ArticleLiterature Review

Natural Bio-Drugs as Matrix Metalloproteinase Inhibitors: New Perspectives on the Horizon?

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Abstract

The matrix metalloproteinases (MMPs), belonging to the family of proteolytic enzymes, are well-known for their ability to degrade the extracellular matrix, and are involved in many aspects of both physiological cellular processes and pathological situations, such as tumor growth, invasion and metastasis. MMPs have been considered prognostic factors in various types of cancer as well as promising targets for cancer therapy. Although preclinical studies of a number of different synthetic MMP inhibitors have been identified as cytostatic and anti-angiogenic agents and have begun clinical testing, the past years have produced a consistent number of disappointments and limited successes. In view of their specific implication in malignant tissues, several natural compounds were utilized, and the results were so satisfactory as to encourage several clinical trials in order to improve efficacy and to reduce the side effect profile. The natural protection against cancer has been receiving a great deal of attention, and the critical examination of previous studies shed light on new information about the source and function of MMPs, focusing the attention on the identification of MMP targets in tumors. This review discusses the current knowledge and research in the field of natural MMP inhibitor as innovative therapeutic intervention in cancer.

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... Matrix metalloproteinase2 (MMP-2) and matrix metalloproteinase7 (MMP-7) genes, that promote invasion and metastasis, were downregulated in breast cancer cells [12]. Also data show that genistein inhibits invasion in human breast carcinoma through diminishing the expression of MMP-2, MMP-9, MT1-, MT2-, MT3-MMPs [13]. Therefore, it is concluded that genistein has a critical role on metastasis of tumors via alteration on MMPs expression. ...
... Determination of MMPs in patient blood and urine samples can be a valuable prediction in estimation of metastasis risk. (e.g. in lung and renal cell carcinoma) [13]. Several studies illustrated that the mediatory role of genistein in decrease the MMPs expression in cancer types prostate cancer [28,30] human breast carcinoma cell lines [12,13] lung injury [25,29,31] and some pediatric tumor cell lines [32]. ...
... (e.g. in lung and renal cell carcinoma) [13]. Several studies illustrated that the mediatory role of genistein in decrease the MMPs expression in cancer types prostate cancer [28,30] human breast carcinoma cell lines [12,13] lung injury [25,29,31] and some pediatric tumor cell lines [32]. In prostate cancer, it has been determined that genistein acts antagonistically role with TGFβ's effects on MMP-2 activation and cell invasion [33]. ...
Article
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The lung cancer is one of the most dangerous cancers and is also the leading cause of cancer death worldwide, accounting for about 1.3 million deaths annually. However in clinical practice, lung cancer therapies commonly do with chemotherapy, although it is hard because the lung cancer may progress to metastasis stage. The metastasis of lung cancer is highly dependent of expression of matrix metalloproteinase, and correlated with phosphorylation of ERK1/2 and PI3K/Akt pathways. Therefore agents' down expressed matrix metalloproteinase or suppressed phosphorylation of ERK1/2 and PI3K/Akt pathways could inhibit the metastasis stage. In this study we aimed to investigate the effects of genistein, an isoflavonoid, on A-549 cell line. Lactate dehydrogenase (LDH) release, Microculture tetrazolium test (MTT assay), real-time PCR and zymography were used to evaluate the effects of genistein on cell cytotoxicity, cell proliferation, expression of mRNA and protein of MMP-2 in lung cancer A549 cell line. The results indicated that genistein, in a dose-dependent manner, without applying any cytotoxic effect, inhibited cell proliferation and downregulated MMP-2 mRNA and protein expression in A549 cell line. In addition, results of inhibition of ERK1/2 and PI3K/Akt pathways phosphorylation by ELISA indicated that genistein inhibited phosphorylation rate of both pathways. Therefore it seems that genistein can decrease recurrence and decreased the migration and invasion of human non-small cell lung cancer cells (A549 cell line) by an efficient antimetastatic effect. This issue should be further examined for the clinical treatment.
... The Ki of DX-2400 for MMP-14 is in the sub-nanomolar range compared to micromolar Ki for other MMPs. DX-2400 [41] MMP-2 (E) [42] MMP-7 (E) [43] MMP-9 (E) [42, 44] Isoflavones Genistein Soy bean MMP-1 (E) [45, 46] MMP-9 (E) [45, 46] MMP-14 (E) [45, 46] MMP-15 (E) [45, 46] MMP-16 (E) [45, 46] Flavanoid Silymarin Silybin Milk thistle MMP-9 (E) [47, 48] Silydianin Flavanols Catechins epicatechin (EC) Green tea MMP-2 (DI) [49] MMP-9 (DI) [49] MMP-12 (DI) [49] MMP-14 (DI) [49, 50] (−)-epicatechin-3-gallate (ECG), (−)-epigallocatechin (EGC) (−)-epigallocatechin-3-gallate (EGCG) Non-flavonoid Resveratrol Red grape MMP-2 (DI) [51] MMP-9 (E) [52, 53] Anthocyanidins Grape seed MMP-2 (E) [54] MMP-9 (E) [54] Proanthocyanidins Cranberry MMP-3 [55] MMP-9 [55] Curcumin MMP-2 (E) [56] MMP-9 (E) [57] MMP-14 (DI) [58] Non-polyphenol Hyperforin St. John's Wort MMP-9 (DI) [49] Saccharoids Carrageenan Red Seaweed MMP-2 (E) [59] Chitooligosaccharide MMP-1 (E) [60] MMP-2 (E) [60] MMP-8 (E) [60] MMP-9 (E) [60] MMP-13 (E) [60] Neovastat (Squalamine) Shark cartilage MMP-1 (DI) [61] MMP-2 (DI) [62] MMP-7 (DI) [61] MMP-9 (DI) [62] MMP-13 (DI) [61] E indicates that the reported method of action is on reducing expression while DI indicates direct inhibition of MMP activity was found to selectively inhibit MMP-14 and the activation of pro MMP-2 without inducing or enhancing the expression of other MMPs, a phenomenon noted with broad-spectrum MMP inhibitors such as GM6001. DX-2400 effectively prevented the growth and angiogenesis of MDA-MB-231 and Her2-positive BT-474 xenografts and significantly contributed to the efficacy of paclitaxel and bevacizumab when applied in combination [75]. ...
... The Ki of DX-2400 for MMP-14 is in the sub-nanomolar range compared to micromolar Ki for other MMPs. DX-2400 [41] MMP-2 (E) [42] MMP-7 (E) [43] MMP-9 (E) [42, 44] Isoflavones Genistein Soy bean MMP-1 (E) [45, 46] MMP-9 (E) [45, 46] MMP-14 (E) [45, 46] MMP-15 (E) [45, 46] MMP-16 (E) [45, 46] Flavanoid Silymarin Silybin Milk thistle MMP-9 (E) [47, 48] Silydianin Flavanols Catechins epicatechin (EC) Green tea MMP-2 (DI) [49] MMP-9 (DI) [49] MMP-12 (DI) [49] MMP-14 (DI) [49, 50] (−)-epicatechin-3-gallate (ECG), (−)-epigallocatechin (EGC) (−)-epigallocatechin-3-gallate (EGCG) Non-flavonoid Resveratrol Red grape MMP-2 (DI) [51] MMP-9 (E) [52, 53] Anthocyanidins Grape seed MMP-2 (E) [54] MMP-9 (E) [54] Proanthocyanidins Cranberry MMP-3 [55] MMP-9 [55] Curcumin MMP-2 (E) [56] MMP-9 (E) [57] MMP-14 (DI) [58] Non-polyphenol Hyperforin St. John's Wort MMP-9 (DI) [49] Saccharoids Carrageenan Red Seaweed MMP-2 (E) [59] Chitooligosaccharide MMP-1 (E) [60] MMP-2 (E) [60] MMP-8 (E) [60] MMP-9 (E) [60] MMP-13 (E) [60] Neovastat (Squalamine) Shark cartilage MMP-1 (DI) [61] MMP-2 (DI) [62] MMP-7 (DI) [61] MMP-9 (DI) [62] MMP-13 (DI) [61] E indicates that the reported method of action is on reducing expression while DI indicates direct inhibition of MMP activity was found to selectively inhibit MMP-14 and the activation of pro MMP-2 without inducing or enhancing the expression of other MMPs, a phenomenon noted with broad-spectrum MMP inhibitors such as GM6001. DX-2400 effectively prevented the growth and angiogenesis of MDA-MB-231 and Her2-positive BT-474 xenografts and significantly contributed to the efficacy of paclitaxel and bevacizumab when applied in combination [75]. ...
... The Ki of DX-2400 for MMP-14 is in the sub-nanomolar range compared to micromolar Ki for other MMPs. DX-2400 [41] MMP-2 (E) [42] MMP-7 (E) [43] MMP-9 (E) [42, 44] Isoflavones Genistein Soy bean MMP-1 (E) [45, 46] MMP-9 (E) [45, 46] MMP-14 (E) [45, 46] MMP-15 (E) [45, 46] MMP-16 (E) [45, 46] Flavanoid Silymarin Silybin Milk thistle MMP-9 (E) [47, 48] Silydianin Flavanols Catechins epicatechin (EC) Green tea MMP-2 (DI) [49] MMP-9 (DI) [49] MMP-12 (DI) [49] MMP-14 (DI) [49, 50] (−)-epicatechin-3-gallate (ECG), (−)-epigallocatechin (EGC) (−)-epigallocatechin-3-gallate (EGCG) Non-flavonoid Resveratrol Red grape MMP-2 (DI) [51] MMP-9 (E) [52, 53] Anthocyanidins Grape seed MMP-2 (E) [54] MMP-9 (E) [54] Proanthocyanidins Cranberry MMP-3 [55] MMP-9 [55] Curcumin MMP-2 (E) [56] MMP-9 (E) [57] MMP-14 (DI) [58] Non-polyphenol Hyperforin St. John's Wort MMP-9 (DI) [49] Saccharoids Carrageenan Red Seaweed MMP-2 (E) [59] Chitooligosaccharide MMP-1 (E) [60] MMP-2 (E) [60] MMP-8 (E) [60] MMP-9 (E) [60] MMP-13 (E) [60] Neovastat (Squalamine) Shark cartilage MMP-1 (DI) [61] MMP-2 (DI) [62] MMP-7 (DI) [61] MMP-9 (DI) [62] MMP-13 (DI) [61] E indicates that the reported method of action is on reducing expression while DI indicates direct inhibition of MMP activity was found to selectively inhibit MMP-14 and the activation of pro MMP-2 without inducing or enhancing the expression of other MMPs, a phenomenon noted with broad-spectrum MMP inhibitors such as GM6001. DX-2400 effectively prevented the growth and angiogenesis of MDA-MB-231 and Her2-positive BT-474 xenografts and significantly contributed to the efficacy of paclitaxel and bevacizumab when applied in combination [75]. ...
Article
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Heightened matrix metalloproteinase (MMP) activity has been noted in the context of the tumor microenvironment for many years, and causal roles for MMPs have been defined across the spectrum of cancer progression. This is primarily due to the ability of the MMPs to process extracellular matrix (ECM) components and to regulate the bioavailability/activity of a large repertoire of cytokines and growth factors. These characteristics made MMPs an attractive target for therapeutic intervention but notably clinical trials performed in the 1990s did not fulfill the promise of preclinical studies. The reason for the failure of early MMP inhibitor (MMPI) clinical trials that are multifold but arguably principal among them was the inability of early MMP-based inhibitors to selectively target individual MMPs and to distinguish between MMPs and other members of the metzincin family. In the decades that have followed the MMP inhibitor trials, innovations in chemical design, antibody-based strategies, and nanotechnologies have greatly enhanced our ability to specifically target and measure the activity of MMPs. These advances provide us with the opportunity to generate new lines of highly selective MMPIs that will not only extend the overall survival of cancer patients, but will also afford us the ability to utilize heightened MMP activity in the tumor microenvironment as a means by which to deliver MMPIs or MMP activatable prodrugs.
... Also in U87 cells, it diminished the gelatinolytic activities of matrix metalloproteinase-9 therefore inhibiting glioma-induced angiogenesis (Perry et al., 2010). Curcumin diplays its inhibitory activity at DNA level, on the messenger level and on enzyme level causing suppression of molecules involved in cell proliferation (Mannello, 2006). Fig. 2 shows the inhibitory effects of morusin and curcumin on MMP expression and reducing Glioma progression. ...
... It was found to down regulate MMP-2 expression by altering the oligosaccharide composition on tumor cells surface in glioma cells (Rooprai et al., 2001). Nobiletin is known to have anti-invasive properties and it works by reducing the expression of certain MMPs and increasing the TIMPs expression levels (Mannello, 2006). ...
... Tea polyphenols are known to regulate cell growth by arresting cell cycle or by promoting apoptosis by increasing p53 levels or by inhibiting AP-1 activity which controls various biological processes (Mannello, 2006). A polyphenol catechin isolated from green tea, Epigallocatechin gallate (EGCG) works as a robust MMPI by interacting with the MMPs through its gallate residues (Lia et al., 2009). ...
Article
Glioblastoma multiforme (GBM), one of the most lethal Brain tumors, characterized by its high invasive nature and increased mortality rates forms a major bottleneck in transport of therapeutics across the Blood Brain Barrier (BBB). Matrix metalloproteinases (MMPs) are classified as enzymes, which are found to be up regulated in the Glioma tumor microenvironment and thus can be considered as a target for inhibition for curbing GBM. Many chemotherapeutics and techniques have been employed for inhibiting MMPs till now but all of them failed miserably and were withdrawn in clinical trials due to their inability in restricting the tumor growth or increasing the overall survival rates. Thus, the quest for finding the suitable MMP inhibitor is still on and there is a critical need for identification of novel compounds which can alter the BBB permeability, restrain tumor growth and prevent tumor recurrence. Currently, naturally derived substances are gaining widespread attention as tumor inhibitors and many studies have been reported by far highlighting their importance in restricting MMP expression thus serving as chemotherapeutics for cancer due to their minimal toxicity. These substances may serve as probable candidates for inhibiting MMP expression in GBM. However, targeting and delivering the inhibitor to its target site is an issue that needs to be overcome in order to attain maximum specificity and sustained release. The birth of nanotechnology served as a boon in delivering drugs to the most complicated areas thus paving way for Nano drug delivery. An efficient Nano carrier with ability to cross the BBB and competently kill the Glioma cells forms the prerequisite for GBM chemotherapy. Vesicular drug delivery systems are one such class of carriers, which have the capacity to release the drug at a predetermined rate at the target site thus minimizing any undesirable side effects. Exploiting vesicular systems as promising Nano drug carriers to formulate naturally derived substances, that can bypass the BBB and act as an inhibitor against MMPs in GBM is the main theme of this review.
... [10,11] The propeptide of the MMPs contains a "cysteine switch" motif, PRCGXPD, in which the cysteine residue interacts with the catalytic zinc domain to maintain inactivity by preventing a water molecule, essential for catalysis, from binding to the zinc atom until the propeptide has been removed by proteolysis. [14] CLASSIFICATION OF MMPS [14][15][16][17][18] Metal-binding proteinases represent a relatively large and evergrowing group of enzymes. [5,10,15] authors have proposed dividing this class of MMPs into clans (based on similarity of protein fold) and families (based on evolutionary relationships). ...
... The MMP family is a continually growing group, now comprising more than 20 enzymes. [1,10,15,16] There are two classification systems of the MMPs: ...
Article
Full-text available
The family of human matrix metalloproteinases (MMPs) comprises several tightly regulated classes of proteases. These enzymes and their specific inhibitors play important roles in tumor progression and the metastatic process by facilitating extracellular matrix (ECM) degradation. As scientific understanding of the MMPs has advanced, therapeutic strategies focusing on blocking these enzymes by MMP inhibitors (MMPIs) have rapidly developed. This paper reviews MMPs in detail. Their perspectives in therapeutic intervention in cancer are also mentioned.
... MMPs are not only involved in cancer progression, but also play an important role in inflammation and immunity [42]. Multiple natural compounds have been identified which seem to block MMP activity [43]. It will be interesting to test the effects of these compounds, some of which are used as food supplements, in relation to osteoporosis and obesity. ...
Article
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Background Patients suffering from osteoporosis show an increased number of adipocytes in their bone marrow, concomitant with a reduction in the pool of human mesenchymal stem cells (hMSCs) that are able to differentiate into osteoblasts, thus leading to suppressed osteogenesis. Methods In order to be able to interfere with this process, we have investigated in-vitro culture conditions whereby adipogenic differentiation of hMSCs is impaired and osteogenic differentiation is promoted. By means of gene expression microarray analysis, we have investigated genes which are potential targets for prevention of fat cell differentiation. ResultsOur data show that BMP2 promotes both adipogenic and osteogenic differentiation of hMSCs, while transforming growth factor beta (TGFβ) inhibits differentiation into both lineages. However, when cells are cultured under adipogenic differentiation conditions, which contain cAMP-enhancing agents such as IBMX of PGE2, TGFβ promotes osteogenic differentiation, while at the same time inhibiting adipogenic differentiation. Gene expression and immunoblot analysis indicated that IBMX-induced suppression of HDAC5 levels plays an important role in the inhibitory effect of TGFβ on osteogenic differentiation. By means of gene expression microarray analysis, we have investigated genes which are downregulated by TGFβ under adipogenic differentiation conditions and may therefore be potential targets for prevention of fat cell differentiation. We thus identified nine genes for which FDA-approved drugs are available. Our results show that drugs directed against the nuclear hormone receptor PPARG, the metalloproteinase ADAMTS5, and the aldo-keto reductase AKR1B10 inhibit adipogenic differentiation in a dose-dependent manner, although in contrast to TGFβ they do not appear to promote osteogenic differentiation. Conclusions The approach chosen in this study has resulted in the identification of new targets for inhibition of fat cell differentiation, which may not only be relevant for prevention of osteoporosis, but also of obesity.
... The first MMP (collagenase) was identified in tadpole tails during metamorphosis in 1962 by Gross and Lapière. 3 Since then, many other MMPs have been discovered and characterized. Most MMPs play a central role in normal physiological conditions (such as stem cell differentiation, cell proliferation, cell motility, ECM remodeling, wound healing, angiogenesis, and apoptosis) [4][5][6] and imbalances between MMPs and their inhibitors are implicated in various pathological conditions (tumor invasion, fibrosis, etc.) via different mechanisms that are primarily related to tissue destruction and aberrant ECM composition. 4,7,8 Classically, MMPs represent a large enzyme family responsible for the degradation and turnover of most ECM components and are able to cleave fibrillar collagens. ...
Chapter
Matrix metalloproteinases (MMPs) are the major protease family responsible for the cleavage of the matrisome (global composition of the extracellular matrix (ECM) proteome) and proteins unrelated to the ECM, generating bioactive molecules. These proteins drive ECM remodeling, in association with tissue-specific and cell-anchored inhibitors (TIMPs and RECK, respectively). In the bone, the ECM mediates cell adhesion, mechanotransduction, nucleation of mineralization, and the immobilization of growth factors to protect them from damage or degradation. Since the first description of an MMP in bone tissue, many other MMPs have been identified, as well as their inhibitors. Numerous functions have been assigned to these proteins, including osteoblast/osteocyte differentiation, bone formation, solubilization of the osteoid during bone resorption, osteoclast recruitment and migration, and as a coupling factor in bone remodeling under physiological conditions. In turn, a number of pathologies, associated with imbalanced bone remodeling, arise mainly from MMP overexpression and abnormalities of the ECM, leading to bone osteolysis or bone formation. In this review, we will discuss the functions of MMPs and their inhibitors in bone cells, during bone remodeling, pathological bone resorption (osteoporosis and bone metastasis), bone repair/regeneration, and emergent roles in bone bioengineering.
... It is conceivable that anacardic acid may preferentially inhibit MMPs that have a deeper S1Ј pocket compared with MMPs with a shallow pocket. Therefore, the potential use of anacardic acid as a natural "bio-drug" suggests that it now joins a small list of previously defined natural product compounds that have interesting activities against MMPs (Mannello, 2006;reviewed in Lia et al., 2009). This list includes the long-chain fatty acid molecules, such as oleic acid and elaidic acid, which are micromolar inhibitors of MMP-2 (Berton et al., 2001). ...
Research
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The results provide the first evidence for inhibition of gelatinase catalytic activity by anacardic acid, providing a novel template for drug discovery and a molecular mechanism potentially involved in CNSL therapeutic action.
... Neovastat (shark cartilage) was analyzed in regard to anti-angiogenic and anti-metastatic effects on the activity of several MMPs. Neovastat inhibits the enzymatic activity of MMP-2 with minor inhibition of MMP-1, 9, 7 and 13 [26]. Hence natural compounds could be a better choice for selective inhibition of MMP-9. ...
Article
Matrix metalloproteinase-9 (MMP-9) is an attractive target for anticancer therapy. In the present study ligand based pharmacophore modeling was performed to elucidate the structural elements for a diverse class of MMP-9 inhibitors. The pharmacophore model was validated through Güner-Henry (GH) scoring method. The final pharmacophore model consisted of three hydrogen bond acceptors (HBA), and two ring aromatic regions (RA). This model was utilized to screen the natural compound database to seek novel compounds as MMP-9 inhibitors. The identified hits were validated using molecular docking and molecular dynamics simulation studies. Finally, one compound named Hinokiflavone from Juniperus communis had high binding free energy of -26.54kJ/mol compared with the known inhibitors of MMP-9. Cytotoxicity for hinokiflavone was evaluated by MTT assay. Inhibition of MMP-9 in the presence of hinokiflavone was detected by gelatin zymography and gelatinolytic inhibition assay. Results revealed that the natural compounds derived based on the developed pharmacophore model would be useful for further design and development of MMP-9 inhibitors.
... Several clinical studies have demonstrated the promising aspects of MMPIs expression but very limited outcomes have been received. The utilization of Natural bioactives as a therapeutic drug targeting system toward MMPs in proliferation of photocarcinoma will be an innovative to support the traditional drug regimen for cancer (Mannello, 2006). ...
Article
The continuous exposure of skin to ultraviolet radiations generates reactive oxygen species leading to photoaging in which degradation of dermal collagen and degeneration of elastic fibers occurs. Matrix metalloproteinase [MMP] enzymes are the proteolytic enzymes which have significant potentiality of cleaving Extracellular Matrix [ECM] against Ultraviolet [UV] radiation. The important MMPs are MMP1, MMP2 & MMP7 which promote skin cancer when irradiated by UV rays. In lieu of this, the investigation of MMPs and their inhibitors are constantly being studied for successive results. Recent researches has focused on some traditionally used bioactive moieties as natural matrix metalloproteinases inhibitors (MMPIs) and emphasized on the need of more extensive and specific studies on MMPIs, so that a good combination of natural or synthetic MMPIs with the conventional drugs can be evolved for cancer chemotherapy. In this review, we discuss the current view on the feasibility of MMPs as targets for therapeutic intervention in cancer. This review also summarizes the role of small molecular weight natural MMPIs and a clinical update of those natural MMPIs that are under clinical trial stage.
... These studies concerned MMP-inhibitory properties of various natural compounds, eg, some antibiotics, curcumin, green tea polyphenols, or resveratrol, as well as many synthetic inhibitors, including phenantroline, hydroxamic acid, carboxylic acid, ethylenediaminetetraacetic acid, and thiazoles. 75,76 Although some of these exogenous inhibitors are widely used in current clinical practice, it is noteworthy that their original applications did not concern modulation of MMPs activity. ...
Article
Alicja Krejner,1 Malgorzata Litwiniuk,1–3 Tomasz Grzela11Laboratory of Cell Molecular Biology, Department of Histology and Embryology, Biostructure Research Center, Medical University of Warsaw, Warsaw, Poland; 2Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland; 3Department of Otolaryngology, Medical University of Warsaw, Warsaw, PolandAbstract: Matrix metalloproteinases (MMPs) are key effector molecules responsible for extracellular matrix (ECM) turnover. They are involved in tissue remodeling and regeneration. Although the main targets for MMPs are ECM components, they are also able to digest a variety of non-ECM molecules including cytokines, their receptors, or carriers. Therefore, the activity of the MMPs remains under tight control. However, when controlling mechanisms are ineffective, MMPs may become highly dangerous molecules, which have a strong destructive effect on affected tissues. Apart from cancer metastasis, aneurysm formation, or airway remodeling in asthma, MMPs have also been identified as main detrimental factors in delayed healing of chronic wounds. In this short review, we describe main representatives of MMPs family, their role in pathophysiology of chronic wounds, as well as current and possible therapeutic strategies for modulation of MMPs’ activity, which may be useful in management of chronic wounds.Keywords: chronic wound, MMPs, MMP inhibitors, wound treatment
... Anti inflammatory activity of ethyl acetate and aqueous extracts of bark of M. nagi at 100 and 200 mg/Kg BW using carrageenan and histamine induced rat paw edema exhibited about 28 and 18 % in wistar rats. While information is available on the medicinal property of M. nagi bark (Khan et al. 2008;Patel et al. 2011;Panthari et al. 2012) and fruits (Mannello 2006), such information is severely lacking for the leaves. This study therefore investigates the leaves of M. nagi for their anti-inflammatory, analgesic and anti-oxidative activities. ...
Article
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Myrica nagi (family Myricaceae) is commonly known as Kathphal (Hindi) and Bayberry (English) and it has a long history of usage in traditional medicine. It is popular actinorhizal plant for its symbiotic relationship with Frankia. This study was taken in force to estimate the analgesic, anti-inflammatory and anti-oxidative activities of methanolic extract of Myrica nagi (MMN) in an animal model. Anti-oxidative property of MMN was assessed by free radical scavenging assay (DPPH method). The acute toxicity test of methanolic extract of MMN revealed that the median lethal dose (LD50) was found to be 2080 mg/kg body weight in mice. The anti-inflammatory property was evaluated by carrageenan-induced acute inflammation in rats by measuring rat paw volume at different time intervals and toxicological analysis using mice. The analgesic effect was measured in Wistar rats using the acetic acid-induced writhing test and MMN at 200 mg/kg BW showed 54.56 % inhibition of writhing. MMN showed higher anti-oxidant activity in DPPH assays as compared to standard. High dose of MMN showed a significant reduction (21.71 %) in inflammation after 4 h of treatment, which was comparable to diclofenac (10 mg/kg BW; 32.75 %)-treated group. Significant reduction (p < 0.05) in the levels of inflammatory cytokine (IL-1β and TNF-α) markers were also observed in serum of MMN-treated animals as compared to control. Taken together, the phenolic compounds of MMN may serve as potential herbal drug for amelioration of acute inflammation due to their modulatory action on free radicals.
... For recent years, more and more researchers have focused on screening the MMP inhibitors from natural products. The various structural types of natural product inhibitors of MMPs, such as flavonoids, anthraquinones, caffeic acids, and aliphatic hydrocarbons with long chain, have been found [20][21][22][23][24][25]. ...
Article
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Matrix metalloproteinase-9 (MMP-9) is an attractive target for cancer therapy. In this study, the pharmacophore model of MMP-9 inhibitors is built based on the experimental binding structures of multiple receptor-ligand complexes. It is found that the pharmacophore model consists of six chemical features, including two hydrogen bond acceptors, one hydrogen bond donor, one ring aromatic regions, and two hydrophobic (HY) features. Among them, the two HY features are especially important because they can enter the S1' pocket of MMP-9 which determines the selectivity of MMP-9 inhibitors. The reliability of pharmacophore model is validated based on the two different decoy sets and relevant experimental data. The virtual screening, combining pharmacophore model with molecular docking, is performed to identify the selective MMP-9 inhibitors from a database of natural products. The four novel MMP-9 inhibitors of natural products, NP-000686, NP-001752, NP-014331, and NP-015905, are found; one of them, NP-000686, is used to perform the experiment of in vitro bioassay inhibiting MMP-9, and the IC50 value was estimated to be only 13.4 µM, showing the strongly inhibitory activity of NP-000686 against MMP-9, which suggests that our screening results should be reliable. The binding modes of screened inhibitors with MMP-9 active sites were discussed. In addition, the ADMET properties and physicochemical properties of screened four compounds were assessed. The found MMP-9 inhibitors of natural products could serve as the lead compounds for designing the new MMP-9 inhibitors by carrying out structural modifications in the future.
... Among marine organisms, marine sponges, by being the most diversified faunal communities of seas, have significantly contributed in discovering bioactive compounds. Potential drug discovery targets include matrix metalloproteinases (MMPs), and in particular gelatinases A (MMP-2) and B (MMP-9), which are involved at different levels in the pathogenesis of several human diseases [34][35][36]. ...
Article
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The aim of this study was to evaluate whether water soluble compounds present in aqueous extracts from seven Mediterranean demosponges exert biological activity towards matrix metalloproteinases (MMPs), which represent important pathogenic factors of human diseases. Aqueous extracts were tested on LPS-activated cultured rat astrocytes, and levels and expression of MMP-2 and MMP-9 were assessed by zymography and RT-PCR, respectively. Our results demonstrated that the studied extracts contain water soluble compounds able to inhibit MMP-2 and MMP-9 activity and expression. We also compared the anti-MMP activities present in aqueous extracts from wild and reared specimens of Tethya aurantium and T. citrina. The results obtained revealed that the reared sponges maintain the production of bioactive compounds with inhibitory effect on MMP-2 and MMP-9 for all the duration of the rearing period. Taken together, our results indicate that the aqueous extracts from the selected Mediterranean demosponges possess a variety of water-soluble bioactive compounds, which are able to inhibit MMPs at different levels. The presence of biological activity in aqueous extracts from reared specimens of T. aurantium and T. citrina strongly encourage sponge aquaculture as a valid option to supply sponge biomass for drug development on a large scale.
... The negative results obtained in human clinical trial analyzing synthetic MMPIs stirred up the impellent need for compounds that could be more effective in treatment and this search found its answer in the field of natural compounds [15] In Chinese medicine, tea is a fundamental element and it is considered one of the most potent substances that can help maintain health and prolong life, and these health benefit shave been scientifically established and are related to the presence of polyphenols called " flavonoids " . Tea (Camelliasinensis) is available in three forms: black, green and oolong, (EC), (-)- epigalattocatechin (EGC), (-)-epicatechin gallate(ECG) and (-)-epigallocatechin gallate (EGCG) Away by which EGCG may decrease tumor size is through the binding to urokinase, which is a proteolytic enzyme, often over expressed in human cancer, necessary for invasion and metastasis of cancer cells [16] The potential medical benefits of consuming green tea have received a great deal of attention over the past few years, most of which has been directed at a group of polyphenolic compounds called catechins. ...
Article
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Chronic obstructive pulmonary disease (COPD) is the occurrence of chronic bronchitis or emphysema, a pair of commonly co-existing diseases of the lungs in which the airways become narrowed. This leads to a limitation of the flow of air to and from the lungs, causing shortness of breath (dyspnea). According to the World Health Organisation, COPD kills more people than HIV-AIDS, Malaria and Tuberculosis all put together in the South East Asian region.COPD was classified in two broad categories Chronic bronchitis and Emphysema. Although cigarette smoking is the main environmental risk factor for developing COPD, only about 15% of smokers develop clinically significant disease , suggesting that there are other influences on disease expression.Subsequent work has suggested other important proteases, such as the matrix metalloproteinases (MMP's) , cathepsin B and collagenases may also play a role, perhaps as part of a protease/anti-protease cascade MMPs are thought to be responsible for the turnover and degradation of connective tissue proteins, a function that is clearly performed by several family members. The mode of action ofMMP1212 protein plays a critical role for causing the COPD disease. The main objective of this paper is to design a small potent drug to block the MMP12 protein through ‘Molecular Docking approach’ by using the In silico tools.
... The natural compound Myricetin isolated from the fruit has been studied for the effective matrix metalloproteinase. Its Inhibition activity has been extensively studied and one patent has been filled for the same 25 . ...
Article
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Myrica nagi, an endangered tree with wide medicinal applications in Indian subcontinent has rich amount of anti-oxidants along with other classes of chemicals. The utilization of leaves and fruits, of the tree as medicine is a highly sustainable source of natural medicines. The utilization of roots, and stem barks for different remedies is also in practice. High tannin content on woody tissues provides the longevity to the timber, commercial noun of the tree ‘box berry’ named after edible berries of this tree. During the last one decade, apart from the chemistry of the Myrica nagi compounds, considerable progress has been achieved regarding its biological activity and medicinal applications. The present review is an effort to consolidate information available on Myrica nagi in the last one decade
... Hence, MMPs were identified as potential targets to control invasive and metastatic cancers (3,4). Regulation of MMPs in pathogenic conditions using MMP inhibitors (MMPIs) derived from synthetic as well as a natural sources (5,6) has been widely studied previously. ...
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Objectives: Considering the bioactivities exhibited by microalgae, the effect of protein extract of Chlorella minutissimma (CP extract) was investigated on the expression of human matrix metalloproteinases-1 (MMP-1) in the breast cancer cell line MDA-MB231, and that of MMP-2 and -9 in hepatocellular cancer cell line HepG2 at different expression levels. The study aimed identification and analysis of inhibitory activity of microalgal components extracted from Chlorella minutissima against human MMPs. Materials and methods: In this experimental study, we analysed the effect of Chlorella extracts on MMP-1, -2, and -9 expression at various levels. Gelatin zymography was performed to study the inhibitory effect of Chlorella exracts on human gelatinases at the activity level, followed by western blotting to analyse the expression of all three MMPs at the protein level. The similar effect at the mRNA level along with the probable mechanism underlying inhibition of MMPs was assessed using real-time polymerase chain reaction (PCR). Results: The results reveal that the treatment with CP extract decreased the mRNA expression of MMP-1, MMP-2, and MMP-9 by 0.26-, 0.29-, and 0.40-fold, respectively, at 20 μg/ml concentration as well as inhibited the activity of MMP-2 and MMP-9 by 37.56 and 42.64%, respectively, at 15 μg/ml concentration. Additionally, upregulated mRNA expression of tissue inhibitor of metalloproteinases-3 (TIMP-3) by 1.68-fold was seen in HepG2 cells at 20 μg/ml concentration treatment group. However, CP extract did not induce any change in the mRNA expression of the TIMP-1, -2 and -4 in HepG2 and TIMP-1, -2, -3 and -4 in MDA-MB231 cells. Activator protein-1 (AP-1)-dependent c-Jun-mediated transcriptional regulation of MMP-1, -2, and -9 was also studied to elucidate the appropriate mechanism involved in the inhibition of MMPs. Conclusions: The CP extract successfully inhibited MMP-1, -2, and -9 at different expression levels through TIMP-3 upregulation and c-Jun downregulation.
... This result was validated by decreased levels of LTB4. The involvement of metalloproteases in colon cancer has previously been identified but the development of treatment strategies targeting these enzymes has been unsuccessful [12]. One problem is the low specificity of metalloprotease inhibitors that have made it to clinical trials. ...
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Matrix metalloproteinase 7 (MMP7), a metallohydrolase involved in the development of several cancers, is downregulated in the Apc(Min/+) colon cancer mouse model following sulindac treatment. To determine whether this effect is relevant to the human condition, HT-29 human colon cancer cells were treated with sulindac and its metabolites, and compared to results obtained from in vivo mouse studies. The expression of MMP7 was monitored. The results demonstrated that sulindac sulfide effectively downregulated both MMP7 expression and activity. Furthermore, activity-based proteomics demonstrated that sulindac sulfide dramatically decreased the activity of leukotriene A4 hydrolase in HT-29 cells as reflected by a decrease in the level of its product, leukotriene B4. This study demonstrates that the effect of sulindac treatment in a mouse model of colon cancer may be relevant to the human counterpart and highlights the effect of sulindac treatment on metallohydrolases.
... MMPs are a class of zinc-dependent endopeptidases capable of degrading all extracellular collagen matrix components that require calcium for their activity. They are secreted as zymogens and require proteolytic cleavage for their activation [10,11]. Under normal physiological conditions, MMPs are inhibited by their endogenous inhibitors, the tissue inhibitor of metalloproteases Contents lists available at SciVerse ScienceDirect ...
... During recent years, natural sources have been of increasing interest due to their potential to contain natural products effective against several pathological complications. The development of natural origin MMP inhibitors has provided a new nutraceutical perspective to drug development studies [34]. Therefore, the current study aimed to investigate the anticancer potential of DCEQA via inhibition of MMPs, in particular MMP-2 and MMP-9. ...
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Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, are very important gelatinases that are overexpressed during tumor metastasis. Up to date, several MMP inhibitors have been developed from natural sources as well as organic synthesis. In the present study, the MMP-2 and MMP-9 inhibitory effects of 3,5-dicaffeoyl-epi-quinic acid (DCEQA), a caffeoylquinic acid derivative isolated from Atriplex gmelinii , were investigated in phorbol 12-myristate 13-acetate (PMA)-treated human HT1080 fibrosarcoma cells. Gelatin zymography and immunoblotting showed that DCEQA significantly inhibited the PMA-induced activation and expression of MMP-9 but was not able to show any effect against MMP-2. DCEQA treatment was also shown to upregulate the protein expression of tissue inhibitor of MMP-1 along with decreased MMP-9 protein levels. Moreover, the effect of DCEQA on phosphorylation of mitogen activated protein kinases (MAPKs), analyzed by immunoblotting, indicated the DCEQA inhibited the MMP-9 by downregulation of MAPK pathway. Collectively, current results suggested that DCEQA is a potent MMP-9 inhibitor and can be utilized as lead compound for treatment of pathological complications involving enhanced MMP activity such as cancer metastasis.
... Considering the role of MMPs in the harmful effects of UV irradiation, diseases and complications such as tumor metastasis, inflammation, atherosclerosis and cardiovascular diseases, numerous natural MMP inhibitors have been studied and developed [17,18]. A considerable portion of these MMP inhibitors was derived from phytochemicals such as polyphenols, flavonoids, coumarins, caffeic acids and their derivatives [19][20][21]. ...
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Ultraviolet A (UVA)-induced detrimental effects in the skin, also known as photoaging, are mediated with several pathways including oxidative stress generation and extracellular matrix (ECM) degradation. UVA irradiation results in excessive production of matrix metalloproteinases (MMPs), enzymes responsible for the degradation of ECM components such as collagen. In this study, the protective effects of (2′S)-columbianetin against UVA-induced changes in matrix metalloproteinase-1 (MMP-1) and collagen production were investigated in human dermal fibroblasts (HDFs). The (2′S)-columbianetin was isolated from Corydalis heterocarpa. UVA exposure increased MMP-1 release from HDFs and diminished the release of type I pro-collagen. Treatment with (2′S)-columbianetin reversed these effects of UVA exposure. The (2′S)-columbianetin treatment also suppressed the intracellular expression of MMP-1 and increased type I pro-collagen expression. UVA exposure elevated the activation of p38, c-Jun-amino-terminal kinase (JNK) and extracellular signal-related kinase (ERK) as the mechanism to stimulate MMP-1 production. The (2′S)-columbianetin suppressed the phosphorylation of JNK and ERK. The (2′S)-columbianetin was also stimulated collagen production via TGFβ signaling cascade, relieving UVA-induced suppression of Smad2/3 phosphorylation and translocation. In conclusion, (2′S)-columbianetin was suggested to be a potential cosmeceutical lead compound with antiphotoaging properties against UVA-induced collagen degradation.
... The products of the tree were examined for the Anti-Oxidant prevention agent exercises and it was discovered that they can be used as normal cell reinforcements. Studies have discovered confirmations that propose unrefined concentrate of Myrica esculenta organic products help in lessening of free radicals [40,60,61]. ...
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Myrica nagi also known as Myrica esculenta (Myricaceae) with common names such as, katphala, boxberry, kaphal is widely used medicinal plant. It's the tastiest wild fruit of sub-Himalayan region. The fruit is very attractive with a distinct flavour. It is a rich source of various flavanoids specially myrecetin which was found to be effective in various metabolic and CNS disorders. Recent studies have shown the presence of new compound myresculoside from methanolic leaf extract which had potent ACE-I inhibitory property. The objective of the present review article is to compile all the relevant published information regarding traditional uses, phytochemistry and therapeutic potential of M. nagi. For this purpose various databases and books were examined. The review clearly demonstrates the importance of this plant in ethno medicine and its immense potential in modern medicine. The present review is an effort to gather and consolidate the most recent information available on Myrica nagi. This will further help in explaining the efficacy and potency of the herb and to incorporating this knowledge into modern medicine.
... End point results on the clinical investigation of synthetic MMPIs at different phases showed only border line effect and they have poor oral availability, more complications and side-effects such as inflammations, musculo-skeletal disorders (Pavlaki & Zucker, 2003;Yuan et al., 2013). Due to these side effects and economic constraints on synthetic MMPIs, there is a growing interest in the use of natural compounds that could be more effective in inhibition of MMPs (Mannello, 2006). Current treatment strategies for BC includes hormonal therapy such as tamoxifen, aromatase inhibitors, fulvestrant, chemotherapy drugs such as doxorubicin, cisplatin, paclitaxel, vinorelbine, targeted therapies like monoclonal antibodies trastuzumab and pertuzumab. ...
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Matrix Metalloproteinase-1 (MMP-1) has been often upregulated in advanced breast cancers, known to participate in ECM degradation, migration, invasion, thus leading to metastasis. Due to these effects, the condition is often reported to inversely correlate with survival in advanced breast cancers. In the present study, in-silico method was adopted based on selective non zinc binding inhibitors of MMP-1. ADME properties were predicted for PASS filtered compounds and docking calculations were performed using Glide XP and IFD protocols of Schrodinger program. We identified six ligands as potent inhibitors and validated by observing structures and the interactions of MMP-1. The identified hits were validated using molecular dynamics simulation studies. Electronic structure analysis was performed for two top hit compounds myricetin and quercetin using density function theory (DFT) at B3LYP/6-31**G level to understand their molecular reactivity. Finally, one compound myricetin has emerged as the structurally stable compound with −7.801 kcal/mol and reasonable pose inside the binding site. Molecular dynamics results indicated that myricetin forms a stable interaction with the key amino acid residues such as Glu209, Glu219, Tyr240 and Pro238. In addition, it did not form any binding with the catalytic zinc at its active site. The interaction pattern of myricetin at its substrate binding site exhibited to be potent MMP-1 inhibitor. DFT study also showed that it has more potent inhibitory effect and solubility. These factors altogether show that myricetin could be considered as the best among the compounds evaluated in inhibiting MMP-1 thereby preventing metastasis of breast cancer. Communicated by Ramaswamy H. Sarma
... Thus, our study demonstrates that S. cumini MSE can be used as a potential functional food to suppress the expression of proinflammatory cytokines and gelatinase-B in HGinduced stress in cardiomyocytes. Although a clear mechanism is not yet known, the presence of hydroxyl/carbonyl groups on the phenolic rings of a number of MMP inhibitors has been suggested to chelate active Zn 2+ ions and inhibit MMP activity [52]. ...
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Black berry (Syzygium cumini) fruit is useful in curing diabetic complications; however, its role in diabetes-induced cardiomyopathy is not yet known. In this study, we investigated the regulation of gelatinase-B (MMP-9) by S. cumini methanol seed extract (MSE) in diabetic cardiomyopathy using real-time PCR, RT-PCR, immunocytochemistry, gel diffusion assay, and substrate zymography. The regulatory effects of MSE on NF-κB, TNF-α, and IL-6 were also examined. Identification and estimation of polyphenol constituents present in S. cumini extract were carried out using reverse-phase HPLC. Further, in silico docking studies of identified polyphenols with gelatinase-B were performed to elucidate molecular level interaction in the active site of gelatinase-B. Docking studies showed strong interaction of S. cumini polyphenols with gelatinase-B. Our findings indicate that MSE significantly suppresses gelatinase-B expression and activity in high-glucose- (HG-) stimulated cardiomyopathy. Further, HG-induced activation of NF-κB, TNF-α, and IL-6 was also remarkably reduced by MSE. Our results suggest that S. cumini MSE may be useful as an effective functional food and dietary supplement to regulate HG-induced cardiac stress through gelatinase.
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Many experimental studies have found that flavonoids including luteolin can inhibit the activities of matrix metalloproteinases (MMPs), but the related theoretical studies are rather lacking. In this paper, we perform PM6 quantum chemistry calculations together with modeling of ligand‐water exchange reactions to investigate the mechanisms of interaction between luteolin and catalytic zinc ion in MMPs. The calculations show that the electron transfer from the luteolin molecule to the catalytic zinc ion in MMPs occurs when the catalytic zinc ion coordinates with the O atoms of substituent groups at various positions of A, B, and C rings of luteolin molecule. It is found that the more the number of the electron transfer from one coordinating O atom of substituent groups of luteolin molecule to the catalytic zinc ion, the stronger the coordinating ability between them. We further find that comparing with the O atoms of hydroxy groups at 5‐, 7‐, 3′‐, and 4′‐positions of luteolin molecule, the coordinating ability for the O atom of carbonyl group at its 4‐position with the catalytic zinc ion is the strongest, which indicates that when luteolin inhibits MMPs activity, the catalytic zinc ion should coordinate with the carbonyl group at 4‐position of luteolin molecule, rather than the hydroxy groups at its other positions, in agreement with the relevant experimental results reported in previous literature. This paper may be helpful for designing the new MMPs inhibitors having higher biological activities by carrying out the structural modifications of luteolin molecule. Copyright © 2012 John Wiley & Sons, Ltd.
Article
Quantum chemistry calculations together with modeling of ligand–water exchange reactions are used to investigate, for the first time, the interaction mechanisms between emodin of anthraquinones and the catalytic zinc ion in matrix metalloproteinases (MMPs), and the coordinating mode between them is determined. The calculations indicate that the electron transfer from the emodin molecule to the catalytic zinc ion in MMPs occurs when the catalytic zinc ion coordinates with the O atoms of substituent groups at various positions of emodin molecule, and the more the number of the electron transfer from the coordinating O atom of substituent group of emodin molecule to the catalytic zinc ion, the stronger the coordinating ability between them. It is found that comparing with the O atoms of hydroxy groups at 1-position, 8-position and 3-position and the O atom of carbonyl group at 9-position of emodin molecule, the coordinating ability for the O atom of carbonyl group at 10-position of emodin molecule with the catalytic zinc ion in MMPs is the strongest. Therefore, when emodin inhibits MMPs activity, the catalytic zinc ion in MMPs should coordinate with the carbonyl group at 10-position of emodin molecule, rather than the hydroxy groups and carbonyl group at its other positions. Our calculated results are in agreement with previous relevant experimental results. This paper may be helpful for designing the new MMPs inhibitors having higher biological activities by carrying out the structural modifications of emodin molecule.
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Bacteria have long been recognized as the primary etiological factor in the development of pulp and periapical lesions. Successful root canal therapy depends on thorough debridement of pulpal tissue, dentin debris, and infective microorganisms. Currently, it is impossible to eradicate intraradicular infection with mechanical instrumentation alone. Therefore, irrigants are required to complete this task. In this article, the different actions and interactions of the most commonly used irrigants are discussed. The aim of this review is to analyze the relevant literature on root canal irrigants.
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Drug design is an integrated and developing system that portends an era of a novel and safe tailored drugs. It involves studying the effects of biologically active synthetic, semi-synthetic, and natural compounds based on molecular interactions in terms of molecular structure with activated functional groups or its unique physico- chemical properties involved. The title compound, N-(2-aminophenyl)-2-(4-bromophenoxy) acetamide (c), was synthesized in a good yield and characterized by different spectroscopic techniques ( 1 H, 13 CNMR, and LC-MS) and finally, the structure was confirmed by X-ray diffraction (XRD) studies. The XRD data confirms that the cryatal structure is orthorhombic with space group of Pca2 1 . The intermolecular interactions (N–H ... O and N–H ... Cg) inside the molecule stabilizes the crystal structure. The existence of this intermolecular interactions are computed by the Hirshfeld surfaces (HS) and two-dimensional (2D) fingerprints plot analysis. In addition to this, Energy frame work analysis is performed to quantify the interaction energies between the molecular pairs in a crystal by incorporating new version of CrystalExplorer17 using the energy model of HF/3-21G. Also to calculate the HOMO and LUMO energies, DFT calculations were carried out.
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Many experimental studies have previously found that flavonoids including luteolin can inhibit the activities of matrix metalloproteinases (MMPs), but the related theoretical studies are rather lacking. In this paper, based on our recently obtained interaction mechanisms between luteolin and the catalytic zinc ion in MMPs (see J. Phys. Org. Chem. 2012, 25, 1306), we perform PM6 quantum chemistry calculations together with modeling of ligand−water exchange reactions to investigate the relevant structural modifications for the inhibition of MMP activities by luteolin. The calculations indicate that among the possible modified positions of A, B, and C rings of the luteolin molecule, 5, 7, 2′, 3′, and 4′ should be the five suitable modified positions, and the several usual substituent groups that have stronger electron-donating abilities should be the suitable substituent groups. We further find that with the increasing number of these substituent groups, the biological activities for the modified luteolin molecules on MMP inhibition can be obviously improved. Our calculated results are in agreement with previous relevant experimental results. This paper gives a new approach for designing the new MMP inhibitors having higher biological activities by carrying out the structural modifications of the luteolin molecule.
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Caries is a multifactorial and transmittable disease that results mainly from bacteria present in the oral cavity. Oral microorganisms can produce metabolic acids that diffuse through dental tissues and interfaces leading to dissolution of mineral. In dentine, after mineral is dissolved, organic matrix is also exposed to breakdown by host enzymes such as matrix metalloproteinases (MMPs) that are activated by low pH followed by neutralization. This review aims to discuss the activity of different antibacterial and antiproteolytic compounds such as chlorhexidine and natural polyphenols in the control of caries progression.
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Since the brain is naturally inefficient in regenerating functional tissue after injury or disease, novel restorative strategies including stem cell transplantation and tissue engineering have to be considered. We have investigated the use of such strategies in order to achieve better functional repair outcomes. One of the fundamental challenges of successful transplantation is the delivery of cells to the injured site while maintaining cell viability. Classical cell delivery methods of intravenous or intraparenchymal injections are plagued by low engraftment and poor survival of transplanted stem cells. Novel implantable devices such as 3D bioactive scaffolds can provide the physical and metabolic support required for successful progenitor cell engraftment, proliferation and maturation. In this study, we performed in situ analysis of laminin-linked dextran and gelatin macroporous scaffolds. We revealed the protective action of gelatin-laminin (GL) scaffolds seeded with mesenchymal stem cells derived from donated human Wharton?s jelly (hUCMSCs) against neuroinflammatory reactions of injured mammalian brain tissue. These bioscaffolds have been implanted into (i) intact and (ii) ischaemic rat hippocampal organotypic slices, and into the striatum of (iii) normaland (iv) focally injured brains of adult Wistar rats. We found that transplantation of hUCMSCs encapsulated in GL scaffolds had a significant impact on the prevention of glial scar formation (low glial acidic fibrillary protein) and in the reduction of neuroinflammation (low interleukin-6, and he microglial markers ED1 and Iba1) in the recipient tissue. Moreover, implantation of hUCMSCs encapsulated within GL scaffolds induced matrix metalloproteinase-2 and -9 proteolytic activities in the surrounding brain tissue. This facilitated scaffold biodegradation while leaving the remaining grafted hUCMSCs untouched. In conclusion: Transplanting GL scaffolds pre-seeded with hUCMSCs into mammalian brain tissue escaped the host?s immune system and protected neural tissue from neuroinflamatory injury. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.
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Cartilage destruction is a crucial process in arthritis and is characterized by the degradation of cartilage proteins, proteoglycans, and type II collagen (CII), which are embedded within the extracellular matrix. While proteoglycan loss can be reversed, the degradation of CII is irreversible and has been correlated with an over-expression and over-activation of matrix metalloproteinases (MMPs). Among the various MMPs, the collagenase MMP-13 possesses the greatest catalytic activity for CII degradation. Here we show that the pomegranate-derived polyphenols, punicalagin (PA) and ellagic acid (EA), inhibit MMP-13-mediated degradation of CII in vitro. Surface plasmon resonance studies and molecular docking simulations suggested multiple binding interactions of PA and EA with CII. The effects of PA on bovine cartilage degradation (stimulated with IL-1β) were investigated by assaying proteoglycan and CII release into cartilage culture media. PA inhibited the degradation of both proteins in a concentration-dependent manner. Finally, the anti-inflammatory effects of PA (daily IP delivery at 10 and 50 mg/kg for 14 days) were tested in an adjuvant-induced arthritis rat model. Disease development was assessed by daily measurements of body weight and paw volume (using the water displacement method). PA had no effect on disease development at the lower dose but inhibited paw volume (P<0.05) at the higher dose.
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Longan, a major fruit crop in Thailand, is a rich source of antioxidant polyphenic compounds, mostly gallic acid and ellagic acid. Dried longan seeds contain large amounts of antioxidant polyphenols. In this study, three fractions of dried longan seed extract were collected by Sephadex LH-20 column chromatography to determine the major compounds in each, and the amounts of gallic acid and ellagic acid were quantified. The first fraction was determined to be the major source of gallic acid, while ellagic acid was mainly found in fraction 3. Antioxidant activities were measured using total phenolic content, total flavonoid content, 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity, and metal chelating activity. Fraction 1 had the highest antioxidant activity. In addition, the effect of each fraction on matrix metalloproteinases (MMPs) activity was analysed using a fluorometric assay. Interestingly, fraction 3 had the greatest MMPs inhibitory effect. Notably, dried longan seeds have been established not only as major sources of antioxidants, but also as potent MMPs inhibitors. Since these properties are associated with anti-cancer effects, dried longan seeds could be a novel natural source for compounds used in chemoprevention and chemotherapy.
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Many experimental studies have found that flavonoids can inhibit the activities of matrix metalloproteinases (MMPs), but the relevant mechanisms are still unclear. In this paper, the interaction mechanisms of MMP-9 with its five flavonoid inhibitors are investigated using a combination of molecular docking, hybrid quantum mechanical and molecular mechanical (QM/MM) calculations, and molecular dynamics simulations. The molecular dynamics simulation results show a good linear correlation between the calculated binding free energies of QM/MM−Poisson–Boltzmann surface area (PBSA) and the experimental −log(EC50) regarding the studied five flavonoids on MMP-9 inhibition in explicit solvent. It is found that compared with the MM−PBSA method, the QM/MM−PBSA method can obviously improve the accuracy for the calculated binding free energies. The predicted binding modes of the five flavonoid−MMP-9 complexes reveal that the different hydrogen bond networks can form besides producing the Zn−O coordination bonds, which can reasonably explain previous experimental results. The agreement between our calculated results and the previous experimental facts indicates that the force field parameters used here are effective and reliable for investigating the systems of flavonoid−MMP-9 interactions, and thus, these simulations and analyses could be reproduced for the other related systems involving protein−ligand interactions. This paper may be helpful for designing the new MMP-9 inhibitors having higher biological activities by carrying out the structural modifications of flavonoid molecules.
Chapter
Matrix metalloproteinases (MMPs) are directly implicated in almost every biological process involving remodeling of the extracellular matrix, including basement membrane, from embryo implantation to tissue necrosis. In the mid-1990s, the design of the first peptide-based potent MMP inhibitors (MMPIs) ushered in an optimistic era in which these enzymes and their potential inhibitors received intense scrutiny. Features of most peptidomimetic MMPIs include (i) chelation of the catalytic Zn2+, (ii) occupancy of subsites along the extended binding site (S, S'), and (iii) quintessential occupancy of the S1' site. Structure-based drug design follows a practical paradigm: the target binding site is first identified and characterized, a library of compounds is "docked" into this binding site, and the predicted ability of the compounds binding is "scored". A growing trend in the field of drug design emphasizes the surface residues distal from the catalytic site as well as accessory domains as targets for allosteric inhibition.
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We recently demonstrated that megakaryocytes differentially express mRNA for MMPs and TIMPs and selectively transfer a subset of these transcripts to platelets.[1][1] As a minor part of this report, we showed that megakaryocytes expressed MMP-9 mRNA while platelets contained only trace amounts of it
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Background and Objective: Chronic inflammatory diseases affected a large number of population. The side effects of currently available anti-inflammatory agents considered as a major problem during their clinical use; therefore, development of newer and more effective and safe anti-inflammatory drugs is necessary. Recently, significant progress has been made through utilization of the application of matrix metallo-proteinase inhibitory properties of some compounds to develop anti-inflammatory drugs that are efficacious, relatively free of side effects, and they can be used effectively for a long time. The present study was designed to evaluate the dose-response relationship of the anti-inflammatory activity of doxycycline and pentoxifylline in rats models of induced chronic inflammation compared to that produced by the standard drugs dexamethasone and methotrexate, and to evaluate the anti-inflammatory activity of the standard drugs when combined with either doxycycline or pentoxifylline. Methods: Two-hundreds and sixty-six rats were used in the present study, and the study protocol includes 4 stages: First stage: 120 rats were used, and allocated into fifteen groups, each containing 8 rats, for the study of the antiinflammatory activity of doxycycline and pentoxifylline in rat model of formaldehyde-induced chronic inflammation. Second stage: 32 rats were used, and allocated into four groups, each containing 8 rats, for the study of the anti-inflammatory activity of doxycycline (2.5 mg/kg) and pentoxifylline (4.0 mg/kg) when used in combination with dexamethasone or methotrexate in rat model of formaldehyde-induced chronic inflammation. Third stage: 90 rats were used, and allocated into fifteen groups, each containing 6 rats, for the study of the anti-inflammatory activity of doxycycline and pentoxifylline in rat model of cotton pellet-induced granuloma. Fourth stage: 24 rats were used, and allocated into four groups, each containing 6 rats, for the study of the anti-inflammatory activity of doxycycline (2.5 mg/kg) and pentoxyfylline (4.0 mg/kg) when used in combination with dexamethasone or methotrexate in rat model of cotton pellet-induced granuloma. Results: The result of the present study indicating that doxycycline in a dose range of (0.1, 0.2. 0.4, 0.6, 1.2, 2.5 mg/kg) and pentoxifylline in a dose range of (0.125, 0.25. 0.5, 1.0, 2.0, 4.0 mg/kg) were given intraperitoneally and significantly suppress inflammation in rats models of formaldehyde induced chronic inflammation and cotton pellet-induced granuloma. Doxycycline (2.5 mg/kg body weight) and pentoxifylline (4.0 mg/kg body weight) in combination with dexamethasone (1.0 mg/kg body weight) significantly suppress inflammation in rats models of formaldehyde induced chronic inflammation and cotton pellet-induced granuloma, which is significantly higher than all of the effects produced by other approaches of treatments. Conclusion: Doxycycline and pentoxifylline, in a dose dependent pattern, are effective in attenuating formaldehyde induced chronic inflammation and cotton-pellet induced granuloma in rats and therefore they could be investigated as a potential treatments for chronic inflammatory conditions in human. Both doxycycline and pentoxifylline have the ability to produce an increment in the anti-inflammatory activity of dexamethasone and methotrexate.
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Abstract People have been using plants for thousands of years due to therapeutic effects exerted by many secondary metabolites. Polyphenols, alkaloids, or terpenoids are components commonly encountered in many herbal formulas. In many cases their pharmacological activity is directly linked with their structures. The structure–activity relationships (SARs) depend both on the structure of a given compound and on the target particle. Plant compounds with OH or ketone groups usually create hydrogen bonds or interact via van der Waals forces with different target molecules. The OH groups may chelate metal ions, in the reaction mixture or in a cell, what have an impact on compounds' antioxidant, antimicrobial, and inhibitory activity toward enzymes. Plant secondary metabolites possessing both phenolic ring and conjugated double bonds are the most potent direct antioxidants, for example, eugenol, cinammic acid derivatives, or flavonols. The antimicrobial activity of some compounds may be due to their interaction with structural or enzymatic proteins of bacteria. Moreover, they may lead to the oxidized condensation, inhibiting the bacterial growth. This review highlights the recent advances in investigating SARs of secondary plant metabolites with antimicrobial, free radical scavenging activities, and inhibitory properties against selected enzymes. Keywords Activity; Enzymes; Inhibition; Natural compounds; Structure–activity relationships (SAR)
Chapter
Irrigation has a key role in successful endodontic treatment. The characteristics of an ideal irrigant and the classification of current irrigants are discussed in this chapter. Sodium hypochlorite (NaOCl) is the medicament of choice during root canal treatments following its efficacy against pathogenic organisms and pulp digestion. Chlorhexidine (CHX) in liquid and gel form has been recommended as an irrigant solution, and its properties have been tested in several studies, both in-vitro and in-vivo . Decalcifying solutions in endodontics comprised only of chelators and acids, commonly ethylenediaminetetraacetic acid (EDTA) and citric acid. Hydroxyethylidene bisphosphonate (HEBP) is a chelator that can be used in combination with NaOCl without affecting its proteolytic or antimicrobial properties. QMiX is recommended to be used at the end of instrumentation after NaOCl irrigation. QMiX contains EDTA, CHX, and a detergent. MTAD and tetraclean are new irrigants based on a mixture of antibiotics, citric acid, and a detergent.
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A fluorimetric method for the determination of cysteine (CSH) and cystine (CSSC) at nanomolar concentrations is reported. The detection limit was 2.46x10-11 M for CSH when derivatisation is performed by 5-iodoacetamidofluorescein (5-IAF) and respectively 7.2x10-10 M when monobromobimane was used as fluorescent reagent. The dynamic range of analytical response was 3x10-10 -3x10-8 M (in the case of CSH-5-IAF). The method was further applied to determine the [CSH]/[CSSC] ratio at nanomolar concentration levels as potential marker of aminoacids oxidative status. An original algorithm to calculate the exact concentrations for each form was established, being provided even the experimental data to support it. Zinc influence on avoiding CSH oxidation was studied. Data were confirmed by high-performance liquid chromatography with fluorescence detection.
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Introduction Lessons Learned from Preclinical and Clinical Studies of MMPIs in Cancer and Possible Alternatives Novel Generation of MMPIs Exploit MMP Function to Improve Drug Bioavailability Conclusion Acknowledgments References
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Density functional theory (DFT) and linear regression analysis method are used to investigate the quantitative structure-activity relationship (QSAR) and structural modification for the inhibition of MMP-9 by flavonoids. It is found that there are good linear relationships between the experimental biological activity data (-l g EC50) for the inhibition of MMP-9 by flavonoids and the calculated lowest unoccupied molecular orbital energies and the molecular hydration energies of flavonoids. The results from leave-one-out cross-validation show that the established two QSAR models have good stability and prediction ability. Further studies indicate that the biological activities for the modified molecules on MMP-9 inhibition can be improved, when the structural modifications are carried out on the suitable positions of A ring, B ring and C ring of flavonoid molecules using the substituent groups that have the strong electron-donating ability and can lower the molecular hydration energies of flavonoids. According to the results (33 compounds) obtained from the structural modifications for the luteolin molecule, we suggest the possible mechanisms for the inhibition of MMP-9 by flavonoids, and design the eight MMP-9 inhibitors whose biological activities are obviously improved by the structural modifications, which are expected to be confirmed experimentally.
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Matrix metalloproteinases (MMPs) play key roles in a number of pathological processes and matrix metalloproteinase inhibitors have been developed for becoming pharmaceutical drugs. In this paper we review the development history of MMP inhibitors and the new concepts for the design and development of the MMP inhibitors. We focus on the enzymatic MMP inhibitors and inhibitors of the MMPs transcription from natural sources. In addition, the anti-cancer activities of these MMP inhibitors are also discussed.
Article
Collagenase-3 (MMP-13) inhibitors have attracted considerable attention in recent years and have been developed as a therapeutic target for a variety of diseases, including cancer. Matrix metalloproteinases (MMPs) can be inhibited by a multitude of compounds, including hydroxamic acids. Studies have shown that materials and compounds containing trivalent metal ions, particularly potassium hexacyanoferrate (III) (K3[Fe(CN)6]), exhibit cdMMP-13 inhibitory potential with a half maximal inhibitory concentration (IC50) of 1.3 μM. The target protein was obtained by refolding the recombinant histidine-tagged cdMMP-13 using size exclusion chromatography (SEC). The secondary structures of the refolded cdMMP-13 with or without metal ions were further analyzed via circular dichroism and the results indicate that upon binding with metal ions, an altered structure with increased domain stability was obtained. Furthermore, isothermal titration calorimetry (ITC) experiments demonstrated that K3[Fe(CN)6]is able to bind to MMP-13 and endothelial cell tube formation tests provide further evidence for this interaction to exhibit anti-angiogenesis potential. To the best of our knowledge, no previous report of an inorganic compound featuring a MMP-13 inhibitory activity has ever been reported in the literature. Our results demonstrate that K3[Fe(CN)6] is useful as a new effective and specific inhibitor for cdMMP-13 which may be of great potential for future drug screening applications.
Article
Cartilage degradation in rheumatoid arthritis is mediated principally by the collagenases and gelatinases. Gelatinase B (also calledMatrix metalloproteinase 9-MMP-9),is a valid target molecule which is known to participate in cartilage degradation as well as angiogenesis associated with the disease and inhibition of its activity shall prevent cartilage damage and angiogenesis. The focus of this study is to investigate the possibilities of MMP-9 inhibition by flavonol class of bioflavonoids by studying their crucial binding interactions at the active site of MMP 9using molecular docking(Glide XP and QPLD) and further improvisation by post docking MM-GBSA and molecular dynamic (MD) simulations. The results show that flavonols can convincingly bind to active site ofMMP-9 asdemonstrated by their stable interactions at the S1’ specificity pocket and favourablebinding energies. Gossypin has emerged as a promising candidate with a docking score of -14.618 kcal/mol, binding energy of -79.97 kcal/mol and a stable MD pattern over 15ns. In addition, interaction mechanisms with respect to catalytic site zinc are also discussed.Further, the drug-like charactersofthe ligands were also analysed using ADME analysis.
Article
Matrix metalloproteinases (MMPs) are important biomarkers and potential therapeutic targets of tumor. In this report, a peptide microarray-based fluorescence assay is developed for MMPs inhibitors evaluation through immobilization of biotin-modified peptides on the poly(glycidyl methacrylate-co-2-hydroxyethyl methacrylate) (P(GMA-HEMA)) brush modified glass slides. After biotin is recognized with Cy3 modified avidin (Cy3-avidin), the microarrays can produce strong fluorescence signal. The biotin moieties detach from microarray while the biotin-modified peptide substrates are specially cleaved by a MMP, resulting in decreased fluorescence intensity of microarray. The decreasing level of fluorescence intensity is correlated with the MMP inhibition. Nine known MMP inhibitors against MMP-2 and MMP-9 are evaluated by the assay, and the quantitative determination of inhibitory potencies (IC50) are obtained, which are comparable with the literatures. Two biocompatible fluorogenic peptides containing MMP specific recognition sequences and FAM/Dabcyl fluorophore-quencher pair are designed as activatable reporter probes for sensing MMP-2 and MMP-9 activities in cell and in vivo. The peptide microarray-based results are well verified by the cell inhibition assay and in vitro fluorescence imaging, and further confirmed by the in vivo imaging of HT-1080 tumor-bearing mice.
Article
Nowadays, cancer continues to plague humanity. The direct destruction and killing of tumor cells by surgery, radiation and chemotherapy has given rise to many side effects with compromised efficacy. Encouragingly, the rapidly-developing nanotechnology offers attractive opportunities to revolutionize the current situations of cancer therapy. Metallofullerenol Gd@C82(OH)22, different from chemotherapeutics that directly kill tumor cells, performs anti-tumor behaviors with high efficiency and low toxicity by modulating tumor microenvironment. Furthermore, Gd@C82(OH)22 is recently reported to specifically target cancer stem cells. In this review, we intend to give a concise introduction on the development of fullerene family and then report the anti-tumor activity of Gd@C82(OH)22 based on its unique physicochemical characteristics followed by a comprehensive summary of anti-tumor biological mechanisms which target different components of tumor microenvironment as well as biodistribution and toxicity of Gd@C82(OH)22. Finally, we describe Gd@C82(OH)22 as 'particulate medicine' to highlight its distinctions from the conventional “molecular medicine” with considerable emphasis put on the advantages of nanomedicine. The in-depth investigation of Gd@C82(OH)22 undoubtedly provides a constructive reference for the development of other nanomedicine, especially fullerene family. The application of nanotechnology in medical field definitely prospects a promising and favorable future in improving the current status of cancer therapy.
Article
Idiopathic pulmonary fibrosis (IPF) is a debilitating condition where excess collagen deposition occurs in the extracellular matrix. At first sight, it is expected that the level of different kinds of matrix metalloproteinases might be downregulated in IPF as it is a matrix degrading collagenase. However, the role of some matrix metalloproteinases (MMPs) is profibrotic where others have anti-fibrotic functions. These profibrotic MMPs effectively promote fibrosis development by stimulating the process of epithelial to mesenchymal transition. These profibrotic groups also induce macrophage polarization and fibrocyte migration. All of these events ultimately disrupt the balance between profibrotic and antifibrotic mediators, resulting aberrant repair process. Therefore, inhibition of these matrix metalloproteinases functions in IPF is a potential therapeutic approach. In addition to the use of synthetic inhibitor, various natural compounds, gene silencing act as potential natural MMP inhibitor to recover IPF.
Article
Abdominal aortic aneurysm (AAA) is a chronic vascular degenerative disease featured by progressive dilation and remodeling of the vascular wall, which may lead to aortic rupture and high mortality. The occurrence and development of AAA involve multiple mechanisms, including extracellular matrix degradation, chronic inflammation, oxidative stress, apoptosis of vascular smooth muscle cells and innate immunity. Extracellular matrix degradation is considered as the most important mechanism causing AAA. Matrix metalloproteinases (MMPs) are key factors in this process, contributing greatly to the occurrence and development of AAA. But whether the zinc-dependent endopeptidases (ADAM/ADAMTS) are involved in this process is very little known. This study is a review about the role of MMPs and ADAM/ADAMT as well as the existing MMP inhibitors in abdominal aortic aneurysm, with the purpose of providing reference for the clinical treatment of abdominal aortic aneurysm.
Article
Matrix metalloproteinases (MMPs) are endopeptidases that are involved in extracellular matrix degradation. They are also implicated in a number of abnormal bioprocesses, such as tumor growth, invasion, and metastasis. Therefore, controlling MMP activities has generated considerable interest as a possible therapeutic target. The tissue inhibitors of metalloproteinases (TIMPs) are the major naturally occurring proteins that specifically inhibit MMPs and assist in maintaining the balance between extracellular matrix destruction and formation. However, TIMPs are probably not suitable for pharmacological applications due to their short half-lives in vivo. During the last few decades, synthetic MMP inhibitors (MMPIs) have undergone rapid clinical development in attempts to control MMP enzymatic activities in abnormal bioprocesses. Although studies with these agents have met with limited clinical success, the field of MMPIs is still expanding, and generation of highly effective and selective MMPIs might be a promising direction of this research area.
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The effects of topical applications of very low doses of curcumin (the major yellow pigment in turmeric and the Indian food curry) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidation of DNA bases in the epidermis and on tumor promotion in mouse skin were investigated. CD-1 mice were treated topically with 200 nmol of 7,12-dimethylbenz[a]anthracene followed one week later by 5 nmol of TPA alone or together with 1, 10, 100 or 3000 nmol of curcumin twice a week for 20 weeks. Curcumin-mediated effects on TPA-induced formation of the oxidized DNA base 5-hydroxymethyl-2'-deoxyuridine (HMdU) and tumor formation were determined. All dose levels of curcumin inhibited the mean values of TPA-induced HMdU formation in epidermal DNA (62-77% inhibition), but only the two highest doses of curcumin strongly inhibited TPA-induced tumor promotion (62-79% inhibition of tumors per mouse and tumor volume per mouse). In a second experiment, topical application of 20 or 100 nmol (but not 10 nmol) of curcumin together with 5 nmol TPA twice a week for 18 weeks markedly inhibited TPA-induced tumor promotion. Curcumin had a strong inhibitory effect on DNA and RNA synthesis (IC50 = 0.5-1 microM) in cultured HeLa cells, but there was little or no effect on protein synthesis.
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Recent evidence supports the theory that tumor growth in vivo depends on evasion of normal homeostatic control mechanisms that operate through induction of cell death by apoptosis. This study tested the hypothesis that several potential chemopreventive agents share the ability to induce apoptosis and that inhibition of apoptosis is a mechanism of tumor promoters. The present study was designed to investigate whether the chemopreventive properties of sulindac, curcumin, and phenylethyl-3-methylcaffeate (PEMC) and the tumor-promoting activity of 6-phenylhexyl isothiocyanate (PHITC) that were observed in our previous studies are associated with the induction or inhibition of apoptosis in azoxymethane (AOM)-induced colon tumors in male F344 rats. At 5 weeks of age, groups of rats were fed control (modified AIN-76A) diet or diets containing 320 ppm of sulindac, 2000 ppm of curcumin, 750 ppm of PEMC, or 640 ppm of PHITC. At 7 weeks of age, all rats except those intended for vehicle (normal saline) treatment were given AOM (15 mg/kg body weight) once weekly for 2 weeks. To study the effect of sulindac administered during promotion/progression stage, the rats were fed the control diet initially and then fed the experimental diet containing 320 ppm of sulindac 14 weeks after the second AOM treatment. The rats were sacrificed 52 weeks after carcinogen treatment, and their colonic tumors were subjected to histopathological evaluation and the appearance of apoptosis. In the current study, chronic administration of sulindac, curcumin, and PEMC or sulindac given only during promotion/progression significantly increased the apoptotic index (percentage of apoptosis) as compared to administration of the control diet; the apoptotic indices in the control, sulindac, curcumin, and PEMC diets were 8.3, 17.6, 17.7, and 18.5%, respectively, and in sulindac administered during promotion/progression stage, the apoptotic index was 19.1%. However, dietary PHITC blocked the process of apoptosis during colon carcinogenesis. The apoptotic index in PHITC diet was 7.0%. Taken together, our data show that chemopreventive properties of agents are correlated with the degree of apoptosis. Therefore apoptosis seems to be a reliable biomarker for the evaluation of potential agents for cancer prevention.
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Epidemiological studies suggest that the consumption of green tea may help prevent cancers in humans; also, breast and prostate cancers in animal models are reduced by green, but not black, tea. Here we offer a possible explanation. We have inferred (using molecular modelling) and subsequently demonstrated that one of the major ingredients of green tea inhibits urokinase, an enzyme crucial for cancer growth.
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Oral administration of green or black tea inhibited UVB light-induced complete carcinogenesis in the skin of SKH-1 mice. Green tea was a more effective inhibitor than black tea. Oral administration of decaffeinated green or black tea resulted in substantially less inhibitory activity than did administration of the regular teas, and in one experiment, administration of a high-dose level of the decaffeinated teas enhanced the tumorigenic effect of UVB. Oral administration of caffeine alone had a substantial inhibitory effect on UVB-induced carcinogenesis, and adding caffeine to the decaffeinated teas restored the inhibitory effects of these teas on UVB-induced carcinogenesis. In additional studies, topical application of a green tea polyphenol fraction after each UVB application inhibited UVB-induced tumorigenesis. The results indicate that caffeine contributes in an important way to the inhibitory effects of green and black tea on UVB-induced complete carcinogenesis.
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Female Sencar mice (6 weeks old) were administered 1 mg of 7,12-dimethylbenz[a]anthracene (DMBA) by oral gavage once a week for 5 weeks. At 20 weeks after the first dose of DMBA, 68% of mice developed mammary tumors (the average 1.08 tumors per mouse) and 45% had lymphomas/leukemias. Feeding 1% dibenzoylmethane (DBM) in AIN 76A diet, starting at 2 weeks before the first dose of DMBA and continuing until the end of the experiment, inhibited both the multiplicity and incidence of DMBA-induced mammary tumor by 97%. The incidence of lymphomas/leukemias was completely inhibited by 1% DBM diet. In contrast, feeding 2% curcumin diet had little or no effect on the incidence of mammary tumors, and the incidence of lymphomas/leukemias was reduced by 53%.
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Angiostatin, a cleavage product of plasminogen, has been shown to inhibit endothelial cell proliferation and metastatic tumor cell growth. Recently, the production of angiostatin has been correlated with tumor-associated macrophage production of elastolytic metalloproteinases in a murine model of Lewis lung cell carcinoma. In this report we demonstrate that purified murine and human matrix metalloproteinases generate biologically functional angiostatin from plasminogen. Macrophage elastase (MMP-12 or MME) proved to be the most efficient angiostatin-producing MMP. MME was followed by gelatinases and then the stomelysins in catalytic efficiency; interstitial collagenases had little capacity to generate angiostatin. Both recombinant angiostatin and angiostatin generated from recombinant MME-treated plasminogen inhibited human microvascular endothelial cell proliferation and differentiation in vitro. Finally, employing macrophages isolated from MME-deficient mice and their wild-type littermates, we demonstrate that MME is required for the generation of angiostatin that inhibits the proliferation of human microvascular endothelial cells.
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Asian women consuming a traditional diet high in soy have a low incidence of breast cancer, yet when they emigrate to the USA the second but not the first generation lose this protection. Accordingly, we hypothesized that early exposure to genistein, a major component of soy, could have a permanent protective effect against breast cancer. Sprague-Dawley CD rats were exposed to genistein from conception to day 21 post-partum in the diet at concentrations of 0, 25 and 250 mg genistein/kg AIN-76A diet. At day 50 post-partum, all animals were treated with 80 mg dimethylbenz[a]anthracene/kg body wt to induce mammary cancers. Dietary genistein resulted in dose-dependent protection against development of mammary tumors (fewer tumors per rat). Analysis of mammary whole mounts showed that 21- and 50-day-old female rats had fewer terminal end buds, terminal ductal structures that were undifferentiated and were most susceptible to carcinogenesis. Bromodeoxyuridine incorporation studies revealed that dietary perinatal genistein resulted in a smaller proliferative compartment for terminal end buds. In rats fed the high genistein dose (250 mg/kg diet) total genistein concentrations in the serum and milk of dams 7 days postpartum were 418+/-198 and 137 pmol/ml, respectively. Total genistein concentrations in stomach milk, serum and mammary glands of 7-day-old offspring were 4439+/-1109 and 726 pmol/ml and 440+/-129 pmol/g, respectively. Total genistein concentrations in the serum and mammary glands of 21-day-old offspring were 1810+/-135 pmol/ml and 370+/-36 pmol/g, respectively. Dietary perinatal genistein did not cause significant toxicity in F0 and F1 females. We conclude that genistein in the diet at 'physiological levels' enhances cell differentiation, resulting in programming of mammary gland cells for reduced susceptibility to mammary cancer, with no observed toxicity to the reproductive tract of F1 females.
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Evidence is provided that proteolytic cleavage of collagen type IV results in the exposure of a functionally important cryptic site hidden within its triple helical structure. Exposure of this cryptic site was associated with angiogenic, but not quiescent, blood vessels and was required for angiogenesis in vivo. Exposure of the HUIV26 epitope was associated with a loss of alpha1beta1 integrin binding and the gain of alphavbeta3 binding. A monoclonal antibody (HUIV26) directed to this site disrupts integrin-dependent endothelial cell interactions and potently inhibits angiogenesis and tumor growth. Together, these studies suggest a novel mechanism by which proteolysis contributes to angiogenesis by exposing hidden regulatory elements within matrix-immobilized collagen type IV.
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: Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in sp...
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The effects of topical applications of very low doses of curcumin (the major yellow pigment in turmeric and the Indian food curry) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidation of DNA bases in the epidermis and on tumor promotion in mouse skin were investigated. CD-1 mice were treated topically with 200 nmol of 7,12-dimethylbenz[a]anthracene followed one week later by 5 nmol of TPA alone or together with 1, 10, 100 or 3000 nmol of curcumin twice a week for 20 weeks. Curcumin-mediated effects on TPA-induced formation of the oxidized DNA base 5-hydroxymethyl-2'-deoxyuridine (HMdU) and tumor formation were determined. All dose levels of curcumin inhibited the mean values of TPA-induced HMdU formation in epidermal DNA (62-77% inhibition), but only the two highest doses of curcumin strongly inhibited TPA-induced tumor promotion (62-79% inhibition of tumors per mouse and tumor volume per mouse). In a second experiment, topical application of 20 or 100 nmol (but not 10 nmol) of curcumin together with 5 nmol TPA twice a week for 18 weeks markedly inhibited TPA-induced tumor promotion. Curcumin had a strong inhibitory effect on DNA and RNA synthesis (IC 50 ) = 0.5-1 μM) in cultured HeLa cells, but there was little or no effect on protein synthesis.
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Asian women consuming a traditional diet high in soy have a low incidence of breast cancer, yet when they emigrate to the USA the second but not the first generation lose this protection. Accordingly, we hypothesized that early exposure to genistein, a major component of soy, could have a permanent protective effect against breast cancer. Sprague‐Dawley CD rats were exposed to genistein from conception to day 21 post-partum in the diet at concentrations of 0, 25 and 250 mg genistein/kg AIN-76A diet. At day 50 post-partum, all animals were treated with 80 mg dimethylbenz[a]anthracene/kg body wt to induce mammary cancers. Dietary genistein resulted in dose-dependent protection against development of mammary tumors (fewer tumors per rat). Analysis of mammary whole mounts showed that 21- and 50-day-old female rats had fewer terminal end buds, terminal ductal structures that were undifferentiated and were most susceptible to carcinogenesis. Bromodeoxyuridine incorporation studies revealed that dietary perinatal genistein resulted in a smaller proliferative compartment for terminal end buds. In rats fed the high genistein dose (250 mg/kg diet) total genistein concentrations in the serum and milk of dams 7 days postpartum were 418 6 198 and 137 pmol/ml, respectively. Total genistein concentrations in stomach milk, serum and mammary glands of 7-day-old offspring were 4439 6 1109 and 726 pmol/ml and 440 6 129 pmol/g, respectively. Total genistein concentrations in the serum and mammary glands of 21-day-old offspring were 1810 6 135 pmol/ml and 370636 pmol/g, respectively. Dietary perinatal genistein did not cause significant toxicity in F 0 and F1 females. We conclude that genistein in the diet at ‘physiological levels’ enhances cell differentiation, resulting in programming of mammary gland cells for reduced susceptibility to mammary cancer, with no observed toxicity to the reproductive tract of F1 females.
Article
In the present study, administration of green tea to SKH-1 mice, via the drinking fluid, was found to significantly reduce the incidence and volume of ultraviolet B (UVB) radiation-induced skin tumors. Thirty-six skin tumors induced by UVB and 32 skin tumors induced by UVB, in mice treated with green tea in their drinking water, were collected and examined for the presence of mutations in the p53 gene. Polymerase chain reaction products from p53 exons 5‐8 were screened by singlestrand conformation polymorphism and direct sequence analyses. Eight of 36 UVB-induced tumors contained nine p53 mutations, with four in exon 5 and five in exon 8. In contrast, nine of 32 UVB-induced tumors in mice treated with green tea contained 11 p53 mutations, with two in exon 5, five in exon 6 and four in exon 8. All of the p53 mutations occurred at dipyrimidine sequences. These results were further corroborated by p53 immunohistochemistry. The most frequent mutations were C→ To r T →C transitions, which are consistent with the genetic alterations caused by UVB exposure. Interestingly, mutations found in exon 6 of the p53 gene occurred only in tumors from the UVB/green tea group. Thus, the tumors observed in UVB/green-tea-treated mice have a different exon distribution of p53 mutations than tumors obtained from mice treated with UVB alone.
Article
Summer diapause in the cotton bollworm, Helicoverpa armigera (Habner), is prolongation of the pupal stage, particularly in males, induced by high temperatures. The effects of exposing a parental generation to temperatures of 33 to 39degreesC on the development, survivorship, longevity and fecundity of their offspring were determined in the laboratory. Three groups of offspring were examined: A, the progeny of control female moths reared as larvae at 27degreesC mated to mate moths that had undergone summer diapause when exposed to high temperature; B, the progeny of control female moths mated to males that had not undergone summer diapause after exposure to high temperature; C, the progeny of control females mated to control males reared at 27degreesC. The developmental times of the immature stages were significantly different between groups. The survival rate in the immature stages varied significantly from 69.8% (Group C) to 34.7% (Group B). The average number of eggs produced per female and the longevity of females and males were not significantly different. The indices of population increase of Groups C, A and B were 286.2, 256.8 and 145.0, respectively. These results indicate that Group A offspring had physiological advantages, such as survival and population increase, compared to Group B offspring. The adaptive significance of summer diapause in the cotton bollworm is discussed in relation to the performance of offspring.
Article
AIM: To examine the inhibitory effect of resveratrol on matrix metalloroteinase-9 (MMP-9) and explore its mechanism. METHODS: MMP-9 activity was analyzed by gelatin zymography; MMP-9 protein was detected by Western blot; MMP-9 mRNA expression was investigated by RT-PCR. Activation of activator protein -1 (AP-1) was measured by electrophoretic mobility shift assay (EMSA). RESULTS: MMP-9 activity in U937 cells increased significantly after exposed to PMA at 10 nmol/L for 24 h without FCS (P
Article
BACKGROUND Given the association of consumption of green tea with prevention of cancer development, metastasis, and angiogenesis, the effect of the main flavanol present, epigallocatechin-3-gallate (EGCG), on two gelatinases most frequently overexpressed in cancer and angiogenesis (MMP-2 and MMP-9) and on tumor cell invasion and chemotaxis were examined.METHODS Zymography, Western blotting, and enzyme linked immuoadsorbent assay were used to analyze the effect of EGCG on MMP-2 and MMP-9 activity, whereas its effect on tumor cell invasion and chemotaxis was examined using modified Boyden chamber assays.RESULTSA Zn2+ chelation-independent, dose-dependent, noncompetitive inhibition by EGCG of both gelatinases was found at concentrations 500 times lower than that reported to inhibit urokinase. Tumor cell invasion of a reconstituted basement membrane matrix, but not chemotaxis, was reduced by 50% with EGCG concentrations equivalent to that in the plasma of moderate green tea drinkers, and 2 orders of magnitude below those of tissue inhibitors of MMPs. Although higher concentrations of EGCG were associated with increased levels of both cell-associated gelatinases and their activator MT1-MMP, no increased gelatinase activation was found, and TIMP-1 and TIMP-2 inhibitors were up-regulated. Finally, concentrations of EGCG active in restraining proliferation and inducing apoptosis of transformed cells were more than 100 times lower than those reported for normal cells.CONCLUSIONS Epigallocatechin-3-gallate is a potent inhibitor of gelatinases and an orally available pharmacologic agent that may confer the antiangiogenic and antimetastatic activity associated with green tea. Cancer 2001;91:822–32. © 2001 American Cancer Society.
Article
The matrix metalloproteinases (MMPs) have been viewed as bulldozers, destroying the extracellular matrix to permit normal remodeling and contribute to pathological tissue destruction and tumor cell invasion. More recently, the identification of specific matrix and non-matrix substrates for MMPs and the elucidation of the biological consequence of cleavage indicates that perhaps MMPs should be viewed more as pruning shears, playing sophisticated roles in modulating normal cellular behavior, cell–cell communication and tumor progression.
Article
Neovastat (AE-941) is an antiangiogenic drug isolated from marine cartilage. It interferes with several steps associated with the development of angiogenesis through its ability to induce endothelial cell apoptosis, and to inhibit matrix metalloproteinase activities and vascular endothelial growth factor-mediated signaling pathways, suggesting that Neovastat behaves as a multifunctional antiangiogenic drug. Neovastat is orally bioavailable, and shows significant antitumor and antimetastatic properties in animal models. An excellent safety profile with few side effects has been monitored in more than 800 patients who have been exposed to Neovastat, some of whom for more than 4 years. This indicates that Neovastat is suitable for long-term use, either alone or in combination with other anticancer therapies. Accordingly, Neovastat is currently under evaluation in three pivotal clinical studies with two phase III clinical trials in patients with lung and renal carcinoma, and a phase II clinical trial in patients with multiple myeloma is ongoing.
Article
It is suspected that diet influences the risk of getting breast cancer. A study of diet and breast cancer was done among 200 Singapore Chinese women with histologically confirmed disease and 420 matched controls. A quantitative food-frequency questionnaire was used to assess intakes of selected nutrients and foods 1 year before interview. Daily intakes were computed and risk analysed after adjustment for concomitant risk factors. In premenopausal women, high intakes of animal proteins and red meat were associated with increased risk. Decreased risk was associated with high intakes of polyunsaturated fatty acids (PUFA), beta-carotene, soya proteins, total soya products, a high PUFA to saturated fatty acid ratio, and a high proportion of soya to total protein. In multiple analysis, the variables which were significant after adjustment for each other were red meat (p less than 0.001) as a predisposing factor, and PUFA (p = 0.02), beta-carotene (p = 0.003), and soya protein (p = 0.02) as protective factors. The analysis of dietary variables in postmenopausal women gave uniformly non-significant results. Our finding that soya products may protect against breast cancer in younger women is of interest since these foods are rich in phyto-oestrogens.
Article
Topical application of curcumin, the yellow pigment in turmeric and curry, strongly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase activity, DNA synthesis, and tumor promotion in mouse skin (Huang et al., Cancer Res., 48: 5941-5946, 1988). Chlorogenic acid, caffeic acid, and ferulic acid (structurally related dietary compounds) were considerably less active. In the present study, topical application of curcumin markedly inhibited TPA- and arachidonic acid-induced epidermal inflammation (ear edema) in mice, but chlorogenic acid, caffeic acid, and ferulic acid were only weakly active or inactive. The in vitro addition of 3, 10, 30, or 100 μM curcumin to cytosol from homogenates of mouse epidermis inhibited the metabolism of arachidonic acid to 5-hydroxyeicosatetraenoic acid (5-HETE) by 40, 60, 66, or 83%, respectively, and the metabolism of arachidonic acid to 8-HETE was inhibited by 40, 51, 77, or 85%, respectively [IC50 (concentration needed for 50% inhibition) = 5-10 μM]. Chlorogenic acid, caffeic acid, or ferulic acid (100 μM) inhibited the metabolism of arachidonic acid to 5-HETE by 36, 10, or 16%, respectively, and these hydroxylated cinnamic acid derivatives inhibited the metabolism of arachidonic acid to 8-HETE by 37, 20, or 10%, respectively (IC50 > 100 μM). The metabolism of arachidonic acid to prostaglandin E2, prostaglandin F(2α), and prostaglandin D2 by epidermal microsomes was inhibited approximately 50% by the in vitro addition of 5-10 μM curcumin. Chlorogenic acid, caffeic acid, and ferulic acid (100 μM) were inactive. In vitro rat brain protein kinase C activity was not affected by 50-200 μM curcumin, chlorogenic acid, caffeic acid, or ferulic acid. The inhibitory effects of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on TPA-induced tumor promotion in mouse epidermis parallel their inhibitory effects on TPA-induced epidermal inflammation and epidermal lipoxygenase and cyclooxygenase activities.
Article
Tumour cells traverse epithelial and endothelial basement membranes during the successive stages of the metastatic process. At the transition from in situ to invasive carcinoma, local dissolution of the basement membrane is observed microscopically1,2, and coincides with tumour cell invasion of the underlying stroma. Tumour cells further traverse the endothelial basement membrane during entry into and egress from blood vessels3-5. Electron microscopic studies have shown local dissolution of basement membrane at its area of contact with invading tumour cells, suggesting an enzymatic mechanism3,6,7. Basement membranes are resilient structures which present a mechanical barrier to invasion8. Type IV collagen is a major structural protein of basement membranes and is chemically and genetically distinct from stroma collagen types I and III and cartilage collagen type II9,10. Previously characterised animal collagenases which cleave collagen types I; II and III fail to degrade type IV collagen11,12. We have recently purified about 1,000-fold and characterised a neutral protease activity preferential for type IV collagen from metastatic tumour cells and shown that it (1) produces specific degradation products, (2) has a molecular weight of 65,000, (3) is not plasmin or a cathepsin, by pH and inhibitor studies, and (4) does not significantly degrade other collagens or fibronectin12,13. Here we extend the relevance of this finding by quantitating the ability of several murine tumour cell lines of known metastatic potential to degrade type IV collagen. The cell lines with the highest incidence of spontaneous metastasis exhibit the greatest level of type IV collagen-degrading activity in two different assays using either living cells or media obtained from cell cultures.
Article
Curcumin, the natural antioxidant from turmeric, an Indian spice, and its derivatives have significant abilities to protect plasmid pBR322 DNA against single-strand breaks induced by singlet oxygen (1O2), a reactive oxygen species with potential genotoxic/mutagenic properties. 1O2 was generated at 37 degrees C in an aqueous buffer system by the thermal dissociation of the endoperoxide of 3,3'-(1,4-naphthylene)dipropionate (NDPO2). Among the compounds tested, curcumin was the most effective inhibitor of DNA damage followed by desmethoxycurcumin, bisdesmethoxycurcumin and other derivatives. The observed antioxidant activity was both time- and concentration-dependent. The protective ability of curcumin was higher than that of the well-known biological antioxidants lipoate, alpha-tocopherol and beta-carotene. However, the highest protective ability with saturating concentrations of curcumin did not exceed 50%. The ability of curcumin and its derivatives to protect DNA against 1O2 seems to be related to their structures and may at least partly explain the therapeutic and other beneficial effects of these compounds including anticarcinogenic and antimutagenic properties.
Article
Seven isoflavones, biochanin A, daidzein, genistein, genistin, prunectin, puerarin, and pseudobaptigenin were tested for cytostatic and cytotoxic effects on 10 newly established cancer cell lines of the human gastrointestinal origin. Proliferation of HSC-41E6, HSC-45M2, and SH101-P4 stomach cancer cell lines was strongly inhibited by biochanin A and genistein, whereas other stomach, esophageal, and colon cancer lines were moderately suppressed by both compounds. Biochanin A and genistein were cytostatic at low concentrations (< 20 micrograms/ml for biochanin A, < 10 micrograms/ml for genistein) and were cytotoxic at higher concentrations (> 40 micrograms/ml for biochanin A, > 20 micrograms/ml for genistein). DNA fragmentation was observed at cytotoxic doses of both compounds, indicating the apoptotic mode of cell death by the compounds. Chromatin condensation and nuclear fragmentation of each cell line were also observed. The advent of apoptosis was dose dependent for both isoflavones. Biochanin A suppressed tumor growth of HSC-45M2 and HSC-41E6 lines in athymic nude mice. Our results suggest that two of isoflavone derivatives, biochanin A and genistein, inhibit the cell growth of stomach cancer cell lines in vitro through activation of a signal transduction pathway for apoptosis. Moreover, in vivo experiments demonstrate that biochanin A can be used as an anticancer agent.
Article
Tea is one of the most popular beverages consumed worldwide. The relationship between tea consumption and human cancer incidence is an important concern. This topic has been studied in different populations by many investigators, but no clear-cut conclusion can be drawn. Whereas some studies have shown a protective effect of tea consumption against certain types of cancers, other studies have indicated an opposite effect. Our purpose is to provide a critical review of this topic, covering basic chemistry and biochemical activity of tea, epidemiologic investigations, and laboratory studies, as well as possible directions for future research. Studies have demonstrated either a lack of association between tea consumption and cancer incidence at specific organ sites or inconsistent results. On the other hand, many laboratory studies have demonstrated inhibitory effects of tea preparations and tea polyphenols against tumor formation and growth. This inhibitory activity is believed to be mainly due to the antioxidative and possible antiproliferative effects of polyphenolic compounds in green and black tea. These polyphenolics may also inhibit carcinogenesis by blocking the endogenous formation of N-nitroso compounds, suppressing the activation of carcinogens, and trapping of genotoxic agents. The effect of tea consumption on cancer is likely to depend on the causative factors of the specific cancer. Therefore, a protective effect observed on a certain cancer with a specific population may not be observable with a cancer of a different etiology. On the basis of this concept, we suggest future laboratory and epidemiologic studies to elucidate the relationship between tea consumption and human cancer risk.
Article
We wish to thank Jeff Arbeit, Karen Smith-McCune, Noel Weidner, Ella Bossy-Wetzel, and Christine Jolicoeur for providing the tissue sections used to prepare Figure 3Figure 3; Noel Bouck, Karen Smith-McCune, David Olson, Dowdy Jackson, and Jeff Arbeit for comments on the manuscript; and Wendy Gee and Terry Schoop of BioMed Arts (San Francisco) for artwork. The work from the authors' laboratories reviewed herein was supported by grants from the National Cancer Institute.
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Curcumin and genistein are two natural products of plants obtained from Curcuma longa Linn (turmeric) and soybeans, respectively. Both compounds when present at micromolar concentrations are able to inhibit the growth of estrogen-positive human breast MCF-7 cells induced individually or by a mixture of the pesticides endosulfane, DDT and chlordane or 17-beta estradiol. When curcumin and genistein were added together to MCF-7 cells, a synergistic effect resulting in a total inhibition of the induction of MCF-7 cells by the highly estrogenic activity of endosulfane/chlordane/DDT mixtures was noted. These data suggest that the combination of curcumin and genistein in the diet have the potential to reduce the proliferation of estrogen-positive cells by mixtures of pesticides or 17-beta estradiol. Since it is difficult to remove pesticides completely from the environment or the diet and since both turmeric and soybeans are not toxic to humans, their inclusion in the diet in order to prevent hormone related cancers deserves consideration.
Article
Theaflavin and theaflavin digallate, which are components of black tea were examined by in vitro invasion assay with mouse Lewis lung carcinoma LL2-Lu3 cells, which are highly metastatic. The compounds inhibited invasion by the tumor cells. Gelatin zymography showed that the cells secreted matrix metalloproteinases (MMPs), probably including MMP-2 and MMP-9, which may be involved in tumor cell invasion and metastasis. Theaflavin and theaflavin digallate also inhibited MMPs from the culture medium of these tumor cells, as did (-)-epigallocatechin gallate. These results suggest that theaflavin, theaflavin digallate, and (-)-epigallocatechin gallate inhibit tumor cell invasion by inhibiting type IV collagenases of the LL2-Lu3 cells.
Article
The purpose of this study was to examine the hypothesis that tea and coffee consumption have a protective effect against development of digestive tract cancers. A comparative case-referent study was conducted using Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) data from 1990 to 1995 in Nagoya, Japan. This study comprised 1,706 histologically diagnosed cases of digestive tract cancers (185 esophagus, 893 stomach, 362 colon, 266 rectum) and a total of 21,128 non-cancer outpatients aged 40 years and over. Logistic regression was used to analyze the data, adjusting for gender; age; year and season at hospital-visit; habitual smoking and alcohol drinking; regular physical exercise; fruit, rice, and beef intake; and beverage intake. The odds ratio (OR) of stomach cancer decreased to 0.69 (95 percent confidence interval [CI] = 0.48-1.00) with high intake of green tea (seven cups or more per day). A decreased risk was also observed for rectal cancer with three cups or more daily intake of coffee (OR = 0.46, CI = 0.26-0.81). The results suggest the potential for protective effect against site-specific digestive tract cancer by consumption of green tea and coffee, although most associations are limited only to the upper category of intake and have no clear explanation for site-specificity.
Article
Inhibitory effects of green tea on carcinogenesis have been investigated in numerous laboratory studies using (-)-epigallocatechin gallate (EGCG) or crude green tea extract, and there is also some epidemiologic evidence. Further, EGCG has been reported to inhibit the growth of cancer cells, lung metastasis in an animal model, and urokinase activity. In this study, we first examined the association between consumption of green tea prior to clinical cancer onset and various clinical parameters assessed at surgery among 472 patients with stage I, II, and III breast cancer. We found that increased consumption of green tea was closely associated with decreased numbers of axillary lymph node metastases among premenopausal patients with stage I and II breast cancer and with increased expression of progesterone receptor (PgR) and estrogen receptor (ER) among postmenopausal ones. Since these are potential prognostic factors, we then investigated the prognosis of breast cancer with special reference to consumption of green tea, in a follow-up study of these patients. We found that increased consumption of green tea was correlated with decreased recurrence of stage I and II breast cancer (P < 0.05 for crude disease-free survival); the recurrence rate was 16.7 or 24.3% among those consuming > or = 5 cups or < or = 4 cups per day, respectively, in a seven-year follow-up of stage I and II breast cancer, and the relative risk of recurrence was 0.564 (95% confidence interval, 0.350-0.911) after adjustment for other lifestyle factors. However, no improvement in prognosis was observed in stage III breast cancer. Our results indicate that increased consumption of green tea prior to clinical cancer onset is significantly associated with improved prognosis of stage I and II breast cancer, and this association may be related to a modifying effect of green tea on the clinical characteristics of the cancer.
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Curcumin (diferuloylmethane), widely used as a spice and coloring agent in food, possesses potent antioxidant, anti-inflammatory and anticarcinogenic properties. Recently, curcumin was further demonstrated to have an antimetastatic effect in mice. In this study, we attempted to clarify the possible mechanisms of this latter effect of curcumin. A highly invasive SK-Hep-1 cell line of human hepatocellular carcinoma (HCC) was selected for this study. An in vitro assay, without or with Matrigel matrix, was used to quantitate cellular migration and invasion. Gelatin-based zymography was adapted to assay the secretion of matrix metalloproteinase (MMP). We found that curcumin, at 10 microM, inhibited 17.4 and 70.6% of cellular migration and invasion of SK-Hep-1, respectively. Compared with a less invasive human HCC cell line, Huh-7, SK-Hep-1 showed a much higher MMP-9 secretion. Further, and parallel with its anti-invasion activity, curcumin inhibited MMP-9 secretion in SK-Hep-1 in a dose-dependent fashion. We conclude that curcumin has a significant anti-invasion activity in SK-Hep-1 cells, and that this effect is associated with its inhibitory action on MMP-9 secretion.
Article
Genistein, a natural flavone compound, has been proposed to be responsible for the lower rate of breast cancer in Asian women. The cellular mechanisms of genistein's inhibition of breast cancer progression are largely unknown. In a previous study our laboratory has presented evidence that genistein inhibits cell proliferation of breast carcinoma cells, an inhibition which is associated with a specific G2/M arrest, induction of p21WAF/CIP1 expression and apoptosis. In the present study, we present experimental evidence that illustrates that the actions of genistein are not limited to anti-proliferation: we show that genistein can inhibit both constitutive as well as epidermal growth factor (EGF)-stimulated invasion in estrogen receptor (ER)-negative human breast carcinoma lines, MDA-MB-231 and MDA-MB-468. This inhibition is characterized by the down regulation of MMP-9 (92 kDa type IV collagenase) and up regulation of TIMP-1 (tissue inhibitor of metalloproteinases) and the trypsin inhibitors: protease nexin-II (PN-II) and alpha 1-antitrypsin (alpha 1-AT). The in vivo actions of genistein may therefore extend beyond those traditionally implicated in chemoprevention, e.g., antiproliferation; genistein may act in vivo by blocking additional stages of breast cancer progression such as those stages resulting in invasion and metastasis.
Article
In the present study, administration of green tea to SKH-1 mice, via the drinking fluid, was found to significantly reduce the incidence and volume of ultraviolet B (UVB) radiation-induced skin tumors. Thirty-six skin tumors induced by UVB and 32 skin tumors induced by UVB, in mice treated with green tea in their drinking water, were collected and examined for the presence of mutations in the p53 gene. Polymerase chain reaction products from p53 exons 5-8 were screened by single-strand conformation polymorphism and direct sequence analyses. Eight of 36 UVB-induced tumors contained nine p53 mutations, with four in exon 5 and five in exon 8. In contrast, nine of 32 UVB-induced tumors in mice treated with green tea contained 11 p53 mutations, with two in exon 5, five in exon 6 and four in exon 8. All of the p53 mutations occurred at dipyrimidine sequences. These results were further corroborated by p53 immunohistochemistry. The most frequent mutations were C-->T or T-->C transitions, which are consistent with the genetic alterations caused by UVB exposure. Interestingly, mutations found in exon 6 of the p53 gene occurred only in tumors from the UVB/green tea group. Thus, the tumors observed in UVB/green-tea-treated mice have a different exon distribution of p53 mutations than tumors obtained from mice treated with UVB alone.
Article
Dietary genistein, a natural flavone compound found in soy, has been proposed to be responsible for the low rate of breast cancer in Asian women. The cellular mechanisms of genistein's chemopreventive effects in vio have been largely unexplored. In our previous studies, we found that genistein exerted pronounced antiproliferative effects on both estrogen receptor-positive and -negative human breast carcinoma cells through G2-M arrest, induction of p21WAF1/CIP1 expression, and apoptosis. Because chemopreventive effects need not be limited to antiproliferation, we decided to examine whether genistein exerted other suppressive effects on breast carcinoma progression. Genistein inhibited invasion in vitro of MCF-7 and MDA-MB-231 cells. This inhibition was characterized by down-regulation of MMP (matrix metalloproteinase)-9 and up-regulation of tissue inhibitor of metalloproteinase-1, the former of which was transcriptionally regulated at activation protein-1 sites in the MMP-9 promoter. Genistein's in vitro effects on MMP-9 and tissue inhibitor of metalloproteinase-1 were also demonstrated in in vivo studies in nude mouse xenografts of MDA-MB-231 and MCF-7 cells. In these xenograft studies, genistein inhibited tumor growth, stimulated apoptosis, and upregulated p21WAF1/CIP1 expression. In the MDA-MB-231 xenograft, genistein also inhibited angiogenesis by decreasing vessel density and decreasing the levels of vascular endothelial growth factor and transforming growth factor-beta1. These in vitro and in vivo studies demonstrate that genistein exerts multiple suppressive effects on breast carcinoma cells, suggesting that its mechanism of chemoprevention is pleiotropic.
Article
The inhibitory effects of curcumin and catechin on lung metastasis induced by B16F-10 melanoma cells were studied in female C57BL/6 mice. Curcumin and catechin significantly (P < 0.001) inhibited lung tumour formation (89.3% and 82.2%, respectively) and significantly increased the life span (143.9% and 80.8%, respectively). Moreover, lung collagen hydroxyproline and serum sialic acid levels were found to be significantly (P < 0.001) lower in treated animals compared to the untreated controls. Curcumin and catechin treatment (10 microg/ml) significantly inhibited the invasion of B16F-10 melanoma cells across the collagen matrix of the Boyden chamber. Gelatin zymographic analysis of the trypsin-activated B16F-10 melanoma cells sonicate revealed that curcumin- and catechin-treated zymograms did not show any metalloproteinase activity. Curcumin and catechin treatment did not inhibit the motility of B16F-10 melanoma cells across a polycarbonate filter in vitro. These findings suggest that curcumin and catechin inhibit the invasion of B16F-10 melanoma cells by inhibition of metalloproteinases, thereby inhibiting lung metastasis.