title: targeting apoptosis pathways in cancer and perspectives with natural compounds ... · 2014....
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Title: Targeting Apoptosis Pathways in Cancer and Perspectives with Natural
Compounds from Mother Nature
Faya Martin Millimouno1,2,3,
† , Jia Dong1
†,
, Liu Yang2
, Jiang Li2
*, Xiaomeng Li1
*
1. The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology,
Northeast Normal University, Changchun 130024, China.
2. Dental Hospital, Jilin University, Changchun 130021, China.
3. Higher Institute of Science and Veterinary Medicine of Dalaba 09, Guinea
† These authors contributed equally to this work.
* Correspondence should be addressed to:
Xiaomeng Li, Telephone: +8613196048876; Fax: +8643185099285; E-mail:
Jiang Li, Tel: +8618686531019; Fax: +8643185579335; E-mail: [email protected]
Financial supports for this article
Ministry of Science and Technology (No. 2010DFA31430),
Ministry of Education of China (NCET-10–0316),
National Natural Science Foundation of China (No. 30871301, 30700827),
Jilin Provincial Science & Technology Department (20130521010JH , YYZX201241),
Changchun Science & Technology Department (No. 2011114-11GH29),
the Program for Introducing Talents to Universities (No. B07017),
and the Fundamental Research Funds for the Central Universities (12SSXM005).
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Abstract
While the incidences are increasing day after day, scientists and researchers taken individually
or by research group are trying to fight against cancer by several ways and also by different
approaches and techniques. Sesquiterpenes, flavonoids, alkaloids, diterpenoids and polyphenolic
represent a large and diverse group of naturally occurring compounds found in a variety of fruits,
vegetables and medicinal plants with various anticancer properties. In this review, our aim is to
give our perspective on the current status of the natural compounds belong to these groups and
discuss their natural sources, their anticancer activity, their molecular targets, and their
mechanism of actions with specific emphasis on apoptosis pathways, which may help the further
design and conduct of preclinical and clinical trials.
Unlike pharmaceutical drugs, the selected natural compounds induce apoptosis by targeting
multiple cellular signaling pathways including transcription factors, growth factors, tumor cell
survival factors, inflammatory cytokines, protein kinases and angiogenesis that are frequently
deregulated in cancers and suggest that their simultaneous targeting by these compounds could
result in efficacious and selective killing of cancer cells. This review suggests they provide a
novel opportunity for treatment of cancer, but clinical trials are still required to further validate
them in cancer chemotherapy.
Keywords: Cancer, Apoptosis, Natural Compounds, Chemoprevention, Signaling pathways.
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1. Introduction
Cancer is a major public health problem and the second leading cause of mortality around the
world, mainly Europe and USA with an incident rate of about 2.6 million cases per year [1, 2]. It
is characterized by unscheduled and uncontrolled cellular proliferation in the spectrum of cell.
Cancer incidence in developing countries has been prevailed by tumor types that are related to
viral, genetic mutations and bacterial contamination [3]. Cancer has a high incidence and a long
period of latency on its development and in the progression of the sickness. There are numerous
risk factors known concerning the development of cancer including age, geographic area and race
[4]. However, cancer is mostly a preventable disease.
Regardless of whether a cancer specifically results from a genetic mutation and viral or bacterial
contamination, the recent extensive research indicated that most cancers are caused by
dysfunction of many genes coding for proteins such as, antiapoptotic proteins, growth factors,
growth factor receptors, transcription factors and tumor suppressors; which constituted the target
for cancer treatment. Prevailing treatment options have limited therapeutic success in cancer in
the past decade. The concept of chemoprevention is gaining increasing attention because it is a
cost-effective alternative for cancer treatment [5]. Cancer chemoprevention by natural
compounds, especially phytochemicals, minerals and vitamins, in a number of studies under both
in vitro and in vivo conditions has shown promising results against various malignancies [6].
In the development of bioactive chemical, natural products have a rich and long history. Herbal
medicines, as an important novel source with a wide range of pharmaceutical potential, are being
used to treat human ailments including almost all kinds of cancer [7].
The involvement of multiple factors underlying developmental stages of cancer at epigenetic,
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genetic, cellular and molecular levels is opening up enormous opportunities to interrupt and
reverse the initiation and progression of the disease and provide scientists and researchers with
numerous targets to arrest by physiological and pharmacologic mechanisms to delay the
development of cancer. The aim of this review is to summarize recent researches on twelve (12)
natural compounds, such as flavonoids (Honokiol, Magnolol, Jaceosidin and Casticin),
sesquiterpenes (Parthenolide, Costunolide, Isoalantolactone and Alantolactone), alkaloid
(Evodiamine), diterpenoids (Oridonin and Pseudolaric Acid B) and polyphenolic (Wedelolactone)
focusing on anticancer activity. The literature was screened from various sites including PubMed,
Scopus, and Elsevier Science Direct Journal. Access to the Elsevier Science Direct Journal was
made possible through library of Northeast Normal University, Changchun, China. We propose
that the development of natural compounds into new anticancer agents has a bright future despite
some difficulties.
2. Natural Sources and Biological Activities of Anticancer Chemopreventive Agents
Natural products are important and valuable resources for drug development. Extensive
researches have been carried out on the phytochemicals, for their health-promoting potential.
They have been found in fruits, vegetables, nuts, seeds, herbs, spices, stems, flowers and tea. The
phyto-constituent from these plants was extracted by several techniques, mainly HPLC, micellar
electrokinetic chromatography (MEKC), microemulsion electrokinetic chromatography
(MEEKC), and their structures were elucidated on the basis of NMR analysis (Figure 1).
The selected natural compounds among diterpenoids, sesquiterpenes, flavonoids, alkaloids and
polyphenolic have been reported for their wide spectrum of biological effects, including
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antifungal, anti-helmintic, antimicrobial, anti-inflammatory, anti-trypanosomal, and
antiproliferative effects on various cancer types as described in Table 1 and Table 2.
3. Role of Natural compounds in Cancer Prevention
Plants provide an extensive reservoir of natural products, demonstrating important structural
diversity, and offer a wide variety of novel and exciting chemical entities and have a long history
of use in the treatment of several illnesses. The significance of natural products in health care is
supported by a report that 80% of the global population still relies on plant derived medicines to
address their health care needs [8]. It is also reported that 50% of all drugs in clinical use are
natural products, or their derivatives, or their analogs [9], and 74% of the most important drugs
consist of plant-derived active ingredients [10]. There are more than 3000 plant species that have
reported to be used in the treatment of cancer in modern medicine [11-14].
There is a continued interest in the investigation of extracts of microorganisms, terrestrial plants
and marine life forms to search for anticancer compounds [12]. Indeed, since 1920s with Berren
blum, chemopreventive have began [11], after a period of relative dormancy, re-entered the
cancer research mainstream in the 1970s through the work of Sporn [15]. Till now, molecules
derived from Mother Nature have played and continue to impart a dominant role in the discovery
of compounds for the development of conventional drug for the treatment of most human
diseases [16].
Medical indications of natural compounds and related drugs, including anticancer, antibacterial,
anti-parasitic, anticoagulant, and immune suppressant agents, are being used to treat 87% of all
categorized human diseases [12]. Since 1970s, drug discovery was based on screening of a large
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number of natural and synthetic compounds; until with the advent of computer and other
molecular biology techniques, resulting in the modern and rational drug discovery [17]. The
selected compounds and many other natural products have traditionally provided a rich source of
drugs for cancer treatment [11].
Although different approaches are available for the discovery of novel and potential therapeutic
agents, natural products from medicinal plants are still one of the best reservoirs for novel agents
with new medicinal activities. Thus, identification of natural compound that selectively has
ability to not only block or inhibit initiation of carcinogenesis but also to reverse the promotional
stages by inducing apoptosis and growth arrest in cancer cells without cytotoxic effects in normal
cells [18]. The chemopreventive properties and molecular targets of selected promising natural
compounds are detailed in Table 1, Figure 2 and Figure 3.
4. Apoptosis Signaling Pathways
Programmed cell death also called apoptosis play crucial roles for embryonic development and
tissue homeostasis of multicellular organisms. It’s carried out in a regulated way, which is
associated with typical morphological features like cell shrinkage, chromatin condensation and
cytoplasmic membrane blabbing. Dysregulated apoptosis has been implicated in a variety of
diseases, including tumor formation or even development of cancer cell drug resistance [19].
Apoptosis is triggered through two well-characterized pathways in mammalian cells. The first
one is extrinsic pathway, depending on triggering of death receptors (e.g. TNF), transmembrane
proteins expressed on the cell surface, and the second is intrinsic pathway, mediated by
molecules released from the mitochondria (e.g. Bcl-2 protein family) [20].
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The extrinsic apoptosis pathway is initiated through the binding of ligand (Fas-associated death
domain (FADD)) to death receptors that contain an intracellular death domain (death-inducing
signaling complexes (DISC)) [21, 22]. The intrinsic pathway is activated by physical or chemical
stimulations, such as hypoxia, growth factor deprivation, cell detachment, or stress signals.
A set of cysteine proteases, both pathways cause the activation of the initiator caspases, which
then activate effector caspases. Caspases are cysteine-dependent aspartate-specific proteases and
are regulated at a post-translational level which ensures that they can be rapidly activated. They
are first synthesized or expressed in cells as inactive proenzyme which consists of a prodomain, a
small subunit and a large subunit forms that require oligomerization and/or cleavage for
activation. However, caspase-independent apoptosis is also reported [23].
Apoptosis is characterized by chromatin condensation and DNA fragmentation, and it is
mediated by caspases [24]. Many apoptotic signals are mediated to cell death machinery through
p53 with other proteins such as TNF, Fas and TRAIL receptors are highly specific physiological
mediators of the extrinsic signaling pathway of apoptosis. Mitochondria are involved in a variety
of key events, such as release of caspases activators, changes in electron transport, loss of
mitochondrial membrane potential, and participation of both pro-and anti-apoptotic Bcl-2 family
proteins [25, 26]. This breakthrough finding may have important implication for targeted cancer
therapy and modern application of natural compounds.
5. Molecular Targets of Natural Chemopreventive Agents
Natural compounds are being actively investigated for their chemopreventive potential, among
flavonoids, sesquiterpenes lactones, alkaloid, diterpenoid and polyphenolic have been extensively
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studied and founded to exhibit chemopreventive properties a broad spectrum of activity against
multiple cancer types in both cell culture and animal models and currently several preventive
trials are ongoing to treat cancers. For insistence, the cell signaling pathways activated by
anticancer natural compounds agents are numerous and different for different targets. Moreover,
the same compound activates different signaling pathways depending on the cell types. The main
signaling pathways activated by anti-cancer chemopreventive agents are illustrated in Figure 2.
6. Targeting Cancer Cells by Regulating Apoptosis Related Proteins Pathway
In normal cells, certain cellular signals control and regulate their growth and all other
mechanisms. When these signals and mechanisms are altered due to various factors, including
mutations that prevent cells to undergo apoptosis, normal cells are transformed into cancerous
cells. Studies thus so far suggest that inhibition of any one of these altered signals or mechanisms
together are helpful in alleviation of cancer.
6.1 p53 and its Family Members Pathway
The tumor suppressor p53 considered as guardian of the genome plays a pivotal role in
controlling the cell cycle, apoptosis, genomic integrity, and DNA repair in response to various
genotoxic stresses [25, 27, 28]. Once active, p53 can bind to regulatory DNA sequences and
activate the expression of target genes, which is important for the suppression of tumor formation
as well as for mediating the cellular responses to many standard DNA damage inducing cancer
therapies by cycle inhibition (p21, reprimo, cyclin G1, GADD45, 14-3-3) and angiogenesis
(TSP1, Maspin, BAI1, GD-AIF), induction of apoptosis (PERP, NOXA, PUMA, p53AIP1,
ASPP1/2, Fas, BAX, PIDD) and genetic stability (p21, DDB2, MSH2, XPC) [29-32].
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Recently, it has also been documented that many natural chemopreventive agents induce cell
cycle arrest and apoptosis by activating p53 and its target genes. Oridonin induced up-regulation
of the functional p53 protein in A2780 [33]. Oridonin increased p53 and its target Bax and
p21waf1 in prostate cancer LNCaP and NCI-H520 cells with wild-type p53 gene [33, 34].
Oridonin also stabilize p53 protein and sensitize TRAIL (TNF receptor apoptosis-inducing ligand)
induced apoptosis, and prevent or delay chemotherapy-resistance in A2780 cells [35]. In human
prostate cancer, honokiol activated p21 (PC-3 and LNCaP) and p53 protein expression (LNCaP)
[36].
Honokiol increased phosphorylated p53 in both HCT116H and CT116-CH3 cell lines [37]. In
skin cancer, p53 activation is lead to the induction of DNA fragmentation and apoptosis [38].
Honokiol is particularly effective in several tumor xenograft systems with deficits in p53
signaling, including PC3, MDA-MD-231, and SVR cells [39]. Furthermore, honokiol in a
concentration-and time-dependent manner independent of their androgen responsiveness or p53
status induced Bax, Bak, and Bad in PC-3, LNCaP, and C4-2 cells [40]. p53 expression had no
remarkable changes in honokiol-induced in human colorectal RKO cell line [41].
Casticin also induced p53-mediated apoptosis by activating its pro-apoptotic protein Bax in
U251, U87 and U373 glioma cell [42]. Casticin induce a p53-independent apoptosis in a human
non-small-cell lung carcinoma cell lines H460, A549 and H157 [43]. Mechanism of casticin for
malignant tumors is suppressed through c-Myc in p53 mutated Hs578T cells [44].
The signaling pathways that depend on p53 are essential components of cellular responses to
stress. Parthenolide in four cell lines, HCT116, RKO colon carcinoma, NCI-H1299 lung
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carcinoma and HL60 myeloblastoma, induced a significant reduction in the frequency of
apoptotic cells in UV-irradiated p53-proficient lines [45, 46]. Parthenolide activated p53 and
other MDM2-regulated tumor-suppressor proteins [47]. Synergistic apoptotic effects of
parthenolide and okadaic acid treatment increased p53 accompanied by lowering in p-Akt and
pS166-Mdm2 levels under PTEN action [48].
It has also been documented that alantolactone significantly increased the expression of p53 in HepG2
cells [49, 50] with concomitant increase of its downstream target genes, mainly cyclin-dependent kinase
inhibitor p21 in adriamycin (ADR)-resistant human erythroleukemia cell line K562/ADR [51].
Alantolactone induce p53-independent apoptosis in prostate cancer PC-3 cells [52].
6.2 Nuclear Factor-kappa B (NF-κB) and its Family Members Pathway
The pro-oncogenic nuclear factor-kappa B (NF-κB) is a master transcription factor consisting of closely
related proteins that generally exist as dimers and bind to a common DNA sequence within the promoters
of target genes, called the κB B site, which promote transcription of target genes through the recruitment
of coactivators and corepressors [53]. NF-κB pathway plays an important role in tumorigenesis through
transactivation of genes involved in cell proliferation, apoptosis, tumor cell invasion, metastasis, and
angiogenesis [54]. The NF-κB1 family of transcription factors consists of five members, NF-κB1 (p50),
NF-κB2 (p52), c-Rel, RelB, and RelA (p65), which share an N-terminal Rel homology domain
responsible for DNA binding and homodimerization and heterodimerization through ankyrin repeats,
covering the nuclear localization sequence of NF-κB [53, 55]. In this momentum, NF-κB is normally
sequestered in the cytoplasm via association with its endogenous inhibitor IκB. Furthermore, IκB-α is
rapidly phosphorylated by kinase IKK (IκB kinase) in two catalytic subunits, IKK-α and IKK-β, and one
regulatory subunit IKK-γ [56].
Nuclear factor-kappa B and other signaling pathways that are involved in its activation by free radicals,
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inflammatory stimuli, cytokines, carcinogens, tumor promoters, endotoxins, γ-radiation, ultraviolet (UV)
light, and x-rays are highly significant in cellular growth and transformation, suppression of apoptosis,
invasion, metastasis, chemotherapy resistance, radio resistance, and inflammation [57]. Furthermore, other
agents including TNF-α , IL-1, IL-6, and COX-2,5 in an inflammatory microenvironment are also highly
involved in tumor progression, incursion of adjoining tissues, angiogenesis, and metastasis [58].
Activation of NF-κB inhibits apoptosis by inducing the expression of Bcl-2 family members and
caspases inhibitor [59]. The major activity of NF-κB and its family members is to help proteolytic matrix
metalloproteinase’s enzyme that promote tumor invasion. Hence, IKKa promotes metastasis in prostate
cancer via inhibition of mammary serine protease inhibitor (maspin) [60, 61] and also stimulates
angiogenesis, by activating IL-8 and vascular endothelial growth factor (VEGF) [58]. However,
accumulation of the IκB-α protein through proteasome inhibition prevents the activation of anti-apoptotic
NF-κB, resulting in tumor cell apoptosis [62].
The detail of these studies validated NF-κB as a potent and novel target for cancer therapy. They
demonstrated that NF-κB signaling pathways played critical role in a wide variety of biological,
physiological and pathological processes, mainly in promoting cell survival through induction of its target
genes. Each study individually taken, stimulate the motivation and dedicated insight for developing
natural compounds NF-κB inhibitors.
Many studies have been carried out on whether natural compounds-related cancer inhibits expression of
NF-κB or not. All the selected natural compounds chemopreventive agents act as potent inhibitors of
NF-κB pathways. Wedelolactone, an inhibitor of I-κB kinase, suppressed both TNF-α-induced I-κB
phosphorylation and NF-κB phosphorylation at Ser 536 and Ser 468 [63], parthenolide [64-66], honokiol
[67, 68]. Costunolide inhibited the activation of Akt and NF-κB and the expression of anti-apoptotic
factors B-cell lymphoma-extra large (Bcl-xL) and X-linked inhibitor of apoptosis protein (XIAP) in 11Z
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cells [69-71], magnolol inhibits ERK1/2 phosphorylation and NF-κB translocation [72, 73],
PI3K/Akt/caspase and Fas-L/NF-κB signaling pathways might account for the responses of A375-S2 cell
death induced by evodiamine [74, 75]. Oridonin [76], alantolactone [77, 78], isoalantolactone [79],
casticin [80], pseudolaric acid B [81], jaceosidin [82], each of them has an inhibitory effect on NF-κB and
its associated proteins. These compounds may inhibit one or more steps in NF-κB signaling pathway and
its upstream growth factor receptors that activate the signaling cascade, translocation of NF-κB to the
nucleus, DNA binding of the dimers, or interactions with the basal transcriptional machinery. Thereupon,
they can induce apoptosis in cancer cells, offering a promising strategy for the treatment of different
malignancies including cancer (Table 1 and Figure 2) [83].
6.3 Nuclear factor-related factor 2 (Nrf2) signaling pathway
In cancer chemoprevention, Nrf2 is a potential molecular target for natural compounds. Several selected
natural compounds are reported as a potential candidate for chemoprevention, by stimulating the
accumulation of NrF2 in the nucleus and plays a major role in transcriptional activation of phase 2
detoxification enzymes. Low concentrations of parthenolide led to Nrf2-dependent HO-1 induction
accompanied by the attenuation of its apoptogenic effect in Choi-CK and SCK cells. Furthermore, with
the protein kinase C-alpha inhibitor Ro317549 (Ro), parthenolide -mediated apoptosis inhibits expression
and nuclear translocation of Nrf2, resulting in blockage of HO-1 expression. Parthenolide also stimulated
oxidation of KEAP1 in normal prostate epithelial cells, leading to increased Nrf2 (NFE2L2) levels
and subsequent Nrf2-dependent expression of antioxidant enzymes [84, 85]. Costunolide and
CH2-BL induced HO-1 expression and Nrf2 nuclear accumulation in RAW264.7 macrophages
[86]. Oridonin activates Nrf2 signaling pathway, leading to accumulation of the Nrf2 protein and
activation of the Nrf2-dependent cytoprotective response [87]. Isoalantolactone stimulates the
accumulation of Nrf2 in the nucleus of both Hepa1c1c7 cells and its mutant BPRc1 cells [88].
Alantolactone also stimulated the nuclear accumulation of Nrf2 in HepG2-C8 cells [89].
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6.4 Transducers and Activators of Transcription and its Family Members Pathway
Signal transducer and activator of transcription is a novel signal transduction pathway to the
nucleus has been uncovered through the study of transcriptional activation in response to
interferon. It has been implicated in many processes including development, differentiation,
immune function, proliferation, survival, and epithelial to mesenchymal transition (EMT) [90,
91].
Activation of various tyrosine kinases leads to phosphorylation, dimerization, and nuclear
localization of the signal transducers and activators of transcription (STAT) proteins, binding to
specific DNA elements and direct transcription. Constitutive activation of STAT3 and STAT5
has been reported to be implicated in many cancers such as myeloma, lymphoma, leukemia, and
several solid tumors [90-92]. Furthermore, seven mammalian STAT family members known such
as STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 have been cloned and
share common structural elements.
During the last decade, the natural compounds have been implicated to modulate STAT
activation in tumor cells. Some selected agents are part, such as honokiol increases expression
and activity of SPH-1 that further deactivates STAT3 pathway [93], wedelolactone inhibits
STAT1 dephosphorylation through specific inhibition of T-cell protein tyrosine phosphatase
(TCPTP), which is important tyrosine phosphatase for STAT1 [94]. Parthenolide shows strong
STAT-inhibition-mediated transcriptional suppression of pro-apoptotic genes [64-66],
alantolactone inhibits STAT3 activation in HepG2 cells [49]. Therefore, these cumulative
observations from both in vitro and/or in vivo studies have not only validated STAT as a novel
target for cancer chemotherapy, and also hence provided the rationale for developing natural
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compounds STAT inhibitors.
6.5 Growth Factors and Their Receptors Family Pathway
Growth factors are proteins that bind to receptors on the cell surface and reported to regulate a
number of cellular processes, with the primary result of activating cellular proliferation and
differentiation [95], apoptosis, and rearrangement of cytoskeleton [96]. Several growth factor
signaling molecules are implicated in carcinogenesis. Among of them include endothelial growth
factor, platelet-derived growth factor, fibroblast growth factor, transforming growth factor,
insulin-like growth factor, and colony-stimulating factor [97].
As an important intracellular pathway consequence of growth factor receptor activation, several
downstream signaling, such as PI3K-Akt and Ras-MAPK also become active. These signaling
pathways have significant impacts on the fact that it is associated with poor prognosis, tumor
progression and become targets for many natural chemopreventive and chemotherapeutic agents.
Isoalantolactone inhibits phosphorylation of PI3K/Akt on SGC-7901 cells [98], alantolactone
appears to induce detoxifying enzymes via activation of PI3K and JNK signaling pathways [89].
In cervical carcinoma HeLa cell line, oridonin may suppress constitutively activated targets of
phosphatidylinositol 3-kinase (Akt, FOXO, and GSK3) [99]. In pancreatic cancer, evodiamine
augment the therapeutic effect of gemcitabine through direct or indirect negative regulation of the
PI3K/Akt pathway [100] and also in A375-S2 cells [74].
Magnolol protects SH-SY5Y cells against acrolein-induced oxidative stress and prolongs
SH-SY5Y cell survival through regulating JNK/mitochondria/caspase, PI3K/MEK/ERK, and
PI3K/Akt/FoxO1 signaling pathways [101]. In addition, in SGC-7901 cells, magnolol induces
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apoptosis through mitochondria and PI3K/Akt-dependent pathways [102]. Magnolol also
suppressed the activation of MAPKs (ERK, JNK and p38) and thePI3K/AKT/mTOR signaling
pathway in mES/EB-derived endothelial-like cells (23708970). Honokiol decreases the
PI3K/mTOR pathway activity in tumor cells, but not in freshly stimulated T cells [103]. It seems
to be mediated by interrupting the early activated intracellular signaling molecule PI3K/Akt, but
not Src, the extracellular signal-regulated kinase, and p38 [104]. These reports showed that
natural compounds mainly the selected one rapidly induce the phosphorylation of Akt after the
stimulation and they can be used as a potent inhibitor against cancer cells.
6.6 Cripto-1 and its allied proteins signaling pathway
In the process of normal cellular function, the dysfunction of activin signaling constituted an
active part of tumor formation. To address this phenomenon, activin is blocked in cancer cells by
the complex formed by Cripto-1, activin, and activin receptor type II (ActRII). In human colon
adenocarcinoma HCT-8 cells, alantolactone performs its anti-tumor effect by interrupting the
interaction between Cripto-1 and the activin receptor type IIA in the activin signaling pathway
[105].
7. Targeting Cancer Cells by Mitochondria-Mediated Apoptosis Pathway
Mitochondria dysfunction is the key links in the chain of development of pathologies associated
with the violation of cellular energy metabolism, including cancer. Mitochondria have become an
important component of the apoptosis execution machinery, cytochrome c, initiator in the
mitochondrial apoptosis pathway, can be released from the inter-membrane of mitochondria after
mitochondria depolarization [106-108].
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Recently, many studies reported that the mitochondria play a fundamental role in the processes
leading to cell death [109]. Identification of the loss of mitochondrial membrane potential
through toxicity is the key piece of natural compounds’ process [110]. Several reports reveal that
the effects of selected natural compounds on the intrinsic and extrinsic pathways of apoptosis
have been examined in many cell lines, including HL-60, costunolide induces the ROS-mediated
mitochondrial permeability transition and resultant cytochrome c release associated with
increased expression of Bax, down-regulation of Bcl-2, survivin and significant activation of
caspase-3, and its downstream target PARP [111, 112]. Honokiol induced release of cytochrome
c into cytosol and a loss of mitochondrial membrane potential (ΔΨm), associated with inhibition
of EGFR-STAT3 signaling and downregulation of STAT3 target genes and downregulation of
Bcl-2 and upregulation of Bax expression in MDR KB and RASMCs cells [113, 114]. Magnolol
induced apoptosis in MCF-7 and HCT-116 cells via the intrinsic pathway with release of AIF
from mitochondria accompanied by downregulation of anti-apoptotic protein Bcl-2 and
upregulation of pro-apoptotic protein p53 and Bax [115, 116]. To get a better insight into the
mechanism of delaying cellular aging by mitochondria targeted natural compounds-induced
cytotoxicity, the changes in membrane permeability, mitochondrial membrane potential (MMP)
and cytochrome c localization, which influence mitochondrial biological mechanisms,
development of mitochondria-addressed compounds highly specific for chemical processes is one
of the most promising ways to develop approaches for chemotherapy.
8. Targeting Cancer Cells by Reactive Oxygen Species-Mediated Apoptosis Pathway
The human body constantly generates free radicals such as superoxide (O2-
), hydrogen peroxide
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(H2O2), nitric oxide, peroxynitrile, and hypochlorous acid and other reactive oxygen species
(ROS) as a result of aerobic metabolism [117, 118]. Reactive Oxygen Species (ROS) are cellular
signals generated ubiquitously by all mammalian cells and long-term exposure to physiological
or psychological stress is associated with the production of oxidative species through intracellular
damage to DNA, RNA, proteins, and lipids but their regulation induced cell proliferation,
differentiation, and apoptosis, which are essential for proper cell functioning [119, 122]. ROS are
well known mediators of intracellular signaling of cascades. During cellular redox, the excessive
generation of ROS can induce oxidative stress, loss of cell functioning, and apoptosis [123].
Induction of apoptosis of cancer cells by n-hexane fraction of sesquiterpene is mediated through
activation of proteases, which act on specific substrates leading to the degradation of PARP and
other cytoskeletal proteins, responsible for many of the morphological and biochemical features
of apoptosis in cancer cells [49, 50, 124-126]. Furthermore, once caspases activated, it might
target the permeability of mitochondria, resulting in the loss of mitochondrial membrane
potential concomitant with increased production of ROS, and this activity eventually causes
disruption of membrane integrity [123]. In addition, several studies revealed that apoptosis
induction in chemotherapy depends on many factors like increase in ROS, oxidation of
cardiolipin, reduced mitochondrial membrane potential, and release of cytochrome c [124]. To
restored cell viability, N-Acetyl Cysteine (NAC), a specific ROS inhibitor blocks completely
apoptosis mediated by several natural compounds such as isoalantolactone in PANC-1 cells. The
activation of p38 MAPK and Bax is directly dependent on ROS generation.
Cancer chemotherapy involves deregulation of cell proliferation and survival, inducing
cell-cycle arrest, cell death and apoptosis by generating ROS and their various enzyme systems,
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including the mitochondrial electron transport chain, cytochrome, lipoxygenase, cyclooxygenase,
the NADPH oxidase complex, xanthine oxidase, and peroxisomes [127, 128].
Several studies reported that the promising natural compounds influenced the generation of
Reactive Oxygen Species. In microglial cells, honokiol and magnolol-induced apoptosis
associated with the inhibition of IFNγ ± LPS-induced iNOS expression, NO, and reactive oxygen
species (ROS) production [129, 130]. Jaceosidin increased intracellular accumulation of reactive
oxygen species (ROS) in MCF10A-ras cells [131]. In HeLa, CasKi, SiHa cell lines, casticin
markedly increased the levels of intracellular reactive oxygen species [132, 133]. Parthenolide
enhanced geldanamycin-induced changes in the apoptosis-related protein levels, reactive oxygen
species formation, nuclear damage and cell death in human epithelial ovarian carcinoma
OVCAR-3 and SK-OV-3 cell lines [134].
Induction of apoptosis in T24 and MDA-MB-231 cells by costunolide is associated with the
generation of ROS and disruption of mitochondrial membrane potential (Δψm) [112]. In ovarian
cancer cell lines (MPSC1 (PT), A2780 (PT), and SKOV3 (PT)), costunolide induced a significant
increase in intracellular reactive oxygen species (ROS) [135]. The specific Reactive Oxygen
Species inhibitor, N-Acetyl Cysteine (NAC) restored cell viability and completely blocked
isoalantolactone-mediated apoptosis indicating that isoalantolactone induces ROSdependant
apoptosis through intrinsic pathway in human pancreatic PANC-1 cells [124]. It also induced
apoptosis in both androgen-sensitive (LNCaP) as well as androgen-independent (PC3 and
DU-145) prostate cancer cells with the generation of Reactive Oxygen Species and dissipation of
mitochondrial membrane potential (Δψm) [136]. Alantolactone-induced apoptosis accompanied
by ROS generation and mitochondrial transmembrane potential dissipation [49, 137]. In hepatic
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stellate, HeLa and U937cells, oridonin induced biological processes, mainly intracellular ROS
generation [138, 139]. Pseudolaric acid B induced reactive oxygen species (ROS) generation and
mitochondrial dysfunction in L929 cells [140]. It also caused the elevation of ROS level in
DU145 cells [141]. In human malignant melanoma A375-S2 and cervix carcinoma HeLa cells,
evodiamine induced apoptotic process associated with ROS release through both extrinsic and
intrinsic pathways [142, 143].
9. Targeting Cancer Cells by Cell Cycle-Mediated Apoptosis Pathway
Checkpoint controls function to ensure that chromosomes are intact and that critical stages of
the cell cycle are completed before the following stage is initiated. One checkpoint operates
during S and G2 to prevent the activation of mitosis-promoting factor (MPF), which is
composed of a cyclin and cyclin-dependent kinase (Cdk) that triggers entrance of a cell into
mitosis by inducing chromatin condensation and nuclear envelope breakdown; it’s also called
maturation-promoting factor. Another checkpoint operates during early mitosis to prevent
activation of Adenomatous Polyposis coli (APC) and the initiation of anaphase until the
mitotic spindle apparatus is completely assembled and all chromosome kinetochores are
properly attached to spindle fibers. Checkpoints that function in response to DNA damage
prevent entry into S or M until the damage is repaired [144-146].
When these signals are altered due to various mutations that prevent cells from undergo
apoptosis, normal cells are transformed into cancerous cells and undergo high proliferation.
Therefore, to arrest cancerous cell proliferation, regulation of apoptosis and its signaling
pathways play a critical role [8, 147, 148]. This behavior may lead to cell cycle arrest and
upregulation of pro-apoptotic related proteins expression [49-51]. In addition, it also documented
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that the selected natural compounds induced cell-cycle arrest either G2/M, or S or G0/G1 phase.
We have reviewed the effects of various signaling pathways that have been reported in selected
natural compounds-induced apoptosis (Figure 3 and Table 2).
10. Cancer clinical study
Antiangiogenic therapy is at the forefront of drug development. Knowledge of the multiple
activities of natural compounds can assist with the development of natural compounds derivatives
and the design of preclinical and clinical trials that will maximize the potential benefit of natural
compounds in the patient setting for cancer disorders. Thereupon, the natural compounds have
been examined in human and recently reported. Parthenolide was found to inhibit the expression
of matrix metalloproteinase-9 and urinary plasminogen activator and the migration of carcinoma
cells in vitro, as well as osteolytic bone metastasis associated with breast cancer in vivo [149]. Its
administration at doses up to 4 mg as a daily oral capsule in the feverfew preparation is not
detectable in the plasma [150]. In combination with ciclopirox, parthenolide demonstrates greater
toxicity against acute myeloid leukemia than treatment with either compound alone [151].
11. Conclusion and Future Perspectives
Natural products have been, and continue to be, a highly useful source of bioactive molecules.
In this review, we have highlighted the recent progress of the natural compounds from Mother
Nature with cytotoxic activities. Plants provide a broad spectrum of sources for modern
anticancer drugs. Various preclinical findings and results of several in vitro and in vivo studies
convincingly argue for potent role of natural compounds in the prevention and treatment of many
types of cancer. Many reports on mechanism of actions of the promising compounds target
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multiple signaling pathways, which vary widely depending on cancer origin [11, 51].
According to the literature, the major molecular targets that have been characterized are the
key challenge for researchers and scientists to use this information for effective cancer prevention
in populations with different cancer risks. Moreover, low potency and poor bioavailability of
natural compounds pose further challenges to scientists and researchers. The future, full with
convergence of chemoprevention and chemotherapy drug development will open new avenues
for natural compounds in reducing the public health impact of major cancers. However,
additional preclinical studies and clinical trials are certainly yet required to elucidate the full
spectrum of cytotoxic activities of the selected natural compounds either alone or in synergistic
combination with other small molecules to further validate the usefulness of these agents as
potent anticancer agents.
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12. Acknowledgements
This study was supported by Ministry of Science and Technology (No. 2010DFA31430),
Ministry of Education of China (NCET-10–0316), National Natural Science Foundation of China
(No. 30871301, 30700827), Jilin Provincial Science & Technology Department
(20130521010JH , YYZX201241), Changchun Science & Technology Department (No.
2011114-11GH29), the Program for Introducing Talents to Universities (No. B07017) and the
Fundamental Research Funds for the Central Universities (12SSXM005).
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Published OnlineFirst August 26, 2014.Cancer Prev Res Faya Martin Millimouno, Jia Dong, Liu Yang, et al. Natural Compounds from Mother NatureTargeting Apoptosis Pathways in Cancer and Perspectives with
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