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Review Article
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Pharmacological Activities and Chemical Constituents of Ferula szowitsiana DC |
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Mohammadjavad Paydar,
Yi Li Wong,
Bushra Abdulkarim Moharam,
Elaheh Movahed,
Won Fen Wong
and
Chung Yeng Looi
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ABSTRACT
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Ferula is a genus of endemic plants in Mediterranean area and central Asia which many species have been traditionally used in folk medicine. Ferula szowitsiana is one of the ethnomedicinal plants in the genus that is mostly used in Azerbaijan and neighbouring countries such as Iran, Turkey and Afghanistan. Many scientific studies have been carried out and a wide range of pharmacological effects of the plant have been reported, including anti-cancer, anti-oxidant, anti-inflammation to anti-microbial and anti-biotic modulation activities. Notably, more than 200 compounds consisting of essential oils, coumarins, phenylpropanoid derivative and steroidal compounds have been identified from different parts of the plant and have been evaluated for a variety of biological activities. Despite this, a comprehensive review for this plant is still lacking. The aim of this review is to cover and summarize the biological activities of the active compounds derived from F. szowitsiana.
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Received: January 28, 2013;
Accepted: March 19, 2013;
Published: May 21, 2013
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INTRODUCTION
Ferula (means rod in Latin) is a genus of about 170 different
species that belongs to the Umbelliferae (Apiaceae) family. The plants grow
mostly in arid climate such as the Mediterranean area and central Asia. Ferula
species are 1-4 m tall herbaceous plants, with tripinnate leaves and yellow
flowers on large umbels. Many species of this genus are used to produce essential
oils or aromatic resins which have unique therapeutic values in traditional
medicine (Chen et al., 2000). Around 15 species
are indigenous in Iran and the Persian name for most of these species is known
as Koma (Mozaffarian, 1966, 1983).
The chemical constituents derived from Ferula sp. (aerial parts and
roots) have been extensively investigated by a few research groups (Diab
et al., 2001; Iranshahi et al., 2004a;
Abd El-Razek et al., 2003). Phytochemical studies
revealed that the plant is a potential source of sesquiterpene derivatives especially
sesquiterpene coumarins (Shahverdi et al., 2006;
Iranshahi et al., 2004b, 2007a,
b, 2008; Ahmed,
1999; Abd El-Razek et al., 2001) humulanes,
daucanes, guainanes, germacranes, eudesmanes and himachalanes (Gonzalez
and Barrera, 1995; Appendino et al., 1997;
Kojima et al., 1999; Su
et al., 2000a, b).
Ferula szowitsiana DC is an ethnomedicinal plant found in Iran, Turkey
and Afghanistan. This plant is widely used as anti-helminthics and anti-septic
in traditional medicine of these countries. A vast variety of biological activities
and pharmacological effects of the extracts or pure compounds isolated from
F. szowitsiana have been reported by many investigators, including anti-cancer
(Barthomeuf et al., 2008; Hanafi-Bojd
et al., 2011; Soltanzad et al., 2012),
anti-oxidant (Soltani et al., 2010), anti-genotoxicity
(Gooshchi et al., 2012), anti-inflammation (Kohno
et al., 2011), anti-microbial (Iranshahi et
al., 2007a; Ozek et al., 2008) and antibiotic
activities (Shahverdi et al., 2007; Bazzazz
et al., 2009; Bazzaz et al., 2010)
(Fig. 1). In this review, we will discuss about the chemical
contents and the medicinal properties of F. szowitsiana.
Chemical Constituents of F. szowitsiana DC: Over the years, many
groups have isolated an array of bioactive compounds from different species
of Ferula. The plant is known to be rich in coumarins, particularly sesquiterpene
coumarins (Abd El-Razek et al., 2003). The phytochemical
investigations of F. szowitsiana DC have resulted in isolation and identification
of various types of compounds including monoterpene coumarins, sesquiterpene
coumarins, phenylpropanoid derivatives and steroidal compounds (Table
1). The isolation of the compounds was obtained by column chromatographic
techniques while identification of compounds was done by spectroscopic methods
including 1H and 13C-NMR, mass experiments. Essential
oils of the aerial, leaves and stems of F. szowitsiana DC were also extracted
by hydrodistillation and analyzed by GC and GC/MS methods.
Anti-cancer property: Malignant melanoma is the most common form of
fatal skin cancer and the eighth most common cancer in the United States (Parker
et al., 1996; Landis et al., 1999).
|
Fig. 1: |
Overview of biological effects and targeted signaling pathways
by F. szwotsiana |
Table 1: |
Essential oils and compounds isolated from F. szowitsiana |
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Its incidence among Caucasian population is in a rise in the past 20 years
(Rigel et al., 1996; Greenlee
et al., 2001). Barthomeuf et al. (2008)
studied the anti-cancer property of F. szowitsiana on malignant melanoma.
They reported high inhibitory activity of umbelliprenin isolated from F.
szowitsiana roots against human M4Beu metastatic pigmented malignant melanoma
cell line. They purified umbelliprenin (C24H30O3,
MW: 366) and auraptene (C19H22O3, MW: 298.4)
to test against a number of melanoma cells using Resazurin Reduction Test (RRT).
Umbelliprenin (IC50 = 12.4±0.5 μM) significantly inhibited
the growth of M4Beu cells at a lower dose, compared to auraptene (IC50
= 17.2±0.7 μM) and the standard drug, cisplatin (IC50
= 23.1±0.8 μM). They also showed the ability of umbelliprenin to
reduce the serum-induced proliferation of M4Beu at 25 mM through cell cycle
blockade in G1 and induction of dose-dependent apoptosis (Barthomeuf
et al., 2008).
In addition to M4Beu, they tested the activity of umbelliprenin and auraptene
in human primary fibroblasts to evaluate the selectivity index of the compounds
and also in other cancer cells including PA1 (ovary teratocarcinoma), MCF7 (breast
adenocarcinoma), PC3 (androgen-resistant prostate carcinoma), DLD1 (colon adenocarcinoma)
and A549 (non-small cell lung carcinoma). Both compounds exhibited high inhibitory
activity against all carcinoma cell lines. At concentration of 25 mM, minimal
cytotoxic effect of umbelliprenin was observed in primary fibroblasts, suggesting
its significant selectivity between normal and malignant cells. However, some
cytostatic effects were observed at that concentration (Barthomeuf
et al., 2008).
Multi-Drug Resistance (MDR) is a phenomenon of tumor cells exhibiting resistance
to different anti-cancer drugs (Liscovitch and Lavie, 2002).
One of the major cellular mechanisms that mediate MDR is the over-expression
of a 170 kDa plasma membrane protein, named ABCB1 or P-gp (Ambudkar
et al., 1999). In the study by Hanafi-Bojd
et al. (2011), P-gp-over-expressing cell line MCF7/Adr was used to evaluate
the inhibitory activity of galbanic acid isolated from F. szowitsiana
roots and farnesiferol A isolated from F. Persica roots, against P-gp
for two exposure times (15 and 30 min). Galbanic acid exhibited high potential
to serve as a proper MDR inverting candidate, due to its significant inhibitory
effect for both exposure times (Hanafi-Bojd et al.,
2011). Meanwhile, farnesiferol A at 0.5 μg mL-1 inhibits
P-gp transporter at 15 min after treatment. At this exposure time, it demonstrated
higher activity compared to standard drug, verapamil. Of note, Farnesiferol
A has been successfully isolated from F. szowitsiana (Kohno
et al., 2011).
Cytotoxicity and anti-cancer activity of methanolic fraction of F. szowitsiana
was also examined on lung cancer (Soltanzad et al.,
2012). Lung cancer is the most frequent cancer in the world, which ranked
as the major cause of world-wide cancer death (Haugen, 2008;
Skarda et al., 2008). Malignant lung cancer
may spread into nearby tissue and other parts of the body through metastasis.
The major difficulty faced in treating lung cancer is the resistance of lung
cancer to chemotherapeutic drugs. Thus, discovery of novel drug with new targets
will ease drug resistance problem in lung cancer (Shanker
et al., 2010).
Soltanzad et al. (2012) showed that the F.
szowitsiana methanolic extract inhibited the proliferation of A549 cells
in a dose-dependent manner using MTT assay. They also studied the expression
of apoptosis related genes such as Bcl-2, Bcl-XL, Bax and p53 in comparison
to 18s housekeeping gene using reverse transcriptase-qPCR. The results from
the qPCR confirmed the significant cytotoxicity and growth inhibitory activity
of the methanolic extract of F. szowitsiana. This suggests its high
potential for further clinical evaluations (Soltanzad
et al., 2012).
Anti-inflammation property: Inflammation is a biological response initiated
by innate immune response in an individual against harmful stimuli such as pathogen.
It is also common condition present in many diseases such as cardiovascular
diseases and diabetes mellitus (Mueller et al.,
2010). It can be related to the excessive production of Nitric Oxide (NO)
which initiates leucocytes recruitment (Laroux et al.,
2001). Study by Kohno et al. (2011) proved
that one of the terpenoid coumarins isolated from F. szowitsiana, methyl
galbanate, demonstrated marked reduction of NO production in lipopolysaccharide
(LPS)- or interferon-γ (IFN-γ)-stimulated RAW264.7 macrophage cells.
From their findings, methyl galbanate treated RAW264.7 cells exhibited decreased
level of LPS/IFN-γ-induced iNOS mRNA expression. Besides, methyl galbanate
was capable of preventing NO-induced apoptosis in neuronally differentiated
tsAM5NE cells (Kohno et al., 2011).
Antioxidant and anti-genotoxicity property: Reactive Oxygen Species
(ROS) had been recognized to enhance the effects of inflammation via activation
of inflammatory cascades (Conner and Grisham, 1996).
Thus, discovery of the capability of F. szowitsiana in reducing ROS supports
its anti-inflammation property as well. Soltani et al.
(2010). demonstrated antioxidant capacity in auraptene isolated from F.
szowitsiana. Auraptene was proved to decrease genotoxicity of H2O2
and its activity was higher than ascorbic acid. They suggest that auraptene
suppress the generation of superoxide anion due to the presence of prenyl moiety
(Soltani et al., 2010). The antioxidant property
of F. szowitsiana was further supported by Gooshchi
et al. (2012). In their study, antioxidant activity of the methanol
extract of F. szowitsiana was proved by using DPPH (1,1-diphenyl-2-picryl-hydrazyl)
assay where it demonstrated remarkable radical scavenging activity (8.85x10-2
mg mL-1) comparable with rutin (5.12x10-2 mg mL-1)
(Gooshchi et al., 2012).
Anti-microbial property: Human leishmaniasis is a severe parasitic infection,
caused by different species of Leishmania, a genus of trypanosomatid
protozoa, with high mortality and morbidity rates in Asia, Africa and Latin.
These intracellular pathogens can accumulate in dogs, rodents and other small
mammals and are normally transmitted via mosquitoes from Lutzomia and
Phlebotomus genera. Although leishmaniasis is difficult to treat due
to the intramacrophagic location of the infectious form, many natural products
have been reported to show anti-leishmanial activity. Due to the side effects
of the alternative drugs used for leishmaniasis treatment, they have been replaced
over the last few years, by plant extract and plant-derived compounds such as
lignans, chalcones, naphthoquinones, alkaloids, triterpenoids and neolignans
(Sauvain et al., 1996; Balana-Fouce
et al., 1998; Torres-Santos et al., 1999;
Kayser et al., 2000; Barata
et al., 2000; Camacho et al., 2000;
Delorenzi et al., 2001; De
Carvalho and Ferreira, 2001).
Iranshahi et al. (2008) isolated a number of
compounds, as shown in Table 1 and evaluated the inhibitory
activity of the acetone extract of F. szowitsiana roots, prenylated coumarins,
szowitsiacoumarin A and szowitsia coumarin B, auraptene, umbelliprenin and galbanic
acid against promastigotes of L. major compared with amphotericin B,
as the positive control (Iranshahi et al., 2008).
They employed stationary-phase promastigotes to evaluate the anti-leishmanial
activity of the compounds via in vitro leishmanicidal assay (Jaafari
et al., 2006). The acetone extract and all of the evaluated compounds
indicated inhibitory activity against L. major promastigotes, especially
umbelliprenin and auraptene which efficiently inhibited the parasite at IC50
values of 13.3 μM and 17.1 μM, respectively (Iranshahi
et al., 2008). Coumarins and auraptene had been previously reported
to show anti-leishmanial and growth inhibitory activities against the tropical
parasite, L. major (Oketch-Rabah et al.,
1997; Bravo et al., 1999; Napolitano
et al., 2004) .
Modulation of antibiotic activity: Antibiotics include a substantial
portion of medications, frequently used in modern medicine. The most significant
problem associated with application of antibiotics is the ability of some important
community and hospital-acquired pathogens, to acquire resistance to these therapeutic
agents. The upward trend in the existence of resistant Gram-positive bacteria
affirms the urgent need for development of new drugs and/or a combination of
different therapies to control the resistant pathogens (Bazzazz
et al., 2009). During the recent decades, many investigations on
combinations of plant extracts and antibiotics have been conducted in order
to find a solution for the problem of emerging resistance in clinical isolates.
Shahverdi et al. (2007) showed that the combination
of cephalexin or penicillin G with galbanic acid isolated from from the acetone
extract of F. szwotsiana roots demonstrated marked decrease in the MIC
of the two antibiotics against S. aureus (Shahverdi
et al., 2007). Later, Bazzazz et al.
(2009), also demonstrated a reduction of MIC by antibiotics ciprofloxacin,
methicillin and tetracycline against resistant isolates of S. aureus
with galbanic acid from F. szwotsiana. Meanwhile, no inhibitory effect
was observed on high concentration of galbanic acid. This suggests that the
positive inhibitory effects demonstrated could be due to the combination of
antibiotics and galbanic acid (Bazzazz et al., 2009).
CONCLUSION Different medicinal potentials of F. szwotsiana in various diseases have been reported by many investigators. However, there is a definite requirement of more detailed mechanistic and clinical studies on the mechanisms of these properties. The current state of research on F. szwotsiana implicates great potential of the isolated bioactive compounds in treating diseases. With the advancement in medicinal chemistry and bioinformatics, the ethnomedicinal usage of F. szwotsiana can be scientifically explained and proved through in vitro or in vivo studies and may consequently be developed as potential plant-based drugs. ACKNOWLEDGMENT This study was supported by UM Research grant (RG434-12HTM) from University of Malaya.
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