Perspective Studies on Novel Anticancer Drugs from Natural Origin:A Comprehensive Review
Cancer occurs when alterations of genetic material create
an abnormal function leading to unregulated proliferation of cells in the body.
Cancer remains as one of the most predominant illnesses causing death, where
each year more than 10 million people are identified worldwide. Due to restrictions
and side effects observed from various chemotherapeutic anti-cancer drugs, as
well as thousands of secondary metabolites formed in plants and other natural
organisms, there is a high trend, toward novel drug discovery from natural sources.
It seems that high throughput screenings based on reverse pharmacology and reverse
pharmacognosy might result in more successful approaches in the future. The
main objective of this review is to exhibit an up-to-date comprehensive overview
on the recently identified natural antitumor compounds from various natural
origins including plants, fungi, endophytic fungi and marine organisms. In order
to facilitate the anticancer drug discovery and development, new strategies
might be considered such as biotechnology and nanoparticle targeting approaches.
The reverse pharmacognosy and its complementary the reverse pharmacology which
are associated with high throughput screening, virtual screening and knowledge
databases from traditional medicine, provide successful and strong tools to
accelerate the process of future drug discovery.
Received: January 16, 2014;
Accepted: April 16, 2014;
Published: June 09, 2014
Undoubtedly, cancer is an important chronic illness, in which accumulation
of DNA alterations and damages may be one of the most considerable causative
parameters. It is revealed that environmental stresses such as infection, food
additives, chemicals and air particles could create damages in the cells, of
which DNA alteration is a serious consequence leading to carcinogenesis. A living
organism has multiple mechanisms to manage the environmental stress. For instance,
immune responses, apoptosis, cell cycle control and induction of antioxidative
enzymes are such examples (Hiramatsu et al., 2006).
It seems that various common types of cancer such as breast, colon and prostate
cancers are initiated through genetic and environmental interactions. Previous
literature revealed that a small number of patients get cancer due to alterations
in the germ cells whereas most cancers are the result of genetic alterations
at the somatic cells (Hiramatsu et al., 2006; Stankovic
et al., 2006). Giving benzene as an example, although most of studies
are focused on neoplastic effects ahead of non-neoplastic effects, the exact
mechanisms have not been fully understood (Bahadar et
al., 2014). However, particular genes have been recognized in different
types of cancer, in which accumulation of the mutations may lead to the tumor
initiation in cells, although this remained elusive so far. The identification
of the cellular origins of cancer is also critical to increase our knowledge
about the mechanisms regulating the various stages of tumors. In the other words,
introducing just an effective compound against neoplastic cells is not enough
but the cellular mechanisms of actions should be identified (Momtaz
et al., 2013). Most recently, lineage-tracing experiments have been
employed to mark individual tumor cells and assess their respective contribution
to tumor growth and relapse after therapy (Blanpain, 2013).
Reactive Oxygen Species (ROS) are found to hurt the biological organisms and
molecules, such as lipids, protein and DNA resulting in initiation of the cancer.
Regarding this point, for many years, it was thought that antioxidants can be
effective in prevention and treatment of cancer by free radical scavenging and
prevention of DNA alterations. In fact, oxidation generally happens in all oxygen-rich
environments during exposure of a compound to ultraviolet light or heat. Polyunsaturated
fats can be oxidized in the presence of oxygen resulting in a chain reaction
and amplification of the basic oxidative damage (Buzzai
et al., 2005; Liu et al., 2011; Momtaz
et al., 2013). Moreover, ROS can play a role as a trigger to initiate
carcinogenesis by permanent damaging of DNA and causing mutations in p53 and
the tumor suppressor gene as well. Furthermore, ROS are able to modulate the
activity of several transcription factors like nuclear factor kappa B (NF-κB)
and activator protein 1 (AP-1) that play a regulatory role for the Jun and c-Fos
as two nuclear oncoproteins. The mentioned mechanisms play roles in initiation,
promotion and progression of cancer. However, interestingly, adequate levels
of ROS may show opposite effects in inhibition of carcinogenesis through enhancing
p53 expression and inducing tumor cell apoptosis (Khosravi-Far
and White, 2008; Alawadi et al., 2011).
Moreover, antioxidants such as vitamin C and E can interfere with some of chemotherapeutic
drugs which need free radicals and oxidative stress condition to act (Saeidnia
and Abdollahi, 2012, 2013a). For these reasons,
many oncologists Now-a-days recommend to their patients not to take vitamin
supplements during chemo or radiotherapies (Bagchi and Preuss,
2005; Watson, 2013).
Actually, there is a serious concern on taking or avoiding the antioxidative
supplements during chemotherapy and chemoprevention which has been already criticized
in details (Abdollahi and Shetab-Boushehri, 2012; Saeidnia
and Abdollahi, 2012, 2013a). The understanding
of the mechanism of action of anticancer drugs is very important. Some anticancer
agents like paclitaxel could attack the cancer cells through generation of ROS
or interfering with ROS metabolism. Also, there are a few anti-angiogenesis
compounds like endostatin that can be an anti-neoplastic medicine when employed
together with another chemotherapeutic agent. Additionally, some natural anticancer
agents like piperlongumine bind to the active sites of several key cellular
antioxidants including glutathione S transferase and carbonyl reductase 1 only
in cancer cells (Schafer et al., 2009; Saeidnia
and Abdollahi, 2013a). Regarding the similarity between mechanisms of aging
and cancer (Hasani-Ranjbar et al., 2012; Momtaz
and Abdollahi, 2012), the thought about usefulness of antioxidants in prevention
of aging or cancer is logically true but when aging or cancer started then use
of antioxidants cannot be that helpful especially if chemotherapies are started
in cancer (Saeidnia and Abdollahi, 2013a). However,
in this study, we aimed to review the novel natural anticancer drugs from plants,
fungi, endophytic fungi and marine origins, especially those recently introduced
and discuss about their mechanism of action suggested by investigators in the
HISTORY OF USING NATURAL ANTICANCER DRUGS
There are some documents originated from the ancient civilizations of Asia
and Middle East countries, in which the application of herbal medicines to keep
the health of human being is explained (Wang et al.,
2010). Among the Egyptian herbal medicines, some plants including opium,
cannabis, myrrh, fennel, cassia, thyme, henna, juniper, aloe, linseed, castor,
caraway seeds, marjoram, spearmint, peppermint and so on have been described.
There is mirrored evidence available in traditional Chinese medicine and Ayurveda
to prove the usage of such herbal remedies (Patwardhan and
Mashelkar, 2009). Traditional Iranian medicine also contains good information
on medicinal plants, of which, yarrow, savory and sage are good examples (Saeidnia
et al., 2005, 2009, 2011;
Gohari et al., 2010, 2012).
An appraisal of the currently used anticancer agents showed that many anticancer
drugs are mainly from natural origin as well as their semi-synthetic products.
However, even synthetic drugs are designed according to natural products as
the leads. As far as we could ascertain, 69% of the approved anticancer agents
since 1980-2002 are originated or developed from natural sources (Newman
and Cragg, 2007; Liu et al., 2009). About
43-80% of patients with prostate cancer are under treatment by complementary
and alternative medicines. A group of those patients had important history of
prostate cancer in their families, while another group was on active surveillance
and the latter ones experienced failure or were on androgen deprivation and
tried to postpone the progression of cancer by use of natural remedies (Trottier
et al., 2010). Although, plants are considered as the main sources
of anticancer drugs, only 5-15% of the approximately 250,000 species of higher
plants have been studied for the presence of bioactive compounds and this is
why there is a huge potential to exploit nature for new anticancer compounds.
Opposite to Western medicine which applies purified compounds and targets a
single physiological endpoint, various traditional medicines employ mixed or
combination of herbal remedies (Monneret, 2010).
Now-a-days, many epidemiologists emphasize that decrease of cancer risk is
related to consumption of particular species of vegetables and fruits suggesting
that phytoceuticals (herbal based food products) may possess cancer preventive
properties. Among the approved anticancer agents, there are many natural compounds
including doxorubicin, daunomycin, mithramycin, paclitaxel, vinblastine and
vincristine. Furthermore, numerous synthetic compounds like flavopiridol, combretastatin
and roscovitine have been listed as the anticancer agents (Cho,
CONVENTIONAL AND ADVANCED CANCER TREATMENTS
Today, there are some general management for diverse kinds of cancers such
as surgery, radiation and chemotherapy. Surgery is often used for removal of
a tumor as the first treatment. However, it has disadvantages including potential
damages to normal cells and tissues. Radiation therapy with X or gamma rays
is widely used to induce death or apoptosis in cancerous cells in order to preserve
the tissues surrounding a tumor and to destroy all cancerous cells as well.
Anyhow, this method cannot remove metastatic cells and meanwhile causes several
adverse effects like weakening of the immune system. The latter method chemotherapy
is defined as the systemic administration of anticancer agents which could migrate
through the blood toward the cancerous tissues. The main purpose of chemotherapy
is to wipe out all cancerous cells in the body even metastatic cells. But there
are many kinds of common cancers that are not treated with chemotherapy alone
and on the other side, different adverse effects might occur including nausea,
anemia, weakening of the immune system, diarrhea, vomiting and hair loss. Resistance
to chemotherapeutic drugs is also another disadvantage of this treatment (Cho,
2011). Usually, chemotherapy is recommended through systemic circulation
for larger tumors or in case of metastasis into lymph nodes. Chemotherapeutic
agents are mainly molecules with high volume of distribution which facilitates
to reach up an adequate therapeutic level in tumor cells. For this reason, normal
tissues are irreversibly exposed to the chemotherapeutic compounds resulting
in adverse effects such as nausea, vomiting, alopecia (hair loss), anorexia
(poor appetite) and bone marrow suppression. On the other hand, critical bioavailability
is observed with high molecular weight chemotherapeutic drugs in comparison
to low molecular weight ones which tends to have quick excretion rate from the
body. Besides, drug resistance remains as one of the most important disadvantages
of chemotherapy. In order to conquer drug resistance or multidrug resistance,
the above drawbacks should be minimized by developing more effective site specific
drug delivery systems which can significantly improve the therapeutic efficacy
to chemotherapeutic drugs with minimal toxicity (Hu and
Zhang, 2009; Egusquiaguirre et al., 2012).
There are advanced methods of cancer treatment via immunotherapy. It is found
that, cancer cells should be targets of the host immune responses in a normal
condition. Cells and molecules of the immune system are important in determining
the anti-tumor immune response. Now-a-days, different strategies are being progressed
to increase the anti-tumor immune responses, such as DC-based vaccines and antagonists
of inhibitory signaling pathways to overcome immune check-points (Alderton
and Bordon, 2012). Recently, monoclonal antibodies have indicated a broad
spectrum of antigens which are presented in human cancer cells and correlated
to abnormal proteins from DNA mutations. Over the past couple of decades, the
US Food and Drug Administration (FDA) approved a number of monoclonal antibodies
to treat certain cancers while the scientists discovered more antigens linked
to various types of cancer. Two types of monoclonal antibodies are employed
in treatments including naked (no drug or radioactive material attached to them)
and conjugated (joined to a chemotherapy drug, toxin, or a radioactive particle)
antibodies (ACS, 2014).
Although, the cancer vaccination is an old idea, today cancer immunotherapy
can be categorized to four aspects: Active, passive, none-specific and adoptive
therapies (Hamdy et al., 2011a, b).
Advanced cancer therapies reveal the application of tissue-specific cytotoxic
agents. For instance, interleukin 13 (IL-13)-conjugated liposomes carrying cytotoxic
agents are introduced as an approach for creating a nanovesicle drug delivery
system in brain tumor therapy. With no doubt, treatment of malignant brain tumors
has many difficulties. Therefore, developing a delivery system for chemotherapeutic
agents is really crucial in order to ablate individual cancer cells without
diffusing to surrounding brain tissues (Madhankumar et
al., 2006; Cho, 2011).
ANTI-CANCER AGENTS FOR THERAPY AND PREVENTION
Well-known approved natural anticancer agents: Some of the important
examples of anticancer drugs that are approved in clinical use originated from
plants are overviewed and summarized in Table 1. However,
there is a major problem with cancer chemotherapy called resistance to chemo-therapeutic
medicines, since the defective apoptotic pathway may result in clonal progression
of resistant transformed cells (Kashkar, 2010).
|| Main examples of approved natural anticancer medicines (Cho,
Among the mentioned drugs in Table 1, docetaxel is widely
applied as a usual care in patients with prostate cancer in order to cause death
of cancer cells among androgen independent cells. Literature reveals that in
hormone-refractory metastatic prostate cancer, docetaxel plus prednisone could
improve prostate specific antigen response rate, pain and health-related quality
of life. Moreover, It is also mentioned that docetaxel plus estramustine were
able to enhance progression-free survival (McKeage and
Keam, 2005). Although, docetaxel-based chemotherapy is well-known as the
standard first-line therapy in metastatic Castration-Resistant Prostate Cancer
(CRPC), most patients finally develop resistance to this treatment. In a recent
study, the alteration in expression of 18 selected genes were investigated by
real-time quantitative reverse transcriptase PCR in cell lines and in about
11 FFPE (formalin-fixed, paraffin-embedded) and five optimal cutting temperature
tumor samples. The results indicated a down-expression of CDH1 and IFIH1 in
docetaxel-resistant tumors (Marin-Aguilera et al.,
2012). The reason should be related to transcription factor NF-κB which
may contribute to chemo-resistance in prostate cancer cells as well as probable
enhancing the high risk of relapse in patients with localized prostate cancer
(Berthold et al., 2008; Karin,
Herbal medicines as the important sources of anticancer compounds: There
are currently limitations in cancer chemotherapy approach, especially when all
focus only on the mono-targeted approach. Actually, cancer happens as a result
of many changes in a variety of genes and signaling processes. On the other
hand, targeting different signaling elements might be the better approach. Regarding
this point, medicinal plants, in both single and multiple applications, can
conserve an amplified potential. Now-a-days, natural products particularly as
combinational mixtures have revealed promise in pre-clinical models, of which
pomegranate, green tea, soy and tomato paste are some examples (Kumar
et al., 2010a). In this regard, the efficacy of tomato paste and
broccoli (either alone or in combination) has been reported in comparison to
lycopene in rodent models of prostate cancer (Kumar et
al., 2010b). Here in this section, the efficacy of some plant-derived
promising candidates for chemoprevention and chemotherapy is concisely discussed
in the Table 2. It is noteworthy that most of data about natural
products and their positive effects in various diseases although come from Asian
countries traditional medicine, in most of cases only experimental studies have
been completed and clinical parts have been remained vacant (Hosseini
and Abdollahi, 2012; Sarwar et al., 2011).
Anticancer fungi: Besides medicinal herbs, there are many fungi found
effective on various cancer cell lines that some of them could surpass the pre-clinical
evaluations to become a promising candidate for further clinical tests. Among
them, Ganoderma lucidum is a saprophytic fungus often growing well in
a humid and ventilated condition with high temperature. In the modern systematics,
it is classified as (Basidiomycotina) Ganodermoideae. This is one of the traditional
medical fungi since ancient times. Phytochemical investigations revealed that
its major constituents are polysaccharides, enzymatic proteins and glycoproteins
and other bioactive compounds such as triterpenoids, steroids and fatty acids
(Akihisa et al., 2007; Fukuzawa
et al., 2008). Numerous biological functions have been reported for
G. lucidum, including anticancer activity (Nonaka
et al., 2006), life-protective effect (Yuen
and Gohel, 2008) and antioxidation (Zhuang et al.,
2009) as well. The anticancer activity of this fungus is mediated via different
mechanisms such as cell cycle arrest at G2/M phase in human immune system-related
cancer cells (Sadava et al., 2009), cell death
via apoptosis (Calvino et al., 2010), inhibiting
the invasion of HCT116 cells mediated by inhibition of nuclear translocation
of NF-κB and degradation of IκB-α inhibitor (Chen
et al., 2010) and inhibiting the early event in angiogenesis (Stanley
et al., 2005).
|| Several important herbal medicines that have been successful
in pre-clinical studies of different types of cancer
However, Ganoderma is applied in combination with other herbs or foods
(such as Dendranthema morifolium, Panax pseudoginseng and Glycyrrhiza
uralensis) to treat cancer patients as an alternative medicine regarding
to their synergistic efficacy (Kim et al., 2008a).
The safety of this fungus is essential to be examined in clinical trials before
administration to cancer patients, although no side effect has been reported
in healthy subjects after oral taking the extract (2 g day-1) for
10 days compared to placebo (Wicks et al., 2007).
Mushrooms are also applied in both traditional and modern clinical practice.
Of them, macrofungus Coriolus versicolor is widely used so far. Modulation
of innate and adaptive immunity, hematopoietic activity and direct toxic effects
are recently reported in details (Cheng and Leung, 2008;
Kim et al., 2008b). The main phytochemical
constituents of this mushroom are polysaccharides (in particular β-D glucans),
polysaccharide peptide and protein-bound polysaccharides, as well as terpenoids,
phenols, lipids and a number of small molecules (Rau et
Schematic interference of garlic metbolites
in cancer initiation, promotion and progress. Garlic acts via interaction
with cell division cycle 25C phosphate (Cdc25C), Interleukin 2, (IL-2),
Nuclear Factor (NF-κB), Reactive Oxygen Species (ROS), Tumor Necrosis
Factor (TNF-β) and Vascular Endothelial Growth Factor (VEGF)
|| Polyphenoles of green tea and their functions as the chemopreventive
Not only the efficacy of polysaccharide portions of this mushroom in restoring
the immune system in cancer patients is well reported but also potent anticancer
activity of its compounds in inhibiting tumor cell proliferation or metastasis
have been documented (Chan et al., 2009; Sadahiro
et al., 2010). Numerous in vitro and in vivo studies
as well as clinical trials have demonstrated that Coriolus is potentially
a novel source of anticancer agents.
Another edible mushroom known as Lentinus edodes is widely used in Japan
and China and also cultivated worldwide.
Mechanism of anticancer activity of Lentinus
edodes, Cluster of Differentiation 8 (CD8), Major Histocompatibility
Complex (MHC), Natural Killer cells (NK) and T-helper (Th)
Actually, the mentioned mushroom has been used from old times as a delicacy
due to beneficial properties in human body. Phytochemical investigations revealed
that several polysaccharides have been identified from this mushroom named:
Lentinan, β-1, 3; 1, 6-D-glucans (Fig. 3), glycogen-like
polysaccharides, α-1, 4; 1, 6-D-glucans, 1, 6-β-D-glucans with 1,
3 and 1, 4-β-bonded heteroglucans, heterogalactan, heteromannan and xyloglucan
(Jong et al., 1983). Anticancer activity of its
polysaccharides may be due to modulation of both innate and adaptive immunity
by enhancement of the numbers and/or functions of macrophages and Natural Killer
(NK) cells, as well as subsets of T cells (Akramiene et
al., 2006). A schematic mechanism of anticancer activity of Lentinus
edodes is shown in Fig. 3.
Clinical evaluations indicated that combinational therapy with lentinan/micellary
β-1, 3-glucan and chemotherapy could prolong the lifespan of cancer patients
(Yoshino et al., 2010). In one study at phase
I clinical trial, the clinical safety and tolerability of AHCC (an extract of
shiitake mushroom of the basidiomycete family of fungi rich in alpha glucans)
has been reported. It is also mentioned in present study that 9 g of AHCC (150
mL day-1 of the currently available liquid AHCC) which was orally
recommended for 14 days to 26 healthy subjects (both sexes and aged 18-61 years)
caused various moderate side effects, including nausea, diarrhea, bloating,
headache, fatigue and foot cramps. No abnormalities in the laboratory parameters
have been reported and the administered dose was well tolerated in 85% of the
persons (Spierings et al., 2007). This mushroom
and its preparations are thought as a promising antitumor medicine, nonetheless
the time of harvesting and keeping conditions may influence its biological properties
and polysaccharide content.
Endophytic fungi: Endophytic fungi are endosymbiont fungi living within
a plant for at least part of their life without causing apparent disease. Additionally,
endophytes are ubiquitous and have been found in many species of plants studied
so far, although the relationships between endophytic fungi and plants have
not been well understood (Faeth, 2009). They have special
mechanisms to penetrate inside the host tissue and regarding their biotransformation
abilities they synthesize many novel secondary metabolites. Actually, endophytic
fungi produce such metabolites to compete with the epiphytes and/or the plant
pathogens to maintain a critical balance between fungal virulence and plant
defense (Chandra, 2012). Recently, anti-cancer activities
have been reported for such endophytes. Hypocrea lixii is a new endophyte
producing cajanol from the roots of pigeon pea that has been recently investigated
for its potential toxicity towards human lung carcinoma cells (A549). However,
the activity was evaluated in vitro but the importance of this study
was in finding an alternative approach for large-scale production of a promising
anti-cancer cajanol (Zhao et al., 2013). Furthermore,
the anti-cancer activity of several endophytic fungi related to the Brazilian
plant Stryphnodendron adstringens has been recently reported. The extracts
of Diaporthe cf. phaseolorum and Xylaria sp., phylotypes
exhibited in vitro cytotoxic activities (Carvalho
et al., 2012). Moreover, camptothecine (CPT) is a well-known inhibitor
of eukaryotic topoisomerase I.
There are several semi-synthetic derivatives of this quinoline alkaloid employing
Now-a-days in clinic against ovarian, small lung and refractory ovarian cancers.
This compound is generally produced by numerous plant species from Asterid clade.
However, its other sources are endophytic fungi. The endophytes Fomitopsis
sp., P. Karst, Alternaria alternata (Fr.) Keissl and Phomposis
sp. (Sacc.), associated with the medicinal plant Miquelia dentata (Icacinaceae),
have been studied for their abilities to produce CPT, 9-methoxy CPT (9-MeO-CPT)
and 10-hydroxy CPT (10-OH-CPT). It was demonstrated that all the three fungi
could produce above mentioned compounds in the artificial media. In addition,
methanolic and ethyl acetate extracts of these endophytes displayed toxic activity
against colon and breast cancer cells (Shweta et al.,
2013). Another bioactive compound named sclerotiorin has been recently isolated
from an endophyte Cephalotheca faveolata and found as an apoptosis inducer
in colon cancer cells (HCT-116) via activation of BCL-2-like protein 4 (BAX)
and down-regulation of B-cell lymphoma 2 (BCL-2) as well as cleaving caspase
3 (Giridharan et al., 2012). An endophytic fungus,
coded as PM0651480 has been isolated from the leaves of the plant Mimosops
elengi (Sapotaceae). Its extract displayed good anti-inflammatory and anticancer
activity due to presence of ergoflavin which induced considerable toxicity in
ACHN, H460, Panc1, HCT116 and Calu1 cancer cells (Deshmukh
et al., 2009). In another study, about 81 Thai medicinal plant species
were collected from different regions of Thailand and evaluated for presence
of possible bioactive endophytic fungi. Literature revealed that about 60 fungi
were active against human oral epidermoid carcinoma cells (EC50 0.42-20
μg mL-1) and also about 48 fungi showed toxicity against breast
cancer cells (EC50 0.18-20 μg mL-1) (Wiyakrutta
et al., 2004). Penicillium melinii Yuan-25 and Penicillium
janthinellum Yuan-27 (extracted from the roots of Panax ginseng),
are also reported to possess anti-cancer activity due to diverse bioactive compounds
known as linesginsenocin, methyl 2, 4-dihydroxy-3, 5, 6-trimethylbenzoate, 3,
4, 5-trimethyl 1, 2-benzenediol, penicillic acid, mannitol, ergosterol and ergosterol
peroxide which all exhibited anti-cancer activity (Zheng
et al., 2013). A dditionally, the EtOAc extract of a culture broth
of the endophytic fungus Perenniporia tephropora Z41 from a variety of
Taxus chinensis is reported to display significant toxicity (IC50
values: 2-15 μg mL-1), while its active components perenniporin
A, rel-(+)-(2aR, 5R, 5aR, 8S, 8aS, 8bR)-decahydro-2, 2, 5, 8-tetramethyl-2H-naphtho[1,
8-bc] genfuran-5-ol (3) and albicanol indicated moderate toxicity (IC50
values: 6-58 μg mL-1) (Wu et al.,
2013). In conclusion, endophytic fungi are relatively novel sources of anti-cancer
agents, thus investigations continue. Further animal and clinical studies are
essential to prove whether they can find a place among future chemotherapeutic
Anticancer compounds from marine sources: For many years, anticancer
drug discovery has concentrated on discovery of new bioactive compounds from
higher plants due to simplicity and accessibility. Recently, other organisms
including marines (like marine algae) have been considered, since not only the
access to those organisms became streamline because of progress in marine technology
but also many scientific developments occurred in the areas of chromatography
and spectroscopy in order to simplify isolation and structural elucidation of
the natural products. Going through a vast bibliography shows that marine organisms
have indicated a diverse biological and pharmacological activities including:
Anticancer, antimicrobial, anti-inflammatory, antispasmodic, antiviral, antioxidant
and enzyme inhibition activities (Kintzios and Barberaki,
2004). As far as we could ascertain, the anticancer activity of some marine
organisms have been reviewed so far (Kintzios and Barberaki,
2004). In this regard, the impressive results of anticancer activity for
some marine algae together with their metabolites which are recently published,
have been reviewed here.
|| Recently reported anticancer activity from marine algae and
other marine organisms
Table 3 exhibits a collection of different anticancer metabolites
recently isolated and identified from marine organisms.
Natural promising anticancer candidates under trials: Piperlongumine
is a natural compound from the Piper longum (Piperaceae) introducing
a potent anticancer medicine. This compound can bind to the active sites of
some key cellular antioxidants such as glutathione S-transferase and carbonyl
reductase-1. Piperlongumine cannot raise ROS in the normal cells (Burgess,
2011; Saeidnia and Abdollahi, 2013a). It is found
that the activity of piperlongumine can be related to two mechanisms. The first
one is to enhance in ROS in cancer cells, while in the second mechanism, it
can be an inhibitor of the Ubiquitin-Proteasome System (UPS). When a tumor cell
exposes to piperlongumine, the accumulation of a reporter substrate (rapidly
degraded by the proteasome) and conjugated proteins occurs. Moreover, the researchers
suggested that the inhibition of the UPS at a pre-proteasomal step is prior
to deubiquitination of malfolded protein substrates at the proteasome and the
induction of ROS might be a consequence of this inhibition (Jarvius
et al., 2013).
Curcumin (Fig. 4) is another natural compound obtained from
Curcuma longa (Zingiberaceae) which can be involved in alkylation of
catalytic cysteine of DNA methyltransferase-1 DNMT1. This compound is well-known
as an epigenetic modulator of miRNAs in cancer cell targeting. Curcumin is reported
to directly induce a tumor-suppressive miRNA, named miR-203 in bladder
cancer. In fact, miR-203 is frequently down-regulated in bladder cancer due
to DNA hypermethylation of its promoter. Curcumin can induce hypomethylation
of the miR-203 promoter and subsequent up-regulation of miR-203 expression (Saini
et al., 2011). On the other side, curcumin is a typical antioxidant
phenolic compound playing role by oxidative coupling reaction on 3'-position
with the lipids and consequently possible Diels-Alder reaction between two molecules.
Meanwhile, various clinical trials for this anticancer natural compound have
been undertaken until now and the efficacy of curcumin or other curcuminoids
or turmeric products has been evaluated. For instance, the toxicology, pharmacokinetics
and biologically effective dose of curcumin in patients with resected urinary
bladder cancer, arsenic-associated Bowen disease of the skin, uterine Cervical
Intraepithelial Neoplasm (CIN), oral leucoplakia and intestinal metaplasia of
the stomach have been studied in a Phase 1 clinical trial. Furthermore, the
results of three month administration of curcumin showed no toxicity by doses
up to 8 g day-1. The bulky volume of the drug was not acceptable
to the patients (>8 g day-1). The peak of serum concentration
for curcumin was commonly found at 1 to 2 h after intake and gradually declined
within 12 h but urinary excretion was not detectable. However, two patients
developed frank malignancies in spite of curcumin treatment. Histologic improvement
of precancerous lesions has been observed in one of two patients with resected
bladder cancer, two of seven patients of oral leucoplakia, one of six patients
of intestinal metaplasia of the stomach, one of four patients with CIN and two
of six patients with Bowen disease.
Probable interference of curcumin in
various stages of carcinogenesis, Activator Protein-18 (AP-18), Nuclear
Factor kappa-B (NF-κB) and Signal Transducer and Activator of Transcription
In conclusion, the safety of curcumin (doses <8 g day-1, orally
for 3 months) has been demonstrated. This trial has also suggested the chemopreventive
ability of this compound against cancerous lesions (Gupta
et al., 2013). Additionally, as an example for phase II clinical
trials, curcumin has been revealed safe and well-tolerated in patients with
advanced pancreatic cancer (Dhillon et al., 2008).
The problem with curcumin is its poor bioavailability due to poor absorption,
rapid metabolism and rapid systemic elimination which affects its therapeutic
efficacy (Anand et al., 2007). However, the
bioavailability of curcumin has been greatly enhanced by reconstituting curcumin
with the non-curcuminoid components of turmeric and also it is reported that
the phospholipid formulation increased the absorption of demethoxylated curcuminoids
much more than that of curcumin (Antony et al.,
2008; Cuomo et al., 2011). The US FDA has
approved curcumin as GRAS (generally recognized as safe). It is now being employed
and marketed as a supplement in several pharmaceutical forms, including capsules,
tablets, ointments etc. (Goel et al., 2008).
Genistein (an isoflavonoid usually find in Genista tinctoria) is one
of the anticancer agents which can act via epigenetic mechanism by regulating
miRNA and removing the Mini-Chromosome Maintenance (MCM) gene in prostate cancer
cells and also suppressing MCM2 by inducing the upstream miRN A-1296 (Schneider-Stock
et al., 2012). However, there is a concern on its antioxidant activity
which is in controversy with its anticancer properties. As it is already discussed,
genistein can enhance the antioxidant enzymes activity including catalase and
SOD as well as glutathione peroxidase and reductase in various organs. Today,
some modes of action have been found for genistein's anticancer effect. For
instance, it can potentially inhibit estrogen activity and regulate gene expression.
Furthermore, the epigenetic mechanism of anticancer for this compound is much
less affected by its antioxidant properties compared to particular enzyme inhibition
(Abdollahi and Shetab-Boushehri, 2012; Saeidnia
and Abdollahi, 2013a; Watson, 2013).
Resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phytoalexin
easily accessible in dietary vegetables and fruits (Chang
et al., 2011; Wallerath et al., 2002).
Chemical structures of some important
natural compounds with anti-neoplastic activity, (a) Genistein, (b) Resveratrol,
(c) Piperlongumine, (d) Fucoxanthin, (e) Fucoidans (f) Hydroperoxy sterol,
(g) Curcumin and (h) Glucans
For the first time, resveratrol was identified as a bioactive compound in 1992.
It is found in a variety of plants, especially in the red grapes. Actually,
there is considerable trend to this compound as a potential cancer chemo-preventive
agent due to its inhibitory activity on various pathways involved in carcinogenesis
(Baur and Sinclair, 2006). Its structure shows similarity
to diethylstilbestrol (DES) known as a phytoestrogen and previous studies showed
that estradiol, DES and resveratrol could alter the FOF1-ATPase activity selectively
with different mechanisms (Kipp and Ramirez, 2001).
However, treatment of MCF-10F cells with DES, a known human carcinogen resulted
in depurinating adducts involving in the induction of breast neoplasia. Literature
reveals the ability of resveratrol to prevent the formation of estrogen-DNA
adducts, thus preventing a key carcinogenic event (Hinrichs
et al., 2011). However, the particular role of resveratrol as an
estrogen agonist (or antagonist) remains to be elucidated. Tissue-specific expression
of α and β estrogen cofactors, regulating DNA binding and different
gene promoters, are important parameters to determine the exact role of resveratrol
(Le Corre et al., 2005). To the best of our
knowledge, resveratrol is well-documented to stop topoisomerase activity. Treatment
of glioblastoma cells has been reported for resveratrol observed as a topoisomerase
poison probably because of prolongation of the topoisomerase-DNA complex
(Leone et al., 2010). Moreover, literature showed
that resveratrol can inhibit telomerase activity in breast and colon cancer
cells correlated with lowering nuclear levels of human telomerase reverse transcriptase
(hTERT) (Fuggetta et al., 2006; Lanzilli
et al., 2006). On the other hand, osteosarcoma and lung cancer therapeutic
properties of resveratrol is associated with causing instable telomer, phosphorylating
of histone H2AX (H2A histone family, member X) and p53 and activating DNA signaling
(Rusin et al., 2009).
Literature demonstrated that ATF3 is a member of the ATF/CREB (cAMP response
element binding) family of bZIP transcription factors and found as a stress
inducible and/or adaptive response gene (Thompson et
al., 2009). On the other side, there are several evidence demonstrating
that ATF3 may act as a tumor inhibitor and mediator of apoptosis, at least in
part, by ATF3 (Whitlock et al., 2011). The structures
of some important natural compounds with anti-neoplastic activity are shown
in Fig. 5.
HIGH THROUGHPUT SCREENINGS AND REVERSE PHARMACOLOGY
In order to facilitate the cancer drug discovery and developments, new strategies
should be considered such as biotechnology approaches to help obtaining more
effective or lead compounds from the natural sources. In addition, traditional
screening of medicinal plants, marine algae or other natural resources is necessary
to find effective compounds with lower toxicity and higher activity rather than
present drugs. New approaches in this area have been created regarding new aspects
of reverse pharmacognosy and its complementary reverse pharmacology
which coupled the high throughput screening, virtual screening and in silico
databases with traditional medicine knowledge. This has made possible to identify
numerous in vitro active and selective hits which will enhance the speed
of drug discovery from natural sources (Saeidnia and Gohari,
2012; Saeidnia et al., 2013). In fact, chemistry
and high-throughput screening are combined and thus resulted in identification
of numerous selective active compounds. But, the problem is that they have been
evaluated in vitro not in vivo. Traditional treatments by use
of natural medicines have been successful in many populations worldwide, representing
various aspects of knowledge that are sometimes neglected in modern medicine
due to differences in the concepts of disease. Actually, reverse pharmacognosy
(from diverse molecules to plants) is a complementary to pharmacognosy (from
biodiverse plants to molecules) and applies new techniques including virtual
screening and a knowledge database containing the traditional uses of plants.
The specialists in this area believe that integrating pharmacognosy and reverse
pharmacognosy may provide an efficient and rapid tool for natural drug discovery
(Do and Bernard, 2004). Alongside reverse pharmacognosy,
reverse pharmacology is defined as a target-based drug discovery. However, this
area covers screening of chemical libraries which can be employed to identify
compounds that bind with high affinity to the target. The hits from these screens
are then used as starting points for drug discovery (Swinney
and Anthony, 2011).
BIOTECHNOLOGY: NEW APPROACH IN ANTICANCER DRUG DISCOVERY
Regarding the restrictions in production of secondary metabolites, biotechnology
can offer an alternative method for more production of high quantitative natural
metabolites or products in a relatively short time. Plant biotechnology comprises
several techniques in vitro, since they allow manipulating the parameters
influencing the growth and metabolism of cultured tissues. As a matter of fact,
plant tissue culture fundamentally consists of inoculating an explant (that
is a piece of plant tissue, such as a leaf or stem segment) from a donor plant
on a medium containing nutrients and growth regulators and then causing the
formation of a more or less dedifferentiated, rapidly growing callus tissue.
The perspectives of plant cell culture in anticancer drug discovery are going
to be highly interested, although the important plant-derived commercial anticancer
drugs including vinblastine and vincristine are still obtained
from cultivated Catharanthus roseus. On the other hand, some commercial
anticancer drugs are semi-synthetically produced from natural metabolites as
lead compounds which can be isolated from in vivo sources too. Now-a-days,
there are only a few natural anticancer products that are being produced
via methods of biotechnology including anhydrovinblastine from Vinca
rosea, paclitaxel from Taxus brevifolia, podophyllotoxin from Podophyllum
hexandrum and galactose binding lectin from Viscum album. However,
these compounds are mostly produced in laboratories (Lata
et al., 2009; Liu and Khosla, 2010; Ionkova,
NANOTECHNOLOGY: NOVEL AND STRONG TARGETED APPROACHES
Finding new targets is the main goal in drug discovery of cancer. Moreover,
nanoparticles show a great promise in the treatment of a wide range of diseases
due to their flexibility in structure, composition and properties. Nanoparticle
targeting anticancer drugs especially those provided by use of poly (lactic-co-glycolic
acid) (PLGA) have been recently more considered because of biodegradability,
biocompatibility, surface modification, stability, excellent pharmacokinetic
control and suitability for entrapping wide range of therapeutic agents but
concerns on the possible toxicity of all nanocompounds still remain (Swinney
and Anthony, 2011; Mostafalou et al., 2013).
As an example, literature reveals that the inhibitory effect of rapamycin on
the maturation of Dendritic Cells (DCs) regarding the phenotype, cytokine production
and functional effects on the proliferation of T cells was significantly increased
by PLGA delivery (Haddadi et al., 2008).
More recently, there has been an important focus on the field of cancer immunotherapy
leading to the development of a safe and effective cancer vaccine formulation.
Now-a-days, poly (d, l-lactic-co-glycolic acid) nanoparticles (PLGA-NPs) have
been applied as the novel cancer vaccine delivery systems. Not only those nanoparticles
(contain antigens along with adjuvants) can target antigen actively to DCs but
also activate the immunity and rescue impaired DCs from tumor-induced immuosupression
(Hamdy et al., 2011c). Furthermore, the same
investigators reported the efficacy of PLGA-based vaccine (PLGA nanoparticles
co-encapsulating the poorly immunogenic melanoma antigen, tyrosinase-related
protein 2 and Toll-like receptor ligand) in breaking immune-tolerance to cancer-associated
self-antigens in mice bearing melanoma B16 tumors. The results demonstrated
that the mentioned vaccine could induce therapeutic anti-tumor effect. Additionally,
the potential of PLGA nanoparticles as competent carriers for future cancer
vaccine formulations was supported (Hamdy et al.,
Cancer occurs when alterations of genetic material create the abnormal status
and activities leading to unregulated proliferation of cells in the body. However,
cancer is one of the most predominant diseases causing death. Due to restrictions
and side effects of the present chemotherapeutic and chemo-preventive antitumor
drugs and also thousands of secondary metabolites formed in natural sources,
there is a high trend toward novel drug discovery from nature. Beside the well-known
anticancer plants, several fungi are found effective on various cancer cells
and some of them may surpass the pre-clinical evaluations to become a promising
candidate for clinical tests, of which Ganoderma lucidum is an important
source of anti-proliferative and immunomodulatory components. Furthermore, marine
organisms have been investigated and proven to be rich sources of extraordinary
chemical structures, some of which possess a good anticancer activity. Until
date, not only a minority of algae has been studied but also many species of
them exhibited geographic variation in their chemical composition. Despite a
rapid growth in the number of drugs available to treat cancer, it still remains
a big concern in the world. Now-a-days, many patients intend to apply complementary
or alternative therapies to manage their diseases while it is hard for healthcare
practitioners to keep up with this evolving field. Additionally, when we focus
on dietary supplements, the science behind the perceived benefits is not sufficient.
Actually, broad spectrum of phytopharmaceuticals are available to practicing
healthcare professionals which hold a great promise in the chemoprevention and
chemotherapy of cancers (Saeidnia and Abdollahi, 2013a,
Regarding huge amount of costs paid each year for discovery and development
of effective cancer drugs, there has been no sufficient progress in introducing
novel effective treatments yet (Dickson and Gagnon, 2004).
Many adverse effects of anticancer drugs are still an ongoing problem. Although
all the scientists are not in agreement with beneficial usage of alternative
therapies in cancer therapy, a number of natural products may lessen or at least
ameliorate some cancers without causing the serious or significant adverse effects
(Bagchi and Preuss, 2005). It seems that many vegetables,
fruits, mushrooms, edible algae and also medicinal plants can be useful in life-improving,
if not life-saving of cancer patients (Cho, 2011).
But there is an important concern regarding consumption of antioxidant containing
supplements and/or herbal and/or natural products suggesting a serious need
to revise the conventional anticancer drug discovery methods (Saeidnia
and Abdollahi, 2013a; Watson, 2013). There are some
strategies, in which researchers try to find out novel anticancer drugs within
antioxidant compounds that are under question due to recent publications on
how the antioxidants interfere with anticancer activity of chemotherapeutic
drugs and lessen their efficacy (Abdollahi and Shetab-Boushehri,
2012; Shetab-Boushehri and Abdollahi, 2012). As
we already described in other study, application of antioxidants during cancer
treatment could diminish benefits of chemotherapy or radiation in the patients,
by scavenging free radicals which destroy quick-dividing cancer cells. For this
reason, the critical advice to patients treated by chemotherapy or radiation
is not to take antioxidant supplements or not to be under treatment with herbal
or natural medicines (even diets), in which high contents of antioxidants such
as polyphenols, vitamin C and E exist (Shetab-Boushehri
and Abdollahi, 2012). However, there is no doubt that some of the phenolic
compounds such as resveratrol, genistein and also piperlongumine are potentially
promising candidates for chemoprevention /chemotherapy of a varieties of cancer.
Some of these compounds have been studied in both in vivo and clinical
trials that are described in the present review. Although, these compounds possess
antioxidant activity, they can act via various mechanisms. Some of those mechanisms
(like epigenetic mode of action) are less impacted by their antioxidative effects.
This invited study is the outcome of an in-house financially non-supported
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