.,
2007; Chen et al.,
2012b; Lim et al.,
2013). Like other flavonoids, luteolin is mainly glycosylated in plants.
During digestion and intestinal absorption, luteolin’s glycosylated form is
mainly hydrolyzed to free luteolin (Hempel et
al., 1999). However, during passage through the intestinal stroma, some luteolin
can reconvert into its glycosylated form (Shimoi et
al., 1998). Luteolin is a heat-stable reagent that degrades relatively little
during cooking (Le Marchand, 2002). Luteolin has
potent activity against cancer, inflammation, and oxidation, and it can reverse
multidrug resistance (MDR) in many types of cancer cells (Park et al.,
2012; Ou et al.,
2013; Chen et al.,
2014; Jeon et al.,
2014; Khan et al.,
2014). Alone or with other chemotherapeutics, luteolin can sensitize MDR
cancer cells (Dellafiora et
al., 2014). It can also ameliorate the cytotoxicity that various chemotherapy
drugs can cause. Despite luteolin’s well-documented anticancer properties,
exactly how these work remains unclear. To the best of my knowledge, no seminal
review has determined the potential mechanisms of luteolin’s anticancer
activities, except that published by Lin et al. (2008).
Apoptosis pathways
Apoptosis occurs through two major
pathways: intrinsic and extrinsic. The intrinsic apoptosis pathway operates by
modulating mitochondrial membrane potential, which releases cytochrome c and
inhibits the expression of antiapoptotic proteins Bcl-2 and Bcl-xL. The
extrinsic apoptosis pathway operates through activation of caspase-3, -7, -8,
and -9 and enhanced expression of death receptors and their downstream factors,
such as DR4, DR5, tumor necrosis factor receptor apoptosis-inducing ligand
(TRAIL), and Fas/FasL (Ham et al.,
2014). When the signal of apoptosis is received, Fas-associated death domain
binds and recruits the death-induced signaling complex, forming initiator
caspases-8 and -10 (Park et al.,
2013b). Any alteration or interruption in the mitochondrial membrane could
activate both intrinsic and extrinsic apoptosis pathways by triggering caspase
activities; promoting imbalance of the Bax/Bcl-xL ratio; and decreasing the
expression of p21, survivin, Mcl-1, and mdm2 proteins (Chang et
al., 2005; Lim do et
al., 2007; Chen et al.,
2012a). Researchers have implicated the endoplasmic reticulum as a third
subcellular compartment involved in apoptosis (Nakagawa et
al., 2000; Rao et al.,
2004).
In many ways, luteolin can trigger both
intrinsic and extrinsic apoptosis pathways in a variety of human cancer cells
(Fig. (Fig.1).1). In part, luteolin
can arrest the cell cycle and then induce apoptosis. For instance, in the
SH-SY5Y neuroblastoma tumor cell line, luteolin arrests G0/G1 cell cycle
growth, accompanied by loss of mitochondrial membrane potential and apoptosis (Wang et al.,
2014). Furthermore, luteolin inhibits SMMC-7721 and BEL-7402 cell
proliferation by arresting the cell cycle at the G1/S phase, enhancing
the level of Bax and reducing the level of antiapoptotic protein Bcl-2, leading
to apoptosis (Ding et al.,
2014). Luteolin can also directly induce apoptosis by activating JNK, which
inhibits the translocation of tumor necrosis factor α (TNF-α)-mediating nuclear
factor-κB (NF-κB) p65 to the nucleus (Cai et al.,
2011). Furthermore, in human non-small-cell lung cancer A549 cells,
apoptosis occurs by phosphorylating JNK and inhibiting NF-κB translocation as a
transcription factor from the nucleus (Hu et al.,
2012). Surprisingly, although luteolin increased Bax and caspase-3
expression and upregulated Bcl-2 expression in liver carcinoma cells, it
exerted almost no effect on normal liver HL-7702 cells (Ding et al.,
2014).
Mechanisms of
luteolin (Lut)-induced apoptosis and autophagy in cancer cells. Luteolin
mediates both the intrinsic and the extrinsic apoptosis pathways. Luteolin
triggers the intrinsic apoptosis pathway by modulating mitochondrial membrane
potential, releasing cytochrome c, and inhibiting the expression of
Bcl-2 and Bcl-xL. Luteolin mediates extrinsic apoptosis by activating caspase
activities; enhances expression of death receptors and their downstream factors
such as Fas/FasL, DR4, DR5, and TRAIL; and suppresses other death receptor
survival pathways. Luteolin also inhibits mdm2 activated by Ras; mdm2
expression triggers p53 degradation. p53, a tumor suppressor protein, mediates
apoptosis by enhancing Bax levels and reducing levels of antiapoptotic protein
Bcl-2. Luteolin can directly mediate apoptosis by mediating DNA damage induced
by ROS. DNA damage signaling, in turn, enhances p53 production and activity.
Luteolin activates JNK, which inhibits TNF-α-mediated NF-κB (p65)
translocation, promoting TNF-α-induced apoptosis in cancer cells. However,
luteolin can mediate autophagy as a cell death mechanism by triggering the
intracellular acidic lysosomal vacuolization and accumulation of
microtubule-associated LC3 II protein, which in turn enhances autophagy flux.
IKK, I-κB kinase; LC3, light chain-3; NF-κB, nuclear factor-κB; ROS, reactive
oxygen species; TNF-α, tumor necrosis factor α; TRAIL, tumor necrosis factor
receptor apoptosis-inducing ligand.
Autophagy
Autophagy is a process of cellular
self-eating activated by lysosomal activity caused by nutrient depletion. In
addition to its role in maintaining cellular balance under normal physiological
conditions, it is also implicated in the development of genetic diseases and
drug resistance in cancer cells (Uekita et
al., 2013; Gewirtz, 2014; Wang and Wu, 2014). Luteolin-induced
autophagy functions as a cell death mechanism (Fig. (Fig.1)1) by accumulating
microtubule-associated protein light chain-3 II protein, which in turn enhances
autophagy flux (Park et al.,
2013a). In metastatic MET4 cells, luteolin stimulated autophagy by triggering
intracellular acidic lysosomal vacuolization (Verschooten et
al., 2012).
Cell cycle regulation
The cell cycle, arranged in the
following phases, leads to cell growth and division:
- In
the G1 phase, the cell grows
and chromosomes prepare for replication.
- In
the S phase, DNA replicates and chromosomes duplicate.
- The
G2 phase represents the
gap between DNA synthesis and mitosis.
- In
the M phase (mitosis), nuclear and cytoplasmic division occurs, yielding
two daughter cells.
Luteolin can keep several human cancers
from growing, but the precise molecular mechanisms are unclear. Figure Figure22 shows the
molecular mechanisms underlying luteolin’s antiproliferative activities.
Luteolin induces cell cycle arrest and apoptosis by decreasing the expression
of AKT, PLK1, cyclin B1, cyclin A, CDC2, CDK2, Bcl-2, and Bcl-xL as well as
increasing the expression of Bax, caspase-3, and p21 (Lee et al.,
2012; Pandurangan et
al., 2013). Luteolin also arrested colon cancer cell growth through
Wnt/β-catenin/glycogen synthase kinase-3β (GSK-3β) signaling (Pandurangan et
al., 2013). However, luteolin can obviously arrest the cell cycle by suppressing
Akt phosphorylation, which dephosphorylates and activates GSK-3β. Activating GSK-3β
enhances phosphorylation of cyclin D1 at Thr-286, followed by proteasomal
degradation (Ong et al.,
2010).
Luteolin (Lut)
modulates cancer cell cycle progression. Luteolin’s antiproliferative activity
is attributed to its ability to inhibit IGF-1 activation, thus preventing the
phosphorylation of the intracellular IRS-1 and its downstream targets.
Furthermore, luteolin inhibits IGF-1-mediated PI3K/Akt activation by reducing
the expression of ERα. Estradiol receptor triggers the PI3K/AKT pathway,
mediating FKHR phosphorylation, which functionally associates with ERα and
forms a FKHR–ERα complex. Inhibiting AKT activity reduces phosphorylation of
its downstream targets, including p70S6K1, GSK-3β, and FKHR. Luteolin
suppresses prostate cancer cell proliferation by downregulating AR expression.
Phosphorylation of the cytoplasmic AR by MAPK and AKT enables AR to form dimers
and enhances ARE. By contrast, luteolin upregulates the expression of PDEF,
which acts as an androgen-independent transcriptional activator of the
prostate-specific antigen promoter. AR, androgen receptor; ARE, androgen
response element; ER, estrogen receptor; Erk, extracellular signal-regulated
kinase; FKHR, forkhead transcription factor; FLT3, Fms-like tyrosine kinase 3;
GSK-3β, glycogen synthase kinase-3β; IGF-1, insulin-like growth factor 1;
IRS-1, insulin receptor substrate 1; ITD, internal tandem duplications; MAPK,
mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PDEF,
prostate-derived Ets factor; PSAP, prosaposin; TDK, tyrosine kinase domain.
Potential molecular
targets of luteolin-mediated cell cycle arrest
Insulin-like growth factor 1 (IGF-1) is
crucial in cellular growth, proliferation, and apoptosis (Katic and Kahn,
2005; Pollak, 2008). Altered IGF-1
function is implicated in tumorigenesis, metastasis, and resistance of human
cancer cells (Lin et al.,
2014). IGF-1 signaling begins when IGF-1 binds with its cell surface
receptor, IGF-1R, forming a homodimer signaling complex, phosphorylating
IGF-1R, which then phosphorylates intracellular insulin receptor substrate 1
(IRS-1) for its downstream targets (Chitnis et
al., 2008; Aleksic et
al., 2010). In HT-29 cells treated with luteolin, reduced IGF-1R signaling
downregulated the PI3K/Akt and ERK1/2 pathways (Lim do et
al., 2012). However, luteolin’s inhibitory action on IGF-1 extends beyond inhibiting
IGF-1R; it can also inhibit Akt signaling (Fang et al.,
2007). Inhibition of Akt signaling in turn dephosphorylates its downstream
targets, including p70S6K1, GSK-3β, and FKHR/FKHRL1 (forkhead human
transcription factor like 1). Moreover, in estrogen receptor (ER)-positive
tumors and cell lines, IGF signaling can also cooperate with the ER to promote
tumor growth and progression, while hindering the efforts of endocrine therapy
(Zhang et
al., 2011; Mancini et
al., 2014). Targeting ERα is a possible mechanism of luteolin’s antiproliferative
effect (Wang et al.,
2012a). Using an ERα-specific small interfering RNA to knock down ERα in
MCF-7 cells reduced luteolin’s ability to inhibit the growth of MCF-7 cells.
This finding suggests that luteolin’s inhibitory effect on cancer cell growth
may inhibit the IGF-1-mediated PI3K/Akt pathway depending on ERα expression.
Thus, the downregulation of the PI3K/Akt and mitogen-activated protein
kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways through
luteolin’s reduction of IGF-1R/ERα signaling pathways may offer promising
routes for cancer therapeutic agents.
Fms-like tyrosine kinase 3 (FLT3) is
another potential means by which luteolin arrests the cell cycle. In one study,
FLT3 was highly overexpressed in most patients with acute myeloid leukemia (Chin et al.,
2013). Luteolin suppressed cell proliferation in MV4-11 cells with
constitutively activated FLT3, suggesting that luteolin may be a potent FLT3
enzyme inhibitor.
Downregulated androgen receptor
expression could be a main mechanism through which luteolin mediates its
antiproliferative and anti-invasive effects in LNCaP human prostate cancer
cells (Chiu and Lin, 2008). By contrast,
luteolin upregulates the expression of prostate-derived Ets factor (PDEF) in
LNCaP cells, which acts as an androgen-independent transcriptional activator of
the prostate-specific antigen promoter (Tsui et al.,
2012).
Molecular targets of luteolin-induced
apoptosis
Nuclear factor-κB-induced
and tumor necrosis factor α-induced apoptosis pathway
NF-κB is synthesized in the cytoplasm
and complexed with its inhibitor I-κB; thus, NF-κB is released as an inactive
form. To activate, I-κB must undergo phosphorylation, followed by proteasomal
degradation of the NF-κB–p-κB complex. The free p-NF-κB then translocates to
the nucleus to transcribe and activate genes to synthesize progrowth and
antiapoptosis proteins (Lun et al.,
2005). NF-κB is a heterodimer composed of two subunits: the DNA-binding
subunit p50 and the transactivator p65. Phosphorylation of IκBα is mediated by
the I-κB kinase (IKK) complex, which consists of NF-κB essential modulators
IKKγ, IKKα, and IKKβ, degrading IκBα through a ubiquitin/proteasomal process (Thomas et
al., 2009). Degrading IκBα allows insertion of NF-κB’s two subunits into the
nucleus to transcribe and activate target genes.
The NF-κB transcription factor plays a
major role in the development and progression of various cancers (Erez et al.,
2013; Wu et al.,
2013; Kagoya et
al., 2014). In many cancers, TNF-α is one of the most important activators for
NF-κB and plays a paramount role in activating pathways for both cancer cell
death and survival. On the one hand, TNF-α’s activation of NF-κB abolishes
TNF-induced cancer cell apoptosis, which plays a marginal role in the
development of resistance in cancer cells. On the other, blocking NF-κB
enhances TNF-α’s anticancer activity (Ju et al.,
2007). Luteolin can suppress NF-κB, thus activating TNF-α-induced apoptosis
(Fig. (Fig.3).3). A possible
mechanism for this process is through its ability to mediate the release of
reactive oxygen species, which suppresses NF-κB and activates JNK, stimulating
cancer cells to undergo TNF-α-induced apoptosis (Ju et al.,
2007). Hwang et
al. (2011) suggested AMPK as a novel regulator of NF-κB in luteolin-induced
cancer cell death (Hwang et
al., 2011), as inhibiting AMPK activity restored luteolin-inhibited NF-κB
DNA-binding activity.
Mechanism of
luteolin (Lut)-triggered TNF-α-induced cancer cell apoptosis. Free p-NF-κB
translocates to the nucleus to mediate the transcriptional activation of genes.
Luteolin can suppress the activity of NF-κB translocation, activating the
TNF-α-induced apoptosis pathway. The generation of ROS caused by treatment with
luteolin plays a marginal role in suppressing NF-κB, further enforcing JNK
activation. ROS activate the AMPK signaling pathway, which interacts with the
NF-κB pathway, thereby inhibiting NF-κB DNA-binding activity. Activating JNK
activates the mitochondrial apoptosis pathway. Furthermore, luteolin’s
inhibition of NF-κB activity augments and prolongs cJNK activation induced by
TNF-α. AMPK, AMP-activated protein kinase; AP-1, activating protein 1; ATF2,
activating transcription factor 2; JNK/cJNK, c-Jun N-terminal kinase; NF-κB,
nuclear factor-κB; ROS, reactive oxygen species; TNF-α, tumor necrosis factor
α.
Reactive oxygen species generation
caused by luteolin treatment is the major mechanism through which luteolin
activates AMPK (Hwang et
al., 2011). However, luteolin can obviously induce apoptosis in human
non-small-cell lung cancer A549 cells by phosphorylating JNK, activating the
mitochondrial pathways of apoptosis while inhibiting NF-κB translocation (Hu et al.,
2012). Furthermore, luteolin’s inhibition of NF-κB augmented and prolonged
TNF-α-induced cJNK activation (Shi et al.,
2004). Taken together, these findings indicate that luteolin’s sensitization
of TNF-α-induced cancer cell death may encompass many cancer types.
Interestingly, inhibiting NF-κB’s transcription activity also downregulated the
expression of vascular endothelial growth factor (VEGF) mRNA, inhibiting VEGF
secretion in pancreatic carcinoma cells (Cai et al.,
2012). This finding suggested that luteolin had potent antiangiogenesis
activity.
Tumor necrosis
factor receptor apoptosis-inducing ligand
TRAIL is an endogenous protein
belonging to the TNF family. TRAIL induces apoptosis in a wide variety of
transformed and cancer cells, but has little or no effect on normal cells (Rushworth and
Micheau, 2009). Luteolin can sensitize TRAIL-induced apoptosis in both
TRAIL-sensitive cancer cells, including HeLa (Horinaka et
al., 2005; Shi et al.,
2005; Yan et al.,
2012) and human 786-O renal cell carcinoma (Ou et al.,
2013), and TRAIL-resistant cancer cells (CNE1, HT-29, and HepG2) (Shi et al.,
2005). Luteolin is also a potential sensitizer of TRAIL in anticancer
therapy against human renal cell carcinoma involving Akt and STAT3 inactivation
(Ou et al.,
2014). However, the Janus tyrosine kinases (Jak1) and tyrosine kinase 2
(Tyk2) mediate most, if not all, cellular responses to peptide hormones, cytokines,
and interferons (IFNs) and are often hyperactivated in tumors (Muller et
al., 2014). In fact, neither Jak1 nor Tyk2 has serine activities (Carbone and Fuchs,
2014); thus, they must undergo phosphorylation before they can act. Luteolin
can sensitize the antiproliferative effect of IFN by enhancing phosphorylation
of Jak1 and Tyk2, thus ensuring the activation of STAT1/2, which promotes STAT1
accumulation in the nucleus and endogenous IFN-α-regulated gene expression (Tai et al.,
2014). Treatment with TRAIL and luteolin markedly reduced the growth of
xenograft tumors in animals (Yan et al.,
2012). Therefore, luteolin’s potent activity to sensitize both
TRAIL-sensitive and TRAIL-resistant cancer cells may represent another
dimension for the development of new techniques enabling us to conjugate
luteolin or use it as a juvenile agent with other anticancer drugs.
Modulation of
Wnt/β-catenin signaling
Wnt/β-catenin signaling regulates the proliferation
and differentiation of many normal and malignant cells (Abdel-Magid, 2014; Draganova et
al., 2015; Zhao and Carrasco,
2014). Luteolin’s antiproliferative effect on cancer may be attributed to
its inhibitory effect on Wnt/β-catenin signaling. For instance, luteolin
decreases the expression of Wnt/β-catenin/GSK-3β signaling, arresting the
growth of colon cancer cells (Pandurangan et
al., 2013). Wnt/β-catenin/GSK-3β signaling is also involved in luteolin-prevented
azoxymethane-induced cellular proliferation (Pandurangan et
al., 2014).
Topoisomerases
Topoisomerases, especially DNA
topoisomerases, are among the most desired targets for chemotherapy drugs.
Topoisomerase inhibition might correlate with the antioxidant capacity of the
flavonoids (Topcu et
al., 2008). Chowdhury et
al. (2002) published the first report on luteolin functionally inhibiting the
catalytic activity of topoisomerase. The second report was by Wu and Fang (2010), speculating that
luteolin has chymotrypsin-like and trypsin-like catalytic activities in tumor
cells. In a canine tumor cell line (DH82), luteolin was highly cytotoxic
without causing considerable DNA damage (Silva et
al., 2013). However, no studies have examined luteolin’s ability to modulate
topoisomerases in human cancer cells. Further studies are needed.
Heat shock protein
90
Heat shock protein 90 (Hsp90)
stabilizes newly synthesized proteins and helps maintain the functional
competency of several signaling transducers involved in cell growth, survival,
and oncogenesis. Therefore, interest grows in Hsp90 as an important target for
molecular cancer therapy (Zhang et
al., 2005; Beck et al.,
2009). In the past few years, many specific inhibitors for Hsp90 have been
developed, such as geldanamycin (GA) and its derivatives. However, GA is not
used clinically because of serious toxic effects in the liver and kidney (Wang et al.,
2006). Despite its effectiveness in clinical trials for cancer, 17-AAG
(17-allylamino-17-demethoxygeldanamycin), a GA derivative, has several
problems, including stability, solubility, and hepatotoxicity. Luteolin can
block Hsp90 by inhibiting its association with STAT3 (Fu et al.,
2012). This action degrades phosphor-STAT3 (Tyr-705) and phosphor-STAT3
(Ser-727)-phosphorylated STAT3 through a proteasome-dependent pathway. Hsp90 is
one of the most important regulators of the Akt signaling pathway (Zhang et
al., 2005; Beck et al.,
2009). Surprisingly, a recent study presented protein phosphatase 2A (PP2A)
as an alternative target for luteolin (Ou et al.,
2013). This study suggests that PP2A activation may work with Hsp90 cleavage
to inactivate Akt and lead to a vicious caspase-dependent apoptotic cycle.
Stabilization of
tumor suppressor protein p53
The tumor suppressor protein p53, a
transcription factor, controls the cell cycle (and arrests it in case of DNA
damage). Inhibition of tumor growth through cell cycle arrest and induction of
apoptosis are functionally related to p53 (Kobayashi et
al., 2002; Didelot et
al., 2003). Luteolin could mediate p53 stabilization and accumulation, which
induces apoptosis and prevents cell proliferation in many cancer cell lines,
including breast cancer (Momtazi-Borojeni et
al., 2013), Eca109 (Wang et al.,
2012b), gastric cancer AGS (Wu et al.,
2008), HT-29 colon cancer (Lim do et
al., 2007), and head and neck and lung cancer (Amin et al.,
2010). In two human colorectal carcinoma-derived cell lines with
microsatellite instability – CO115 with wild-type p53 and HCT15 harboring a p53
mutation – luteolin enhanced p53 expression (Xavier et
al., 2011). In an in-vivo nude mouse xenograft model, luteolin enhanced
cisplatin’s anticancer activity by promoting p53 stabilization and accumulation
(Shi et al.,
2007). Also, luteolin ameliorates cisplatin’s nephrotoxicity by
downregulating the p53-dependent apoptotic pathway in the kidney (Kang et al.,
2011).
Mammalian target of
rapamycin signaling
Mammalian target of rapamycin (mTOR), a
key regulator of various cellular activities, belongs to the family of PI3K-related
kinases and is one of the most commonly activated signaling pathways in human
cancer (Faivre et
al., 2006). Chiang et
al. (2007) showed that luteolin inhibited cell proliferation and mediated
apoptosis in HER2-overexpressing cancer cells. Also, in nude mice with
xenografted SKOV3.ip1-induced tumors, luteolin inhibited HER2 expression and
tumor growth. In that study, but only at low doses, luteolin upregulated the
expression of p21 and transiently inhibited mTOR signaling. That finding
suggests luteolin’s inability to cause sustained Akt/mTOR inhibition, which may
contribute to the p21 induction that may confer a survival advantage on
HER2-overexpressing cancer cells (Fig. (Fig.4).4). Therefore, suppressing
p21 expression along with mTOR inhibition may be a good way to improve
anticancer drugs against HER2-overexpressing tumors.
Luteolin (Lut)
modulates the Raf/PI3K signaling pathway in KRAS and BRAF mutated cancer cells
and HER2-overexpressing cancer cells. Luteolin inhibits Ras’s downstream client
proteins and PI3K signaling pathways. Luteolin noncompetitively binds with ATP
to abolish Raf activity and competitively binds with ATP to inhibit PI3K
activity. However, p21 induction by luteolin could confer on cancer cells a
survival advantage by activating mTOR signaling. mTOR, mammalian target of
rapamycin.
Raf and PI3K
KRAS and BRAF mutations are common in
colorectal carcinoma and can activate proliferation and survival through
MAPK/ERK and/or PI3K signaling pathways. In KRAS-mutated HCT15 cells, luteolin
decreased ERK phosphorylation, whereas it had no effect on phospho-ERK in
BRAF-mutated CO115 cells. This finding suggests that luteolin’s
antiproliferative and apoptotic effects can be attributed to its activity on
KRAS and PI3K, but not on BRAF (Xavier et
al., 2009). In another study, luteolin inhibited Raf and PI3K activities and
attenuated phosphorylation of MEK and Akt (Kim et al.,
2013). The potential mechanism for this event is that luteolin
noncompetitively binds with ATP to suppress Raf activity and competitively
binds with ATP to inhibit PI3K activity (Fig. (Fig.44).
Preventing tumor invasion and
metastasis
Metastasis is the major cause of death
from cancer (Weng and Yen, 2012; Lin et al.,
2013). In metastasis, cancer cells migrate from the primary tumor to other
sites, forming secondary tumors. Several reports showed that flavonoids
naturally inhibit cancer invasion and metastasis. As discussed above, studies
have confirmed luteolin’s antiproliferative activities in many cancer cell
lines, but how it affects invasion by cancer cells remains unclear.
Figure Figure55 shows the
possible molecular targets whereby luteolin inhibits the invasion of cancer
cells.
Possible molecular
targets whereby luteolin (Lut) inhibits the invasion of cancer cells. Luteolin
inhibits hypoxia-induced EMT, at least in part, by inhibiting the expression of
integrin β1 and FAK. Luteolin prevents cancer cell migration by activating the
modulator protein of cell division, Cdc42, which modulates PI3K/AKT activity by
facilitating its degradation through the proteasomal pathway. Luteolin acts as
a novel HGF/c-Met inhibitor by suppressing phosphorylation of c-Met tyrosine
kinase, induced by HGF, thereby inhibiting cancer cell invasion. Because it can
reduce AKT phosphorylation, luteolin mediates inhibition of mdm2, upregulating
E-cadherin. Of note, downregulation of E-cadherin results in the loss of
cell–cell adhesion. Luteolin could interfere in the PI3K–Akt–NF-κB–Snail
pathway, thus attenuating TGF-β1-induced EMT of cancer cells. Luteolin reduces
the expression of VEGF mRNA by inhibiting NF-κB transcription activity, thus
inhibiting VEGF secretion. Furthermore, luteolin suppresses VEGF-A-induced
phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT,
ERK, and mTOR, thus reducing cell viability and possibly leading to apoptosis.
Cdc42, cycle 42; EMT, epithelial–mesenchymal transition; ERK, extracellular
signal-regulated kinase; FAK, focal adhesion kinase; FASN, fatty acid
synthesis; HGF, hepatocyte growth factor; ; mdm2, mouse double minute 2
homolog; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; TGF-1,
transforming growth factor-1; VEGF, vascular endothelial growth factor.
Integrin β1 and
focal adhesion kinase
Hypoxia-induced epithelial–mesenchymal
transition (EMT) is an essential step in cancer metastasis. Luteolin inhibits
the expression of integrin β1 and focal adhesion kinase (FAK), which are
closely related to EMT formation. This relationship suggests that luteolin
inhibits hypoxia-induced EMT, at least in part, by inhibiting the expression of
integrin β1 and FAK (Ruan et al.,
2012a). Luteolin also inhibits EMT in malignant melanoma cells both in
vitro and in vivo by regulating β3 integrin (Ruan et al.,
2012b). Taken together, these findings show luteolin’s potential as an
anticancer chemopreventive and chemotherapeutic agent to prevent EMT.
Cycle 42
A recent study showed that luteolin
prevents the migration of glioblastoma cells by affecting PI3K/AKT activation,
modulating the expression of cell division protein cycle 42 (Cdc42), and
facilitating its degradation by the proteasome pathway (Cheng et
al., 2013). This finding suggests that pharmacological inhibition of migration by
luteolin is likely to preferentially facilitate the degradation of Cdc42.
Understanding Cdc42’s function and degradation by specific inhibitors adds
another dimension for the development of potent therapeutic modalities in the
context of invasion and metastasis and may be useful for cancer patients.
Fatty acid
synthesis
Fatty acid synthesis is now associated
with clinically aggressive tumor behavior and tumor cell growth and has become
a novel target pathway for chemotherapy development (Cheng et
al., 2014; Hamada et
al., 2014). Coleman et
al. (2009) reported a novel connection between fatty acid synthesis activity
and c-Met protein expression, suggesting that luteolin could act as a novel
hepatocyte growth factor (HGF)/c-Met inhibitor by reducing the expression of
this receptor. However, adding palmitate prevented luteolin from suppressing
c-Met protein expression.
c-Met tyrosine
kinase
c-Met tyrosine kinase plays paramount
roles in cancer invasion and metastasis in many types of cancer cells. c-Met
tyrosine kinase acts as a membrane receptor for HGF. Aberrant activation of the
HGF/MET signaling is strongly implicated in the malignant transformation and
progression of many tumors which are characterized by an aggressive metastatic
phenotype and a poor prognosis (Hack et al.,
2014; Lee et al.,
2014; Vigna and Comoglio,
2014). Luteolin acts as a novel HGF/c-Met inhibitor by suppressing
phosphorylation of c-Met tyrosine kinase. Luteolin thus inhibits HGF-induced
cell invasion in human DU145 prostate and hepatoma HepG2 cancer cells (Lee et al.,
2006; Coleman et
al., 2009). Luteolin’s inhibition of HGF/MET signaling represents a validated and
effective therapeutic tool in the battle against cancer.
E-cadherin
E-cadherin, a marker of epithelial
cells, maintains cell–cell adhesion. Decreased expression of E-cadherin thus
leads to a prominent increase of cell invasion (Borchers et
al., 1997; Soncin et
al., 2009; Chen et al.,
2010; Lin et al.,
2011).
Luteolin prevents the invasion of
prostate cancer PC3 cells by inhibiting mdm2 expression and inducing E-cadherin
expression (Zhou et al.,
2009). Moreover, pretreatment of A549 lung cancer cells with luteolin
prevented TGF-β1 from downregulating E-cadherin, maintained normal
morphological appearance, and prevented EMT of lung cancer cells (Chen et al.,
2013). Furthermore, TGF-β1’s activation of the PI3K–Akt–IκBα–NF-κB–Snail
pathway reduced the activity of E-cadherin, which pretreatment with luteolin
prevented. This finding suggests that luteolin could be involved as a juvenile
agent with chemotherapeutics to prevent EMT of a wide spectrum of cancer cells.
Angiogenesis
Angiogenesis, the formation of new blood
vessels from existing vascular beds, plays a marginal role in tumor growth,
invasion, and metastasis. Luteolin exerted strong antiangiogenesis activity in
chick chorioallantoic membrane and anti-invasive activity on breast cancer
cells. It also downregulates the expression of astrocyte elevated gene 1
(AEG-1), a novel oncoprotein, and matrix metalloproteinase-2 (MMP-2) (Jiang et
al., 2013). Luteolin can inhibit the in-vivo growth of gastric tumors; this
mechanism may correlate with downregulated expression of VEGF-A and MMP-9 (Lu et al.,
2013). In prostate cancer cells, luteolin suppressed VEGF-A-induced
phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT,
ERK, and mTOR, reducing cell viability, followed by induction of apoptosis (Pratheeshkumar et
al., 2012). Alternatively, luteolin can reduce the expression of VEGF mRNA by
inhibiting NF-κB transcription activity, inhibiting VEGF secretion in
pancreatic carcinoma cells (Cai et al.,
2012).
Luteolin with other anticancer drugs
MDR is an obstacle in cancer treatment,
often because less drug accumulates in tumor cells owing to enhanced drug
efflux (Limtrakul et
al., 2004). In oxaliplatin-resistant cell lines, luteolin inhibited the Nrf2
pathway and reversed MDR (Chian et
al., 2014a). Furthermore, in non-small-cell lung cancer, luteolin inhibits the
Nrf2 pathway in vivo and can serve as an adjuvant in
chemotherapy (Chian et
al., 2014b). Pretreatment of BxPC-3 human pancreatic cancer with luteolin,
followed by gemcitabine inhibited protein expression of nuclear GSK-3β and
NF-κB p65, was accompanied by increased proapoptotic cytosolic cytochrome c (Johnson and
Gonzalez de Mejia, 2013). Coadministration of luteolin and paclitaxel
activated caspase-8 and -3 and increased expression of Fas by blocking STAT3 (Yang et al.,
2014). In an in-vivo nude mouse xenograft model, luteolin enhanced p53
accumulation, reinforcing cisplatin’s therapeutic activity (Shi et al.,
2007). Surprisingly, luteolin prevented cisplatin from causing
nephrotoxicity by downregulating the p53-dependent apoptotic pathway in the
kidney (Kang et al.,
2011). Finally, luteolin may act against metastasis because it can suppress
the production of MMP-9 and MMP-2 and upregulate TIMP2 gene
expression (Pandurangan et
al., 2014). Taken together, these findings show that luteolin can serve as an
adjuvant – not only to enhance the potency of chemotherapeutics but also to
reduce their cytotoxicity.
Epigenetic regulation
In recent years, researchers have
extensively documented that epigenetic mechanisms such as DNA methylation and
histone modification regulate activities of many cancer cells (Mirza et
al., 2013; Yu et al.,
2013; Farkas et
al., 2014). Therefore, epigenetic regulation is an attractive target for cancer
therapeutics (Ptak and Petronis,
2008). In fact, the human genome has four DNA methyltransferase genes (DNMT),
encoding proteins with distinct functions (Mirza et
al., 2013). However, histone tails (and their modifications) regulate diverse
biological processes such as transcription, DNA repair, cell division, and
differentiation (Van Attikum and
Gasser, 2005; Duncan et
al., 2008). Unfortunately, the literature offers no precise information on the
epigenetic regulation of luteolin in cancer cells. In a study on the HeLa cell
line, luteolin-induced E3 ubiquitin-protein ligase UHRF1 and DNMT1
downregulation was accompanied by global DNA hypomethylation (Krifa et
al., 2013). Attoub et
al. (2011) first presented luteolin as a potent histone deacetylase (HDAC)
inhibitor that enhances cisplatin cytotoxicity in LNM35 cells and reduces the
growth of LNM35 tumor xenografts in athymic mice (Attoub et
al., 2011). However, an urgent need remains to study epigenetic regulation of
luteolin in different cancer cell lines. By taking advantage of epigenetic
modifications, we can use HDAC and DNMT inhibitors to control various cancer
cell activities. Moreover, luteolin may be a promising HDAC inhibitor for
cancer treatment. The US Food and Drug Administration has already approved some
HDAC and DNMT inhibitors, such as azanucleoside drugs, to treat myelodysplastic
syndromes and acute myeloid leukemia (Garcia-Manero and
Fenaux, 2011; Yu et al.,
2013).
Conclusion
Luteolin is a potent anticancer agent
that could halt a wide spectrum of tumors and cancer cells, including MDR
cells. Preclinical and clinical trials using luteolin as an adjuvant supplement
for cancer therapy should place this fascinating agent at the forefront of new
therapeutic approaches and then translate this study’s concepts into clinical
applications.
References
- Abdel-Magid
AF. (2014). Wnt/beta-catenin signaling pathway inhibitors: a
promising cancer therapy. ACS Med Chem Lett 5:956–957. [PMC free
article] [PubMed]
- Aleksic
T, Chitnis MM, Perestenko OV, Gao S, Thomas PH, Turner GD, et al.
(2010). Type 1 insulin-like growth factor receptor translocates to
the nucleus of human tumor cells. Cancer Res70:6412–6419. [PMC free
article] [PubMed]
- Amin
AR, Wang D, Zhang H, Peng S, Shin HJ, Brandes JC, et al.
(2010). Enhanced anti-tumor activity by the combination of the
natural compounds (−)-epigallocatechin-3-gallate and luteolin: potential
role of p53. J Biol Chem 285:34557–34565. [PMC free
article] [PubMed]
- Attoub
S, Hassan AH, Vanhoecke B, Iratni R, Takahashi T, Gaben AM, et al.
(2011). Inhibition of cell survival, invasion, tumor growth and
histone deacetylase activity by the dietary flavonoid luteolin in human
epithelioid cancer cells. Eur J Pharmacol 651:18–25. [PubMed]
- Beck
R, Verrax J, Gonze T, Zappone M, Pedrosa RC, Taper H, et al.
(2009). Hsp90 cleavage by an oxidative stress leads to its client
proteins degradation and cancer cell death. Biochem
Pharmacol77:375–383. [PubMed]
- Borchers
AH, Sanders LA, Bowden GT. (1997). Regulation of matrilysin
expression in cells of squamous cell carcinoma by E-cadherin-mediated
cell–cell contact. J Cancer Res Clin Oncol123:13–20. [PubMed]
- Cai
X, Ye T, Liu C, Lu W, Lu M, Zhang J, et al. (2011). Luteolin induced
G2 phase cell cycle arrest and apoptosis on non-small cell lung cancer
cells. Toxicol In Vitro 25:1385–1391. [PubMed]
- Cai
X, Lu W, Ye T, Lu M, Wang J, Huo J, et al. (2012). The molecular
mechanism of luteolin-induced apoptosis is potentially related to
inhibition of angiogenesis in human pancreatic carcinoma cells. Oncol
Rep 28:1353–1361. [PubMed]
- Carbone
CJ, Fuchs SY. (2014). Eliminative signaling by Janus kinases: role in
the downregulation of associated receptors. J Cell
Biochem 115:8–16. [PMC free
article] [PubMed]
- Chang
J, Hsu Y, Kuo P, Kuo Y, Chiang L, Lin C. (2005). Increase of
Bax/Bcl-XL ratio and arrest of cell cycle by luteolin in immortalized
human hepatoma cell line. Life Sci 76:1883–1893. [PubMed]
- Cheng
WY, Chiao MT, Liang YJ, Yang YC, Shen CC, Yang CY. (2013). Luteolin
inhibits migration of human glioblastoma U-87 MG and T98G cells through
downregulation of Cdc42 expression and PI3K/AKT activity. Mol Biol
Rep 40:5315–5326. [PMC free
article] [PubMed]
- Cheng
CS, Wang Z, Chen J. (2014). Targeting FASN in breast cancer and the
discovery of promising inhibitors from natural products derived from
traditional chinese medicine. Evid Based Complement Alternat
Med 2014:232946. [PMC free
article] [PubMed]
- Chen
T, Yuan D, Wei B, Jiang J, Kang J, Ling K, et al.
(2010). E-cadherin-mediated cell–cell contact is critical for induced
pluripotent stem cell generation. Stem
Cells 28:1315–1325. [PubMed]
- Chen
Q, Liu S, Chen J, Zhang Q, Lin S, Chen Z, Jiang J. (2012a). Luteolin
induces mitochondria-dependent apoptosis in human lung adenocarcinoma
cell. Nat Prod Commun 7:29–32. [PubMed]
- Chen
Z, Kong S, Song F, Li L, Jiang H. (2012b). Pharmacokinetic study of
luteolin, apigenin, chrysoeriol and diosmetin after oral administration
of Flos Chrysanthemi extract in
rats. Fitoterapia83:1616–1622. [PubMed]
- Chen
KC, Chen CY, Lin CJ, Yang TY, Chen TH, Wu LC, Wu CC. (2013). Luteolin
attenuates TGF-beta1-induced epithelial–mesenchymal transition of lung
cancer cells by interfering in the PI3K/Akt–NF-kappaB–Snail
pathway. Life Sci 93:924–933. [PubMed]
- Chen
R, Hollborn M, Grosche A, Reichenbach A, Wiedemann P, Bringmann A, Kohen
L. (2014). Effects of the vegetable polyphenols
epigallocatechin-3-gallate, luteolin, apigenin, myricetin, quercetin, and
cyanidin in primary cultures of human retinal pigment epithelial
cells. Mol Vis 20: , 242–258. [PMC free
article] [PubMed]
- Chian
S, Li YY, Wang XJ, Tang XW. (2014a). Luteolin sensitizes two
oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic
drugs via inhibition of the Nrf2 pathway. Asian Pac J Cancer
Prev 15:2911–2916. [PubMed]
- Chian
S, Thapa R, Chi Z, Wang XJ, Tang X. (2014b). Luteolin inhibits the
Nrf2 signaling pathway and tumor growth in vivo. Biochem Biophys Res
Commun 447:602–608. [PubMed]
- Chiang
CT, Way TD, Lin JK. (2007). Sensitizing HER2-overexpressing cancer
cells to luteolin-induced apoptosis through suppressing p21(WAF1/CIP1)
expression with rapamycin. Mol Cancer Ther 6:2127–2138. [PubMed]
- Chin
YW, Kong JY, Han SY. (2013). Flavonoids as receptor tyrosine kinase
FLT3 inhibitors. Bioorg Med Chem Lett 23:1768–1770. [PubMed]
- Chitnis
MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM. (2008). The type 1
insulin-like growth factor receptor pathway. Clin Cancer
Res 14:6364–6370. [PubMed]
- Chiu
FL, Lin JK. (2008). Downregulation of androgen receptor expression by
luteolin causes inhibition of cell proliferation and induction of
apoptosis in human prostate cancer cells and
xenografts. Prostate 68:61–71. [PubMed]
- Chowdhury
AR, Sharma S, Mandal S, Goswami A, Mukhopadhyay S, Majumder HK.
(2002). Luteolin, an emerging anti-cancer flavonoid, poisons
eukaryotic DNA topoisomerase I. Biochem J366:653–661. [PMC free
article] [PubMed]
- Coleman
DT, Bigelow R, Cardelli JA. (2009). Inhibition of fatty acid synthase
by luteolin post-transcriptionally down-regulates c-Met expression independent
of proteosomal/lysosomal degradation. Mol Cancer
Ther 8:214–224. [PMC free
article] [PubMed]
- Dellafiora
L, Mena P, Del Rio D, Cozzini P. (2014). Modelling the effect of
phase II conjugations on topoisomerase I poisoning: pilot study with
luteolin and quercetin. J Agric Food Chem 62:5881–5886. [PubMed]
- Didelot
C, Mirjolet JF, Barberi-Heyob M, Ramacci C, Teiten MH, Merlin JL.
(2003). Oncoprotein expression of E6 and E7 does not prevent
5-fluorouracil (5FU) mediated G1/S arrest and apoptosis in 5FU resistant
carcinoma cell lines. Int J Oncol 23:81–87. [PubMed]
- Ding
S, Hu A, Hu Y, Ma J, Weng P, Dai J. (2014). Anti-hepatoma cells
function of luteolin through inducing apoptosis and cell cycle
arrest. Tumour Biol 35:3053–3060. [PubMed]
- Draganova
K, Zemke M, Zurkirchen L, Valenta T, Cantu C, Okoniewski M, et al.
(2015). Wnt/beta-catenin signaling regulates sequential fate
decisions of murine cortical precursor cells. Stem
Cells33:170–182. [PubMed]
- Duncan
EM, Muratore-Schroeder TL, Cook RG, Garcia BA, Shabanowitz J, Hunt DF,
Allis CD. (2008). Cathepsin L proteolytically processes histone H3
during mouse embryonic stem cell
differentiation. Cell 135:284–294. [PMC free
article] [PubMed]
- Erez
N, Glanz S, Raz Y, Avivi C, Barshack I. (2013). Cancer associated
fibroblasts express pro-inflammatory factors in human breast and ovarian
tumors. Biochem Biophys Res Commun 437:397–402. [PubMed]
- Faivre
S, Kroemer G, Raymond E. (2006). Current development of mTOR
inhibitors as anticancer agents. Nat Rev Drug
Discov 5:671–688. [PubMed]
- Fang
J, Zhou Q, Shi XL, Jiang BH. (2007). Luteolin inhibits insulin-like
growth factor 1 receptor signaling in prostate cancer
cells. Carcinogenesis 28:713–723. [PubMed]
- Farkas
SA, Vymetalkova V, Vodickova L, Vodicka P, Nilsson TK. (2014). DNA
methylation changes in genes frequently mutated in sporadic colorectal
cancer and in the DNA repair and Wnt/beta-catenin signaling pathway
genes. Epigenomics 6:179–191. [PubMed]
- Fu
J, Chen D, Zhao B, Zhao Z, Zhou J, Xu Y, et al. (2012). Luteolin
induces carcinoma cell apoptosis through binding Hsp90 to suppress
constitutive activation of STAT3. PLoS One 7:e49194. [PMC free
article] [PubMed]
- Garcia-Manero
G, Fenaux P. (2011). Hypomethylating agents and other novel
strategies in myelodysplastic syndromes. J Clin
Oncol 29:516–523. [PMC free
article] [PubMed]
- Gewirtz
DA. (2014). An autophagic switch in the response of tumor cells to
radiation and chemotherapy. Biochem Pharmacol 90:208–211. [PubMed]
- Hack
SP, Bruey JM, Koeppen H. (2014). HGF/MET-directed therapeutics in
gastroesophageal cancer: a review of clinical and biomarker
development. Oncotarget 5:2866–2880. [PMC free
article] [PubMed]
- Ham S,
Kim KH, Kwon TH, Bak Y, Lee DH, Song YS, et al. (2014). Luteolin
induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and
activation of extrinsic and intrinsic signaling pathways in
HPV-18-associated cells. Oncol Rep 31:2683–2691. [PubMed]
- Hamada
S, Horiguchi A, Asano T, Kuroda K, Asakuma J, Ito K, et al.
(2014). Prognostic impact of fatty acid synthase expression in upper
urinary tract urothelial carcinoma. Jpn J Clin Oncol 44:486–492. [PubMed]
- Hempel
J, Pforte H, Raab B, Engst W, Böhm H, Jacobasch G. (1999). Flavonols
and flavones of parsley cell suspension culture change the antioxidative
capacity of plasma in rats. Nahrung 43:201–204. [PubMed]
- Horinaka
M, Yoshida T, Shiraishi T, Nakata S, Wakada M, Nakanishi R, et al.
(2005). The combination of TRAIL and luteolin enhances apoptosis in
human cervical cancer HeLa cells. Biochem Biophys Res
Commun 333:833–838. [PubMed]
- Hu
C, Cai X, Hu T, Lu W, Cao P. (2012). Mechanism of growth inhibition
effect of 3′,4′,5,7-tetrahydroxyflavone on A549 cells. Zhongguo Zhong
Yao Za Zhi 37:1259–1264. [PubMed]
- Hwang
JT, Park OJ, Lee YK, Sung MJ, Hur HJ, Kim MS, et al.
(2011). Anti-tumor effect of luteolin is accompanied by AMP-activated
protein kinase and nuclear factor-kappaB modulation in HepG2
hepatocarcinoma cells. Int J Mol Med 28:25–31. [PubMed]
- Jeon
IH, Kim HS, Kang HJ, Lee HS, Jeong SI, Kim SJ, Jang SI.
(2014). Anti-inflammatory and antipruritic effects of luteolin from
Perilla (P. frutescens L.)
leaves. Molecules 19:6941–6951.[PubMed]
- Jiang
Y, Xie KP, Huo HN, Wang LM, Zou W, Xie MJ. (2013). Inhibitory effect
of luteolin on the angiogenesis of chick chorioallantoic membrane and
invasion of breast cancer cells via downregulation of AEG-1 and
MMP-2. Sheng Li Xue Bao 65:513–518. [PubMed]
- Johnson
JL, Gonzalez de Mejia E. (2013). Interactions between dietary
flavonoids apigenin or luteolin and chemotherapeutic drugs to potentiate
anti-proliferative effect on human pancreatic cancer cells, in
vitro. Food Chem Toxicol 60: , 83–91. [PubMed]
- Ju
W, Wang X, Shi H, Chen W, Belinsky SA, Lin Y. (2007). A critical role
of luteolin-induced reactive oxygen species in blockage of tumor necrosis
factor-activated nuclear factor-kappaB pathway and sensitization of
apoptosis in lung cancer cells. Mol Pharmacol 71:1381–1388.[PubMed]
- Kagoya
Y, Yoshimi A, Kataoka K, Nakagawa M, Kumano K, Arai S, et al.
(2014). Positive feedback between NF-kappaB and TNF-alpha promotes
leukemia-initiating cell capacity. J Clin Invest124:528–542. [PMC free
article] [PubMed]
- Kang
KP, Park SK, Kim DH, Sung MJ, Jung YJ, Lee AS, et al.
(2011). Luteolin ameliorates cisplatin-induced acute kidney injury in
mice by regulation of p53-dependent renal tubular apoptosis. Nephrol
Dial Transplant 26:814–822. [PubMed]
- Katic
M, Kahn CR. (2005). The role of insulin and IGF-1 signaling in
longevity. Cell Mol Life Sci62:320–343. [PubMed]
- Khan
HY, Zubair H, Faisal M, Ullah MF, Farhan M, Sarkar FH, et al.
(2014). Plant polyphenol induced cell death in human cancer cells
involves mobilization of intracellular copper ions and reactive oxygen
species generation: a mechanism for cancer chemopreventive
action. Mol Nutr Food Res 58:437–446. [PubMed]
- Kim
HY, Jung SK, Byun S, Son JE, Oh MH, Lee J, et al. (2013). Raf and
PI3K are the molecular targets for the anti-metastatic effect of
luteolin. Phytother Res 27:1481–1488. [PubMed]
- Kobayashi
T, Nakata T, Kuzumaki T. (2002). Effect of flavonoids on cell cycle
progression in prostate cancer cells. Cancer
Lett 176:17–23. [PubMed]
- Krifa
M, Alhosin M, Muller CD, Gies JP, Chekir-Ghedira L, Ghedira K, et al.
(2013). Limoniastrum guyonianum aqueous gall extract induces
apoptosis in human cervical cancer cells involving p16 INK4A re-expression
related to UHRF1 and DNMT1 down-regulation. J Exp Clin Cancer
Res 32: , 30. [PMC free
article] [PubMed]
- Le
Marchand L. (2002). Cancer preventive effects of flavonoids – a
review. Biomed Pharmacother56:296–301. [PubMed]
- Lee
WJ, Wu LF, Chen WK, Wang CJ, Tseng TH. (2006). Inhibitory effect of
luteolin on hepatocyte growth factor/scatter factor-induced HepG2 cell
invasion involving both MAPK/ERKs and PI3K–Akt pathways. Chem Biol
Interact 160:123–133. [PubMed]
- Lee
EJ, Oh SY, Sung MK. (2012). Luteolin exerts anti-tumor activity
through the suppression of epidermal growth factor receptor-mediated pathway
in MDA-MB-231 ER-negative breast cancer cells. Food Chem
Toxicol 50:4136–4143. [PubMed]
- Lee
YH, Morrison BL, Bottaro DP. (2014). Synergistic signaling of tumor
cell invasiveness by hepatocyte growth factor and hypoxia. J Biol
Chem 289:20448–20461. [PMC free
article] [PubMed]
- Lim
SH, Jung SK, Byun S, Lee EJ, Hwang JA, Seo SG, et al.
(2013). Luteolin suppresses UVB-induced photoageing by targeting JNK1
and p90 RSK2. J Cell Mol Med 17:672–680. [PMC free
article] [PubMed]
- Lim
do Y, Jeong Y, Tyner AL, Park JH. (2007). Induction of cell cycle
arrest and apoptosis in HT-29 human colon cancer cells by the dietary
compound luteolin. Am J Physiol Gastrointest Liver
Physiol292:G66–G75. [PubMed]
- Lim
do Y, Cho HJ, Kim J, Nho CW, Lee KW, Park JH. (2012). Luteolin
decreases IGF-II production and downregulates insulin-like growth factor-I
receptor signaling in HT-29 human colon cancer cells. BMC
Gastroenterol 12:9. [PMC free
article] [PubMed]
- Limtrakul
P, Anuchapreeda S, Buddhasukh D. (2004). Modulation of human
multidrug-resistance MDR-1 gene by natural curcuminoids. BMC
Cancer 4:13. [PMC free
article] [PubMed]
- Lin
Y, Shi R, Wang X, Shen HM. (2008). Luteolin, a flavonoid with
potential for cancer prevention and therapy. Curr Cancer Drug
Targets 8:634–646. [PMC free
article] [PubMed]
- Lin
YS, Tsai PH, Kandaswami CC, Cheng CH, Ke FC, Lee PP, et al.
(2011). Effects of dietary flavonoids, luteolin, and quercetin on the
reversal of epithelial–mesenchymal transition in A431 epidermal cancer
cells. Cancer Sci 102:1829–1839. [PubMed]
- Lin
YC, Tsai PH, Lin CY, Cheng CH, Lin TH, Lee KP, et al. (2013). Impact
of flavonoids on matrix metalloproteinase secretion and invadopodia
formation in highly invasive A431-III cancer cells. PLoS
One 8:e71903. [PMC free
article] [PubMed]
- Lin
YC, Lin JC, Hung CM, Chen Y, Liu LC, Chang TC, et al. (2014). Osthole
inhibits insulin-like growth factor-1-induced epithelial to mesenchymal
transition via the inhibition of PI3K/Akt signaling pathway in human brain
cancer cells. J Agric Food Chem 62:5061–5071. [PubMed]
- Lu
XY, Li YH, Xiao XW, Li XB. (2013). Inhibitory effects of luteolin on
human gastric carcinoma xenografts in nude mice and its
mechanism. Zhonghua Yi Xue Za Zhi 93:142–146. [PubMed]
- Lun
M, Zhang PL, Pellitteri PK, Law A, Kennedy TL, Brown RE.
(2005). Nuclear factor-kappaB pathway as a therapeutic target in head
and neck squamous cell carcinoma: pharmaceutical and molecular validation
in human cell lines using Velcade and siRNA/NF-kappaB. Ann Clin Lab
Sci35:251–258. [PubMed]
- Mancini
M, Gariboldi MB, Taiana E, Bonzi MC, Craparotta I, Pagin M, Monti E.
(2014). Co-targeting the IGF system and HIF-1 inhibits migration and
invasion by (triple-negative) breast cancer cells. Br J
Cancer 110:2865–2873. [PMC free
article] [PubMed]
- Miean
KH, Mohamed S. (2001). Flavonoid (myricetin, quercetin, kaempferol,
luteolin, and apigenin) content of edible tropical plants. J Agric
Food Chem 49:3106–3112. [PubMed]
- Mirza
S, Sharma G, Parshad R, Gupta SD, Pandya P, Ralhan R. (2013). Expression
of DNA methyltransferases in breast cancer patients and to analyze the
effect of natural compounds on DNA methyltransferases and associated
proteins. J Breast Cancer 16:23–31. [PMC free
article] [PubMed]
- Momtazi-Borojeni
AA, Behbahani M, Sadeghi-Aliabadi H. (2013). Antiproliferative
activity and apoptosis induction of crude extract and fractions of Avicennia
marina. Iran J Basic Med Sci16:1203–1208. [PMC free
article] [PubMed]
- Montaser
R, Luesch H. (2011). Marine natural products: a new wave of
drugs? Future Med Chem3:1475–1489. [PMC free
article] [PubMed]
- Müller
S, Chen Y, Ginter T, Schäfer C, Buchwald M, Schmitz LM, et al.
(2014). SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma
cells. Oncotarget 5:3184–3196. [PMC free
article][PubMed]
- Nakagawa
T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J.
(2000). Caspase-12 mediates endoplasmic-reticulum-specific apoptosis
and cytotoxicity by amyloid-beta. Nature 403:98–103.[PubMed]
- Ong
CS, Zhou J, Ong CN, Shen HM. (2010). Luteolin induces G1 arrest in
human nasopharyngeal carcinoma cells via the Akt–GSK-3beta–cyclin D1
pathway. Cancer Lett 298:167–175. [PubMed]
- Ortholand
JY, Ganesan A. (2004). Natural products and combinatorial chemistry:
back to the future. Curr Opin Chem Biol 8:271–280. [PubMed]
- Ou
YC, Kuan YH, Li JR, Raung SL, Wang CC, Hung YY, Chen CJ.
(2013). Induction of apoptosis by luteolin involving akt inactivation
in human 786-o renal cell carcinoma cells. Evid Based Complement
Alternat Med 2013:109105. [PMC free
article] [PubMed]
- Ou
YC, Li JR, Kuan YH, Raung SL, Wang CC, Hung YY, et al. (2014). Luteolin
sensitizes human 786-O renal cell carcinoma cells to TRAIL-induced
apoptosis. Life Sci 100:110–117. [PubMed]
- Pandurangan
AK, Dharmalingam P, Sadagopan SK, Ramar M, Munusamy A, Ganapasam S.
(2013). Luteolin induces growth arrest in colon cancer cells through
involvement of Wnt/beta-catenin/GSK-3beta signaling. J Environ Pathol
Toxicol Oncol 32:131–139. [PubMed]
- Pandurangan
AK, Dharmalingam P, Sadagopan SK, Ganapasam S. (2014). Luteolin
inhibits matrix metalloproteinase 9 and 2 in azoxymethane-induced colon
carcinogenesis. Hum Exp Toxicol33:1176–1185. [PubMed]
- Park
SW, Cho CS, Jun HO, Ryu NH, Kim JH, Yu YS, et al.
(2012). Anti-angiogenic effect of luteolin on retinal
neovascularization via blockade of reactive oxygen species
production. Invest Ophthalmol Vis Sci 53:7718–7726. [PubMed]
- Park
SH, Park HS, Lee JH, Chi GY, Kim GY, Moon SK, et al.
(2013a). Induction of endoplasmic reticulum stress-mediated apoptosis
and non-canonical autophagy by luteolin in NCI-H460 lung carcinoma
cells. Food Chem Toxicol 56:100–109. [PubMed]
- Park
W, Amin AR, Chen ZG, Shin DM. (2013b). New perspectives of curcumin
in cancer prevention. Cancer Prev Res (Phila) 6:387–400. [PMC free
article] [PubMed]
- Pollak
M. (2008). Insulin and insulin-like growth factor signalling in
neoplasia. Nat Rev Cancer8:915–928. [PubMed]
- Pratheeshkumar
P, Son YO, Budhraja A, Wang X, Ding S, Wang L, et al.
(2012). Luteolin inhibits human prostate tumor growth by suppressing vascular
endothelial growth factor receptor 2-mediated angiogenesis. PLoS
One 7:e52279. [PMC free
article] [PubMed]
- Ptak
C, Petronis A. (2008). Epigenetics and complex disease: from etiology
to new therapeutics. Annu Rev Pharmacol Toxicol 48: ,
257–276. [PubMed]
- Rao
RV, Ellerby HM, Bredesen DE. (2004). Coupling endoplasmic reticulum
stress to the cell death program. Cell Death
Differ 11:372–380. [PubMed]
- Rengarajan
T, Nandakumar N, Rajendran P, Haribabu L, Nishigaki I, Balasubramanian MP.
(2014). d-Pinitol promotes apoptosis in MCF-7 cells via induction of
p53 and Bax and inhibition of Bcl-2 and NF-kappaB. Asian Pac J Cancer
Prev 15:1757–1762. [PubMed]
- Ruan
J, Zhang L, Yan L, Liu Y, Yue Z, Chen L, et al. (2012a). Inhibition
of hypoxia-induced epithelial mesenchymal transition by luteolin in
non-small cell lung cancer cells. Mol Med Rep6:232–238. [PubMed]
- Ruan
JS, Liu YP, Zhang L, Yan LG, Fan FT, Shen CS, et al.
(2012b). Luteolin reduces the invasive potential of malignant
melanoma cells by targeting beta3 integrin and the epithelial–mesenchymal
transition. Acta Pharmacol Sin 33:1325–1331. [PMC free
article] [PubMed]
- Rushworth
SA, Micheau O. (2009). Molecular crosstalk between TRAIL and natural
antioxidants in the treatment of cancer. Br J
Pharmacol 157:1186–1188. [PMC free
article] [PubMed]
- Shi
RX, Ong CN, Shen HM. (2004). Luteolin sensitizes tumor necrosis
factor-alpha-induced apoptosis in human tumor
cells. Oncogene 23:7712–7721. [PubMed]
- Shi
RX, Ong CN, Shen HM. (2005). Protein kinase C inhibition and X-linked
inhibitor of apoptosis protein degradation contribute to the sensitization
effect of luteolin on tumor necrosis factor-related apoptosis-inducing
ligand-induced apoptosis in cancer cells. Cancer Res 65:7815–7823. [PubMed]
- Shi
R, Huang Q, Zhu X, Ong YB, Zhao B, Lu J, et al. (2007). Luteolin
sensitizes the anticancer effect of cisplatin via c-Jun NH2-terminal
kinase-mediated p53 phosphorylation and stabilization. Mol Cancer
Ther 6:1338–1347. [PubMed]
- Shimoi
K, Okada H, Furugori M, Goda T, Takase S, Suzuki M, et al.
(1998). Intestinal absorption of luteolin and luteolin
7-O-beta-glucoside in rats and humans. FEBS
Lett 438:220–224. [PubMed]
- Silva
G, Fachin AL, Beleboni RO, França SC, Marins M. (2013). In vitro
action of flavonoids in the canine malignant histiocytic cell line
DH82. Molecules 18:15448–15463. [PubMed]
- Soncin
F, Mohamet L, Eckardt D, Ritson S, Eastham AM, Bobola N, et al.
(2009). Abrogation of E-cadherin-mediated cell-cell contact in mouse
embryonic stem cells results in reversible LIF-independent
self-renewal. Stem Cells 27:2069–2080. [PubMed]
- Sun
T, Xu Z, Wu CT, Janes M, Prinyawiwatkul W, No HK. (2007). Antioxidant
activities of different colored sweet bell peppers (Capsicum annuum L.). J
Food Sci 72:S98–S102. [PubMed]
- Tai
Z, Lin Y, He Y, Huang J, Guo J, Yang L, et al. (2014). Luteolin
sensitizes the antiproliferative effect of interferon α/β by activation of
Janus kinase/signal transducer and activator of transcription pathway
signaling through protein kinase A-mediated inhibition of protein tyrosine
phosphatase SHP-2 in cancer cells. Cell
Signal 26:619–628. [PubMed]
- Thomas
GS, Zhang L, Blackwell K, Habelhah H. (2009). Phosphorylation of
TRAF2 within its RING domain inhibits stress-induced cell death by
promoting IKK and suppressing JNK activation. Cancer
Res 69:3665–3672. [PMC free
article] [PubMed]
- Topcu
Z, Ozturk B, Kucukoglu O, Kilinc E. (2008). Flavonoids in Helichrysum
pamphylicum inhibit mammalian type I DNA topoisomerase. Z
Naturforsch C 63:69–74. [PubMed]
- Tsui
KH, Chung LC, Feng TH, Chang PL, Juang HH. (2012). Upregulation of
prostate-derived Ets factor by luteolin causes inhibition of cell
proliferation and cell invasion in prostate carcinoma cells. Int J
Cancer 130:2812–2823. [PubMed]
- Uekita
T, Fujii S, Miyazawa Y, Hashiguchi A, Abe H, Sakamoto M, Sakai R.
(2013). Suppression of autophagy by CUB domain-containing protein 1
signaling is essential for anchorage-independent survival of lung cancer
cells. Cancer Sci 104:865–870. [PubMed]
- Van
Attikum H, Gasser SM. (2005). The histone code at DNA breaks: a guide
to repair? Nat Rev Mol Cell Biol 6:757–765. [PubMed]
- Verschooten
L, Barrette K, Van Kelst S, Rubio Romero N, Proby C, De Vos R, et al.
(2012). Autophagy inhibitor chloroquine enhanced the cell death
inducing effect of the flavonoid luteolin in metastatic squamous cell
carcinoma cells. PLoS One 7:e48264. [PMC free
article] [PubMed]
- Vigna
E, Comoglio PM. (2014). Targeting the oncogenic Met receptor by
antibodies and gene therapy. Available at: http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2014142a.html. [Accessed May 2014] [PubMed]
- Wang
F, Gao F, Pan S, Zhao S, Xue Y. (2014). Luteolin induces apoptosis,
G0/G1 cell cycle growth arrest and mitochondrial membrane potential loss
in neuroblastoma brain tumor cells. Available at: http://www.ncbi.nlm.nih.gov/pubmed/?term=Luteolin+induces+apoptosis%2C+G0%2FG1+Cell+cycle+growth+arrest+and+mitochondrial+membrane+potential+loss+in+neu-+roblastoma+brain+tumor+cells. [Accessed May 2014][PubMed]
- Wang
J, Wu GS. (2014). Role of autophagy in cisplatin resistance in
ovarian cancer cells. J Biol Chem 289:17163–17173. [PMC free
article] [PubMed]
- Wang
LM, Xie KP, Huo HN, Shang F, Zou W, Xie MJ. (2012a). Luteolin
inhibits proliferation induced by IGF-1 pathway dependent ERalpha in human
breast cancer MCF-7 cells. Asian Pac J Cancer Prev 13:1431–1437. [PubMed]
- Wang
TT, Wang SK, Huang GL, Sun GJ. (2012b). Luteolin induced-growth
inhibition and apoptosis of human esophageal squamous carcinoma cell line
Eca109 cells in vitro. Asian Pac J Cancer Prev13:5455–5461. [PubMed]
- Wang
X, Ju W, Renouard J, Aden J, Belinsky SA, Lin Y.
(2006). 17-Allylamino-17-demethoxygeldanamycin synergistically
potentiates tumor necrosis factor-induced lung cancer cell death by
blocking the nuclear factor-kappaB pathway. Cancer
Res 66:1089–1095. [PubMed]
- Weng
CJ, Yen GC. (2012). Flavonoids, a ubiquitous dietary phenolic
subclass, exert extensive in vitro anti-invasive and in vivo
anti-metastatic activities. Cancer Metastasis Rev 31:323–351.[PubMed]
- Wu
B, Zhang Q, Shen W, Zhu J. (2008). Anti-proliferative and
chemosensitizing effects of luteolin on human gastric cancer AGS cell
line. Mol Cell Biochem 313:125–132. [PubMed]
- Wu
YX, Fang X. (2010). Apigenin, chrysin, and luteolin selectively
inhibit chymotrypsin-like and trypsin-like proteasome catalytic activities
in tumor cells. Planta Med 76:128–132. [PubMed]
- Wu
Z, Peng X, Li J, Zhang Y, Hu L. (2013). Constitutive activation of
nuclear factor kappaB contributes to cystic fibrosis transmembrane
conductance regulator expression and promotes human cervical cancer
progression and poor prognosis. Int J Gynecol Cancer 23:906–915. [PubMed]
- Xavier
CP, Lima CF, Preto A, Seruca R, Fernandes-Ferreira M, Pereira-Wilson C.
(2009). Luteolin, quercetin and ursolic acid are potent inhibitors of
proliferation and inducers of apoptosis in both KRAS and BRAF mutated
human colorectal cancer cells. Cancer Lett 281:162–170. [PubMed]
- Xavier
CP, Lima CF, Rohde M, Pereira-Wilson C. (2011). Quercetin enhances
5-fluorouracil-induced apoptosis in MSI colorectal cancer cells through
p53 modulation. Cancer Chemother Pharmacol68:1449–1457. [PubMed]
- Yan
J, Wang Q, Zheng X, Sun H, Zhou Y, Li D, et al. (2012). Luteolin
enhances TNF-related apoptosis-inducing ligand’s anticancer activity in a
lung cancer xenograft mouse model. Biochem Biophys Res
Commun 417:842–846. [PubMed]
- Yang
MY, Wang CJ, Chen NF, Ho WH, Lu FJ, Tseng TH. (2014). Luteolin
enhances paclitaxel-induced apoptosis in human breast cancer MDA-MB-231
cells by blocking STAT3. Chem Biol Interact 213:60–68. [PubMed]
- Yu
J, Peng Y, Wu LC, Xie Z, Deng Y, Hughes T, et al. (2013). Curcumin
down-regulates DNA methyltransferase 1 and plays an anti-leukemic role in
acute myeloid leukemia. PLoS One 8:e55934. [PMC free
article] [PubMed]
- Zhang
R, Luo D, Miao R, Bai L, Ge Q, Sessa WC, Min W. (2005). Hsp90-Akt
phosphorylates ASK1 and inhibits ASK1-mediated apoptosis. Oncogene 24:3954–3963. [PubMed]
- Zhang
Y, Moerkens M, Ramaiahgari S, de Bont H, Price L, Meerman J, van de Water
B. (2011). Elevated insulin-like growth factor 1 receptor signaling
induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt
signaling routes. Breast Cancer Res 13:R52. [PMC free
article][PubMed]
- Zhao
JJ, Carrasco RD. (2014). Crosstalk between microRNA30a/b/c/d/e-5p and
the canonical Wnt pathway: implications for multiple myeloma
therapy. Cancer Res 74:5351–5358. [PMC free
article][PubMed]
- Zhou
Q, Yan B, Hu X, Li XB, Zhang J, Fang J. (2009). Luteolin inhibits
invasion of prostate cancer PC3 cells through E-cadherin. Mol Cancer
Ther 8:1684–1691. [PubMed]