Mar Drugs. 2009 June; 7(2): 71–84.
Published online 2009 March 31. doi: 10.3390/md7020071
PMCID: PMC2707034
Matrix Metalloproteinase Inhibitors (MMPIs) from Marine Natural Products: the Current Situation and Future Prospects
This article has been cited by other articles in PMC.
Abstract
Matrix
metalloproteinases (MMPs) are a family of more than twenty five
secreted and membrane-bound zinc-endopeptidases which can degrade
extracellular matrix (ECM) components. They also play important roles in
a variety of biological and pathological processes.
Matrix metalloproteinase inhibitors (MMPIs) have been identified as potential therapeutic candidates for metastasis, arthritis, chronic inflammation and wrinkle formation. Up to present, more than 20,000 new compounds have been isolated from marine organisms, where considerable numbers of these naturally occurring derivatives are developed as potential candidates for pharmaceutical application. Even though the quantity of marine derived MMPIs is less when compare with the MMPIs derived from terrestrial materials, huge potential for bioactivity of these marine derived MMPIs has lead to large number of researches.
Saccharoids, flavonoids and polyphones, fatty acids are the most important groups of MMPIs derived from marine natural products. In this review we focus on the progress of MMPIs from marine natural products.
Matrix metalloproteinase inhibitors (MMPIs) have been identified as potential therapeutic candidates for metastasis, arthritis, chronic inflammation and wrinkle formation. Up to present, more than 20,000 new compounds have been isolated from marine organisms, where considerable numbers of these naturally occurring derivatives are developed as potential candidates for pharmaceutical application. Even though the quantity of marine derived MMPIs is less when compare with the MMPIs derived from terrestrial materials, huge potential for bioactivity of these marine derived MMPIs has lead to large number of researches.
Saccharoids, flavonoids and polyphones, fatty acids are the most important groups of MMPIs derived from marine natural products. In this review we focus on the progress of MMPIs from marine natural products.
Keywords:
Matrix metalloproteinases (MMPs),
Matrix metalloproteinase inhibitors (MMPIs),
Tissue inhibitors of metalloproteinase (TIMPs),
Marine natural products,
NF-κB,
AP-1
Matrix metalloproteinases (MMPs),
Matrix metalloproteinase inhibitors (MMPIs),
Tissue inhibitors of metalloproteinase (TIMPs),
Marine natural products,
NF-κB,
AP-1
Introduction
Matrix
metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases
that degrade extracellular matrix (ECM) components and play important
roles in a variety of biological and pathological processes [1].
MMPs regulate the synthesis and secretion of cytokines, growth factors,
hormone receptors, and cell adhesion molecules. They also contribute to
the growth and development, morphogenesis, tissue remodeling,
angiogenesis, arthritis, cardiovascular disease, stroke, multiple
sclerosis, neurodegenerative diseases, allergies, as well as cancer and a
series of physiological and pathological processes [2, 3].
In tumor progression MMPs are important not only in invasion,
angiogenesis, and metastasis, but also MMPs have roles in cancer cells
transformation, growth, apoptosis, signal transduction and immune
regulation [4, 5].
Therefore, the development of matrix metalloproteinase inhibitors (MMPIs) to treat some important diseases, including cancers, neurodegenerative diseases, cardiovascular diseases and various kinds of inflammatory diseases have broad prospects [3–9].
Therefore, the development of matrix metalloproteinase inhibitors (MMPIs) to treat some important diseases, including cancers, neurodegenerative diseases, cardiovascular diseases and various kinds of inflammatory diseases have broad prospects [3–9].
Generally
MMPs consist of a propeptide domain having about 80 amino acids, a
catalytic metalloproteinase domain of about 170 amino acids, a linker
peptide of variable lengths (also called the “hinge region”) and a
hemopexin domain of about 200 amino acids [10].
However, not all of these domains are essential for MMPs; some MMPs
lack the linker peptide and the hemopexin domain. MMPs contain a Zn2+
catalytic core; this zinc-binding site has a conservative HEXXHXXGXXH
amino acid sequence. The catalytic domains of MMPs show homology, as
their three-dimensional (3D) structure of the enzyme active site are
highly conservative. The catalytic domain includes a pocket called
the“S1′ pocket” located to the right of the zinc atom. This pocket is
hydrophobic in nature, but variable in depth depending on the MMP. It is
therefore one of the determining factors of substrate specificity of
MMPs. Accordingly, the S1′ pocket in the catalytic domains of MMPs is
most notable, and its depth, as well as the length and amino acid
sequence of the peptide which around the S1′ pocket is important basis
for design and synthesis of the MMPIs [11–13].
MMPs’ activities can be regulated by endogenous inhibitors, such as tissue inhibitors of metalloproteinase (TIMPs), α2-macroglobin, heparin and the reversion-inducing cysteine-rich protein with kazal motifs (RECK) [4, 5].
There are four TIMPs in humans (TIMP-1, -2, -3 and -4) with 22–29 kDa. TIMP-1 and TIMP-3 are glycoproteins, but TIMP-2 and TIMP-4 do not contain carbohydrates. They inhibit all MMPs tested so far [14]. These four TIMPs have different expression and distribution in the tissue and may be responsible for regulating the activity of a large number of protease families in vivo, including the metalloproteinases of a disintegrin and metalloproteinases (ADAMs) family. However, the TIMPs and other endogenous inhibitors have diversity of biological functions and also the protein delivery techniques are not developed, the use of these endogenous inhibitors in clinical applications have been delayed [4, 5].
There are four TIMPs in humans (TIMP-1, -2, -3 and -4) with 22–29 kDa. TIMP-1 and TIMP-3 are glycoproteins, but TIMP-2 and TIMP-4 do not contain carbohydrates. They inhibit all MMPs tested so far [14]. These four TIMPs have different expression and distribution in the tissue and may be responsible for regulating the activity of a large number of protease families in vivo, including the metalloproteinases of a disintegrin and metalloproteinases (ADAMs) family. However, the TIMPs and other endogenous inhibitors have diversity of biological functions and also the protein delivery techniques are not developed, the use of these endogenous inhibitors in clinical applications have been delayed [4, 5].
Design and synthesis of MMPIs has gone through several stages of development over the past 20 years [13].
Originally MMPIs was designed by simulating MMPs substrate, this is the first-generation of MMPIs. Most of them are peptides and their derivatives. Inhibition is occurred by chelating the Zn2+ of the MMP by the group present in inhibitors, such as hydroxylamine, carboxyl, SH, etc.. Mainly the Zn2+ is chelated with the oxyammonia-base by combining the substrate analogs peptide, at the same time through the substrate analogs peptide combine with the catalytic domains of MMP, and thus plays the inhibitory effect.
Strong Zn2+ chelating agents such as hydroxamate as a class of MMPIs have been developed, representative of these inhibitors are the British Biotech’s Batimastat (BB-94) and Marimastat (BB-2516), and they all have ideal inhibitory activity with the MMPs. Even through, these compounds can interact with Zn2+; they can’t distinguish between different MMPs.
Therefore, the uses of first-generation of MMPIs as drugs in clinical applications were restricted.
Their shortcomings include: poor selectivity of MMPs, hydroxylamine substances have low oral bioavailability, the metabolism is not stable, poor solubility and the drug toxicity increase after amelioration. Therefore it was strongly suggested that the first generation of MMPIs must use another group in place of hydroxylamine group as a Zn2+ chelating group, or design new non-peptide MMPIs.
For these proposed MMPIs, first, lead (Pb) compounds were selected through high-throughput screening, then these lead compounds are reformed with the Safety Analysis Report (SAR) guidance, finally these new reagents with better effect was formed.
The second-generation MMPIs also contain Zn2+ chelating group. These drugs have eliminated some of shortcomings of peptide drugs with considerable selectivity towards MMPs. However, in clinical applications they also have been impeded due to effectiveness and side effects [15, 16].
Originally MMPIs was designed by simulating MMPs substrate, this is the first-generation of MMPIs. Most of them are peptides and their derivatives. Inhibition is occurred by chelating the Zn2+ of the MMP by the group present in inhibitors, such as hydroxylamine, carboxyl, SH, etc.. Mainly the Zn2+ is chelated with the oxyammonia-base by combining the substrate analogs peptide, at the same time through the substrate analogs peptide combine with the catalytic domains of MMP, and thus plays the inhibitory effect.
Strong Zn2+ chelating agents such as hydroxamate as a class of MMPIs have been developed, representative of these inhibitors are the British Biotech’s Batimastat (BB-94) and Marimastat (BB-2516), and they all have ideal inhibitory activity with the MMPs. Even through, these compounds can interact with Zn2+; they can’t distinguish between different MMPs.
Therefore, the uses of first-generation of MMPIs as drugs in clinical applications were restricted.
Their shortcomings include: poor selectivity of MMPs, hydroxylamine substances have low oral bioavailability, the metabolism is not stable, poor solubility and the drug toxicity increase after amelioration. Therefore it was strongly suggested that the first generation of MMPIs must use another group in place of hydroxylamine group as a Zn2+ chelating group, or design new non-peptide MMPIs.
For these proposed MMPIs, first, lead (Pb) compounds were selected through high-throughput screening, then these lead compounds are reformed with the Safety Analysis Report (SAR) guidance, finally these new reagents with better effect was formed.
The second-generation MMPIs also contain Zn2+ chelating group. These drugs have eliminated some of shortcomings of peptide drugs with considerable selectivity towards MMPs. However, in clinical applications they also have been impeded due to effectiveness and side effects [15, 16].
Clinical
trials for the anti-cancer and anti-arthritis effects have been carried
out using many early MMPIs. However, only a few MMPIs were effective
(such as Marimastat, the overall survival rate of the gastric cancer and
pancreatic cancer patients increase). Therefore they have not been used
in the later stages of clinical trials.
At present, only one MMPI (Periostat) is being used clinically for periodontitis therapy [5, 15].
At present, only one MMPI (Periostat) is being used clinically for periodontitis therapy [5, 15].
With
intensive studies on MMPs, the MMPs host-cell defense functions and
physiological functions have been discovered by researchers. The early
MMPIs whether peptide inhibitors or small molecule inhibitors, their
activities are most dependent on the Zn2+ chelating group and MMPs S1′ pocket combined group. However the Zn2+
chelating group also reduces these early MMPIs’ selectivity. In
addition, these early MMPIs inhibit some MMPs physiological functions
and some other metalloprotease such as DPP III and leucine
aminopeptidase, when they inhibit the abnormal MMPs in pathology
situation [5, 17].
To
sum up the above arguments, the clinical trials of MMPIs in
broad-spectrum, face the obstacle, as well as the normal physiological
functions of MMPs should be further studied for the choice of drugs
which are selectively acting on them for the MMPs relevant diseases.
MMPs S1′ pocket determine the specificity of substrates and inhibitors
in a large extent, therefore the S1′ pocket is very important for the
design and synthesis of MMPIs. Design of MMPIs should be based on the
unique functions of MMPs S1′ pocket, not only to increase the
selectivity for this MMP, but also greatly reduce the inhibition of
other class of metalloprotease such as ADAMs.
At present, development of the new generation of MMPIs is guided by this idea. In addition, development of new type of MMPIs with different inhibiting mechanisms can increase the drugs’ selectivity; which may play a key role in the treatment of various diseases related to MMPs [18–21].
At present, development of the new generation of MMPIs is guided by this idea. In addition, development of new type of MMPIs with different inhibiting mechanisms can increase the drugs’ selectivity; which may play a key role in the treatment of various diseases related to MMPs [18–21].
Broadly
speaking, the mechanisms of inhibiting the activity of MMPs include,
direct inhibition of the enzymes, blocking the MMPs proenzyme
activation, suppressing the synthesis of MMPs in the gene level, and so
on.
The MMPIs can be divided into four classes:
The MMPIs can be divided into four classes:
- the natural MMPIs secreted by tissues;
- synthetic MMPIs;
- MMPIs screened from natural products
- and the MMPIs screened from the phage display random peptide library and antibody library.
Lots of
successful research work have been conducted to identify MMPIs from land
natural products, also got a lot of results. For instance, Kim et al.
were screened for nearly 90 kinds of extracts from clinical application
herbal medicines, and found that the extracts from Baicalin, Cinnamon,
Euonymus, and Magnolia have strong inhibitory effects on MMPs [22–24].
However we should not forget that the ocean is treasure house which is
full of natural products with amazing biological and pharmacological
activities. About 80% of the planet’s animal and plant growth in the
ocean, and the variety of marine bacteria can reach 500–100 million.
Therefore discovering the ideal MMPIs from marine natural products is a
very hot topic at present.
The leitmotiv along this review is to sum up the progress of research work carried out on identifying MMPIs from marine natural products. We divided the marine derived MMPIs into three classes, marine saccharoid MMPIs, marine flavonoids and polyphenols MMPIs and marine fatty acid MMPIs, and their properties will be discussed in this review.
The leitmotiv along this review is to sum up the progress of research work carried out on identifying MMPIs from marine natural products. We divided the marine derived MMPIs into three classes, marine saccharoid MMPIs, marine flavonoids and polyphenols MMPIs and marine fatty acid MMPIs, and their properties will be discussed in this review.
2. MMPIs from marine natural products
2.1. Marine saccharoid MMPIs
The
marine saccharoid MMPIs are very popular among marine derived MMPIs
area. The most of marine saccharoid MMPIs inhibit MMP by direct
down-regulation of MMP-9 transcription or via inhibition of activator
protein-1(AP-1) pathway or nuclear factor κB (NF-κB) pathway. Kim et al.
report the inhibitory effect of chitooligosaccharides (COS) on
activation and expression of matrix metalloproteinase-2 (MMP-2) in
primary human dermal fibroblasts (HDFs) for the first time. COS with 3–5
kDa exhibited the highest inhibitory effect on MMP-2 activity in HDFs,
and protein expression of MMP-2 was also inhibited by COS with same
molecular weight. This inhibition was caused by the decrease in gene
expression and transcriptional activity of MMP-2[25]. Quang et al.
have investigated the effect of Chitooligosaccharides (COS) on activity
and expression of MMP-9 in HT1080 cells by gelatin zymography, RT-PCR,
gene reporter assay, and western blot analysis. They found that MMP-9
inhibition in the presence of COS was clearly observed in gelatin
zymography. Specifically, 1- to 3-kDa COS (COS-I) exhibited the highest
inhibitory effect on MMP-9 activity in HT1080 cells among tested
molecular mass fractions. It was also found that COS-I was capable of
inhibiting both gene and protein expression of MMP-9 (P<0 .01="" a="" class="bibr popnode tag_hotlink tag_tooltip jig-ncbipopper" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707034/#b26-marinedrugs-07-00071" id="__tag_175004346" role="button">26
Adriana et al. investigated on the shrimp heparin-like glycosaminoglycan isolated from L. vannamei
which was able to interfere on MMP-9 activity in activated human
leukocytes. And it has the capacity to reduce 90% MMP-9 activity, either
in a lower or higher concentrations (10 and 100 μg/mL), with pronounced
effects [28].
In present studies, sulfated glucosamine (SG) has been reported to
relieve joint pain and inflammation in many arthritis patients. Niranjan
et al. studied for SG inhibitory effects on MMP-2 and MMP-9 in
human fibrosarcoma cells. Expression and activity of above MMPs studied
suggested SG as a potent MMP inhibitor, and inhibition of MMP-2 and
MMP-9 was due to down-regulation of transcription factor, NF-κB.
However, expression of activator protein-1 (AP-1) was not affected by SG
treatment. Moreover, down-regulation of NF-κB resulted in production of
low levels of both NF-κB p50 and p65 proteins and directly affected
activation process of MMP-2 and MMP-9 expressions [29].
Angiogenesis
is involved in initiating and promoting several diseases such as cancer
and cardiovascular events. Chen et al. obtained highly sulfated
λ-carrageenan oligosaccharides (λ-CO) by carrageenan depolymerization.
They have demonstrated that λ-carrageenan oligosaccharides could
effectively inhibit angiogenesis in the CAM (chick chorioallantoic
membrane) model and human umbilical vein endothelial cells (HUVECs).
Significant inhibition of vessel growth was observed at 200 μg/pellet. A
histochemistry assay also revealed a decrease of capillary plexus and
connective tissue in λ-CO treated samples. λ-CO inhibited the viability
of cells at the high concentration of 1 mg/mL, whereas it affected the
cell survival slightly (>95%) at a low concentration (<250 300="" a="" action="" also="" and="" at="" cell="" cells.="" class="bibr popnode tag_hotlink tag_tooltip jig-ncbipopper" concentrations="" down-regulation="" endothelial="" expression="" furthermore="" g="" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707034/#b30-marinedrugs-07-00071" id="__tag_175004360" in="" inhibitory="" intracellular="" invasion="" low="" matrix="" metalloproteinases="" migration="" ml="" observed="" of="" on="" relatively="" role="button" the="" through="" was="">30
].
Wang et al. isolated the sulfated S. maindroni ink polysaccharide (SIP-SII) from cuttlefish Sepiella maindroni,
and examined the effects of SIP-SII on the expression of matrix
metalloproteinases MMP-2 and MMP-9 as well as tumor cell invasion and
migration. SIP-SII (0.8–500 mg/ml) significantly decreased the
expression of MMP-2 activity in human ovarian carcinoma cells SKOV3. No
significant decrease of MMP-9 was detected in the cell line after
SIP-SII treatment [31].
Fucoidan
is a uniquely-structured sulfated polysaccharide found in the cell
walls of several types of brown seaweed which has been recently
evaluated for its bioactivities by Ye et al. [32].
Enzyme-digested fucoidan extracts prepared from seaweed, Mozuku of
Cladosiphon novae-caledoniae kylin showed in vitro invasion and
angiogenesis abilities of human tumor cells. The mechanism of
significant inhibition of HT1080 cells invasion by fucoidan extracts,
possibly via suppressing MMP-2 and MMP-9 activities. Further, they
investigated the effects of the fucoidan extracts on angiogenesis of
human uterine carcinoma HeLa cells, and found that fucoidan extracts
suppressed expression and secretion of vascular endothelial growth
factor (VEGF) [32].
Marine
saccharoid MMPIs exhibit high MMPs inhibitory activity either by direct
inhibition of the enzyme or by inhibiting the expression of MMPs. And
also these marine saccharoid MMPIs have shown low toxicity levels.
However, due to high molecular weight of theses MMPIs the
structure-activity relationship and also the mechanism of the activities
are hard to be addressed by the researchers. If these shortcomings are
overcome in the future, marine saccharoid MMPIs have a great potential
to be used in clinical applications.
2.2. Marine flavonoids and polyphenols MMPIs
Flavonoid glycosides, isorhamnetin 3-O-b-D-glucosides, and quercetin 3-O-b-D-glucoside were isolated from Salicornia herbacea and their inhibitory effects on matrix metalloproteinase-9 and -2 were evaluated in human fibrosarcoma cell line [31].
These flavonoid glycosides led to the reduction of the expression
levels and activities of MMP-9 and -2 without any significant difference
between these flavonoid glycosides in zymography experiments. Protein
expression levels of both MMP-9 and MMP-2 were inhibited and TIMP-1
protein level was enhanced by these flavonoid glycosides [33].
Kim et al., for the first time, report a detailed study on the inhibitory effects of phlorotannins in brown algae, Ecklonia cava
(EC) on MMP activities. A novel gelatin digestion assay could visualize
complete inhibition of bacterial collagenase-1 activity at 20 μg/ml of
EC extract during preliminary screening studies. Sensitive fluorometric
assay revealed that EC extract can specifically inhibit both MMP-2 and
MMP-9 activities significantly (P<0 .001="" 100="" 10="" a="" activities="" addition="" and="" anticipating="" any="" artificially="" as="" at="" by="" cells="" class="bibr popnode tag_hotlink tag_tooltip jig-ncbipopper" control="" cytotoxic="" dermal="" did="" doxycycline.="" ec="" effect="" even="" exert="" extract="" fibroblasts="" g="" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707034/#b34-marinedrugs-07-00071" ht1080="" human="" id="__tag_175004388" in="" induced="" inhibited="" inhibitor="" interestingly="" its="" less="" manner="" ml.="" ml="" mmp-2="" mmp-9="" mmp="" more="" not="" of="" or="" positive="" potential="" role="button" safe="" similar="" the="" to="" use="" were="">34
The active compound from methanol extracts prepared from roots of Rhodiola sacra has been identified as 3-(3, 4-dihydroxy-phenyl)-acrylic acid phenethyl ester (caffeic acid phenethyl ester, CAPE) [35, 36]. And Lee et al. found that these active compounds can down-regulate enhanced MMP -9 activities [37].
Joe et al.
examined the inhibitory effects of 29 seaweed extracts on
transcriptional activities of MMP-1 expression. And found that the eckol
and dieckol from Ecklonia species have showed strong
inhibition of both NF-κB and AP-1 reporter activity, which were well
correlated with their abilities to inhibit MMP-1 expression. In
addition, MMP-1 expression was dramatically attenuated by treatment with
the eckol or dieckol [38].
Matrix
metalloproteinases (MMPs), a key component in photoaging of the skin
due to exposure to ultraviolet A, appear to be increased by
UV-irradiation-associated generation of reactive oxygen species (ROS).
Ryu et al. demonstrates that the alga Corallina pilulifera
methanol extract which has been shown a high phenolic content, reduced
the expression of UV-induced MMP-2 and -9 in human dermal fibroblast by
dose dependently manner, and has also antioxidant activity capable of
strongly inhibiting free radicals [39].
In murine asthma model, Kim et al. observed that MMP-9 expression was significant reduced via the administration of Ecklonia cava extracts. And Ecklonia cava
extracts reveal Suppressor of cytokine signaling-3 (SOCS-3) expression
and a reduction in the increased eosinophil peroxidase (EPO) activities.
Their results indicate that Ecklonia cava extracts may prove to be a useful therapeutic agent for the treatment of ovalbumin -induced asthma [40].
The
compounds eckol, 2dieckol, 6,6′-bieckol and 1-(3′,5′-dihydroxyphenoxy)
-7-(2″,4″,6″-trihydroxy-phenoxy)-2,4,9-trihydroxydibenzo-1,4,-dioxin
were extracted from brown algae, Ecklonia cava, and Ryu et al.
have investigated these compounds inhibited the proinflammatory
cytokines induced expression of MMP-1, -3 and -13 [41].
Flavonoids
and polyphenols MMPIs have excellent MMPs inhibitory activities;
however they show a high toxicity level. Therefore, the pharmaceutical
applications of these MMPIs are limited. Researchers should pay
attention to reduce their toxicity levels by altering the structure in a
way by preserves it’s bioactivity. Then this class of MMPIs will gain a
huge potential to be used in clinical applications
2.3. Marine fatty acid MMPIs
Researchers
have identified that the long-chain fatty acids could inhibit MMPs.
however for different MMPs the degree of inhibition is different, such
as oleic acid, elaidic acid can inhibit MMP-2 and MMP-9 with the
micromol Ki values, although their inhibitory effects on collagenase-1
(MMP-1) are weak, as assessed using synthetic or natural substrates [42].
The fatty acid chain length and its degree of saturation is related to
the level of inhibition, as the fatty acids with long carbon chains
showed stronger inhibition than the short ones, and the nonsaturation
degree showed a positive correlation to the overall inhibitory capacity
of the fatty acid chains [42,43].
Fatty acids also bind to neutrophil elastase, the parinaric acids,
fluorescent-conjugated tetraenoic fatty acids of plant origin, are
inhibitors of neutrophil elastase. cis-Parinaric acid (cis-PA) interacts
with the enzyme in two inhibitory modes. The high affinity interaction
(Ki = 55 +/− 6 nM) results in partial noncompetitive inhibition of
amidolytic activity, with 82% residual activity. A lower affinity
interaction with cis-PA (Ki = 4 +/− 1 microM) results in competitive
inhibition [44, 45].
the fatty acids also bind to plasmin, such as The ability of oleic acid
to modulate fibrinolysis was measured by following the
urokinase-mediated and plasminogen-dependent cleavage of 125I-labelled
fibrin clots. Oleic acid levels within the physiological range exerted a
concentration-dependent inhibition of urokinase-mediated fibrinolytic
activity [46, 47], and some other serine proteinases, meanwhile modulate their catalytic activities.
It
is well known that the marine fishes are rich in omega-3 long-chain
polyunsaturated fatty acids (ω3 LC-PUFAs), especially eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA), which are active nutrients [48]. Suzuki et al.
found that the inhibition of lung metastasis of a colon cancer cell
line by EPA and DHA was associated with a reduced activity of MMP-9,
however MMP-2 activity was not affected by the diet containing PUFAs [49, 50].
The MMP-9 activity was reduced by in uterus, placenta and liver tissues
of rat fed diets enriched with DHA, with a decreased activity of MMP-2 [50].
They explained their finding by a competition of the ω3 LC-PUFAs with
arachidonic acid for incorporation into membrane phospholipids. This
would consequently change the production of prostaglandin PGE2 and
thereby affect on MMP activities.
Acetylenic fatty acids isolated from marine sponges have exhibited wide range of biological activities such as cytotoxicity [51], antimicrobial [52] and antifouling [53] activities, and enzyme inhibition [54]. Callysponginol sulfate A is the first sulfated C24 acetylenic fatty acid from marine organisms. Fujita et al.
2002 extracted the sodium 1-(12-hydroxy)octadecanyl sulfate from an
ascidian collected in western Japan, inhibited MMP-2 in 2002. And both
natural and synthetic forms inhibited MMP-2 with an IC50 value at 9.0 μg/mL; thus the stereochemistry of the hydroxyl group did not influence the activity [55]. And after one year, they reported another compound, callysponginol sulfate A, a new sulfated C24 acetylenic fatty acid, extracted from the marine sponge, Callyspongia truncate [56]. This compound inhibited recombinant MT1-MMP with an IC50
value at 15.0 μg/mL, however the desulfated callysponginol sulfate A
did not show any inhibitory activity against MT1-MMP. Considering this
result as well as the similar activity of structurally unrelated
sulfated compounds, the MT1-MMP inhibition activity is probably a
consequence of the sulfate [56].
2.4. Other marine natural products MMPIs
Shark cartilage extracts researches are very popular in recently [57].
The compounds extracted from shark cartilage (such as NeovastatÒ,
AE-941, U-995 etc.) have been investigated on their potential use as
MMPIs. These compounds were analyzed with regard to their
anti-angiogenic and antimetastatic effects on the activity of several
MMPs [58],
because MMPs are intimately connected with angiogenetic and metastatic
processes. The results revealed that NeovastatÒ inhibits enzymatic
activity of MMP-2 with minor inhibition of MMP-1, -7, -9 and -13. And
also interestingly the western blot analysis evidenced the presence of
TIMP-like proteins within AE-941, could be responsible for its specific
MMP inhibitory property [59].
The tissue inhibitors of metalloprotease 1, 2 and 3 (TIMP-1, -2, -3)
and tumor suppressor protein genes have been cloned and characterized
from shark cartilage extracts [52, 60, 61].
Alkaloid Ageladine A extract from the marine sponge, Agelas nakamurai, and Ageladine A inhibited not only MMP-2, but also MMPs-1, -8, -9, -12, and -13 with IC50
values of 2.0, 1.2, 0.39, 0.79, 0.33, and 0.47 μg/mL, respectively,
while its N-methylated derivatives did not inhibit MMP-2. As we know
that many potent MMP inhibitors are known to bind with Zn2+ in the catalytic domain. But Ageladine A was not capable to chelate Zn2+.
Moreover, the kinetic analysis indicated that inhibition of MMP-2 by
Ageladine A was not competitive when judged in the Lineweaver-Burk plot.
Thus, the inhibition mechanism of Ageladine A was presumed to be unique
[62].
The
Atlantic cod (Gadus morhua) muscle contains a 21-kDa proteinase
inhibitor. The inhibitor had properties similar to human TIMP-2. The
inhibitor was found to inhibit the gelatin-degrading enzymes present in
the gelatin-bound fraction. In addition, it inhibited gelatinolytic
activity obtained from a human macrophage cell medium rich in MMP-9 [63].
(+)-Aeroplysinin-1,
an antibacterial brominated compound produced by certain sponges, was
selected during a blind high-throughput screening as new potential
antiangiogenic compounds obtained from marine organisms. The
concentration of MMP-2 in the medium conditioned by aeroplysinin-treated
cells was clearly lower than that in untreated cell medium. The MMP-2
bands in aeroplysinin-treated cell conditioned media were 60 + 4%
compared to those of untreated cells, whereas extracts of treated cells
yielded MMP-2 bands that were almost twofold (1.77 + 0.04) those of
untreated cells. Thus, aeroplysinin-1 seems to affect mainly the release
of MMP-2 to the medium [64].
3. Conclusions
The
marine environment is characterized by high biodiversity offering vast
variety of natural products which could be used as potential drugs,
particularly in the area of cancer chemotherapy, such like the matrix
metalloproteinase inhibitors. Therefore continuation of finding new
leads in this area of extracting bioactivity compounds from marine
natural products will make much sense.
MMPIs design and
synthesis has been done for ages and has gone through several
development stages. Although many of the synthetic inhibitors of MMPs
showed good inhibitory activity, however, the compounds do not have an
ideal MMPs selectivity, combined with others limitations such as the low
oral bioavailability, unstable metabolism, biological toxicity, and
also these inhibitors in clinical trials show excessive side effects.
Due to these major shortcomings this type of MMPIs failed to be used as
drugs [3, 5, 65].
With MMPIs finding of functionality of MMP’s in normal physiology functions, the development of MMPIs entered a new period [66, 67].
In recent years, the non-metal chelating agent class of MMPIs reports
has begun to appear. Isolating MMPs from marine natural products has
been gradually gained more attention. Some marine natural products have
been isolated with MMPs inhibitory activities and further, some
compounds have special restraint or high selectivity [68].
Such as Ageladine A which inhibit MMP-2 was not competitive judging
from the Lineweaver-Burk plot. Thus, the inhibition mechanism of
Ageladine A was presumed to be unique [62]. These MMPIs will be the focus of future work.
Acknowledgements
This
research was supported by a grant (M2007-0) from Marine Bioprocess
Research Center of the Marine Bio 21 Center funded by the Ministry of
Land, Transport and Maritime, Republic of Korea.
Abbreviations
- MMPs
- matrix metalloproteinases
- ECM
- extracellular matrix
- MMPIs
- matrix metalloproteinase inhibitors
- TIMPs
- tissue inhibitors of metalloproteinase
- RECK
- reversion-inducing cysteine-rich protein with kazal motifs
- ADAMs
- a disintegrin and metalloproteinases
- SAR
- safety analysis report
- COS
- chitooligosaccharides
- HDFs
- human dermal fibroblasts
- CCOS
- carboxylated chitooligosaccharides
- SGlc
- sulfated glucosamine
- NF-κB
- nuclear factor κB
- AP-1
- activator protein-1
- λ-CO
- λ-carrageenan oligosaccharides
- HUVECs
- human umbilical vein endothelial cells
- SIP-SII
- sulfated S. maindroni ink polysaccharide
- EC
- Ecklonia cava
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