Cytotoxicity of a mitochondriotropic quercetin derivative: mechanisms.

The mitochondriotropic compound 7-O-(4-triphenylphosphoniumbutyl)quercetin iodide (Q-7BTPI) in the µM concentration range caused necrotic death of cultured cells by acting as a prooxidant, with generation of superoxide anion in the mitochondria. Externally added membrane-permeating superoxide dismutase or catalase largely prevented death. Rescue by permeant catalase indicates that the toxicant is H(2)O(2), or reactive species derived from it. Rescue by permeant dismutase suggests the possibility of a chain mechanism of H(2)O(2) production, in which dismutation of superoxide constitutes a termination step. Oxidative stress was due to the presence of free phenolic hydroxyls and to accumulation in mitochondria, since the analogous mitochondriotropic per-O-methylated compound -3,3',4',5-tetra-O-methyl,7-O-(4-triphenylphosphoniumbutyl) quercetin iodide (QTM-7BTPI)-or Quercetin itself induced no or little superoxide production and cell death. Q-7BTPI did not cause a significant perturbation of the mitochondrial transmembrane potential or of respiration in cells. On the other hand its presence led to inhibition of glutathione peroxidase, an effect expected to accentuate oxidative stress by interfering with the elimination of H(2)O(2). An exogenous permeable glutathione precursor determined a strong increase of cellular glutathione levels but did not rescue the cells. Death induction was selective for fast-growing C-26 tumoral cells and mouse embryonic fibroblasts (MEFs) while sparing slow-growing MEFs. This suggests a possible use of Q-7BTPI as a chemotherapeutic agent.

[Mobile phones and head tumours: it is time to read and highlight data in a proper way]. / Telefoni mobili e tumori alla testa: è tempo che i dati vengano letti e valorizzati correttamente.

The uncertainty about the relationship between the use of mobile phones (MPs: analogue and digital cellulars, and cordless) and the increase of head tumour risk can be solved by a critical analysis of the methodological elements of both the positive and the negative studies. Results by Hardell indicate a cause/effect relationship: exposures for or latencies from ≥ 10 years to MPs increase by up to 100% the risk of tumour on the same side of the head preferred for phone use (ipsilateral tumours) - which is the only one significantly irradiated - with statistical significance for brain gliomas, meningiomas and acoustic neuromas. On the contrary, studies published under the Interphone project and others produced negative results and are characterised by the substantial underestimation of the risk of tumour. However, also in the Interphone studies a clear and statistically significant increase of ipsilateral head tumours (gliomas, neuromas and parotid gland tumours) is quite common in people having used MPs since or for ≥ 10 years. And also the metaanalyses by Hardell and other Authors, including only the literature data on ipsilateral tumours in people having used MPs since or for ≥ 10 years - and so also part of the Interphone data - still show statistically significant increases of head tumours.

Matrix metalloproteinases and their inhibitors in canine mammary tumors.

BACKGROUND: Malignant canine mammary tumors represent 50% of all neoplasms in female dogs. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are thought to be involved in tumor progression, and they are also associated with the reactive stroma, which provides structural and vascular support for tumor growth. RESULTS: MMP-2, MMP-9 and MT1-MMP were expressed at both the mRNA and protein levels in tumor samples. MMP-2 and MMP-9 immunohistochemical reactions were evident both in the epithelial tumor cells and in the stromal compartment to varying degrees; in particular, the intensity of the MMP-2 staining was stronger in the stromal fibroblasts close to epithelial tumor cells in simple carcinomas than in adenomas. These data were supported by gelatin-zymography; bands for the active form of MMP-2 were found in 94% of carcinoma samples, compared with 17% of benign tumor samples. The gene expression and immunohistochemical results for MT1-MMP were comparable to those for MMP-2. The immunoreactivity for MMP-13 and TIMP-2 was lower in carcinomas than in adenomas, confirming the mRNA data for MMP-13 and the other MMP inhibitors that were evaluated. The active form of MMP-9, but not the active form of MMP-2, was identified in the plasma of all of the tested dogs. CONCLUSIONS: Our findings suggest that MMP-9, MMP-2 and MT1-MMP, which are synthesized by epithelial cancer cells and cancer-associated fibroblasts, play an important role in malignant canine mammary tumors. The reduction of MMP-13 and TIMP-2 could also be a significant step in malignant transformation. MMP-2 and MT1-MMP could be further evaluated as future biomarkers for predicting the progression and prognosis of canine mammary tumors.

Mobile phones and head tumours. The discrepancies in cause-effect relationships in the epidemiological studies - how do they arise?

BACKGROUND: Whether or not there is a relationship between use of mobile phones (analogue and digital cellulars, and cordless) and head tumour risk (brain tumours, acoustic neuromas, and salivary gland tumours) is still a matter of debate; progress requires a critical analysis of the methodological elements necessary for an impartial evaluation of contradictory studies. METHODS: A close examination of the protocols and results from all case-control and cohort studies, pooled- and meta-analyses on head tumour risk for mobile phone users was carried out, and for each study the elements necessary for evaluating its reliability were identified. In addition, new meta-analyses of the literature data were undertaken. These were limited to subjects with mobile phone latency time compatible with the progression of the examined tumours, and with analysis of the laterality of head tumour localisation corresponding to the habitual laterality of mobile phone use. RESULTS: Blind protocols, free from errors, bias, and financial conditioning factors, give positive results that reveal a cause-effect relationship between long-term mobile phone use or latency and statistically significant increase of ipsilateral head tumour risk, with biological plausibility. Non-blind protocols, which instead are affected by errors, bias, and financial conditioning factors, give negative results with systematic underestimate of such risk. However, also in these studies a statistically significant increase in risk of ipsilateral head tumours is quite common after more than 10 years of mobile phone use or latency. The meta-analyses, our included, examining only data on ipsilateral tumours in subjects using mobile phones since or for at least 10 years, show large and statistically significant increases in risk of ipsilateral brain gliomas and acoustic neuromas. CONCLUSIONS: Our analysis of the literature studies and of the results from meta-analyses of the significant data alone shows an almost doubling of the risk of head tumours induced by long-term mobile phone use or latency.

Antidepressant hyperforin up-regulates VEGF in CNS tumour cells.

Vascular endothelial growth factor (VEGF) is a key player in neo-angiogenesis; it sustains the progression of solid neoplasias, brain tumours included. It has recently been demonstrated that the use of antidepressants correlates with increasing VEGF levels in the central nervous system (CNS). In order to elucidate whether the most used natural antidepressant [St. John's wort (SJW) extract] modulates VEGF expression, possible relationship between≤µM hyperforin (Hyp, the bioactive component in SJW) and VEGF in CNS tumours has been now examined in medulloblastoma and glioblastoma cells. Real-time PCR and ELISA revealed that under Hyp VEGF expression increased more than three fold in DAOY medulloblastoma cells; while, U87 glioblastoma cells - constitutively expressing high VEGF levels - showed no significant differences. Moreover, Hyp induced endothelial pro-angiogenic behaviour in a multi-parametric Matrigel colonisation assay, and down-modulation of pro-MMP-2 and pro-MMP-9 activities as measured by gelatin zymography. Should these results be confirmed in vivo for this and other types of CNS tumour, the antidepressant use of SJW extracts must be carefully re-considered, in particular for brain tumour patients.

Determination of quercetin and resveratrol in whole blood--implications for bioavailability studies.

Resveratrol (trans-3,4',5-trihydroxystilbene) and quercetin (3,3',4',5,7-pentahydroxyflavone) are two naturally occurring polyphenols with the potential to exert beneficial health effects. Since their low bioavailability is a major obstacle to biomedical applications, efforts are being made to improve their absorption and slow down phase II metabolism. An accurate evaluation of the corresponding levels in the bloodstream is important to assess delivery strategies, as well as to verify claims of efficacy based on in vitro results. In the present work we have optimized a simple method ensuring complete stabilization and extraction of resveratrol and quercetin from whole blood. The suitability of different protocols was evaluated by measuring the recovery of polyphenol and internal standard from spiked blood samples via HPLC/UV analysis. The optimized procedure ensured a satisfactory recovery of both internal standards and compounds. Comparing plasma and whole blood, up to 76% of the analyte, being associated with the cellular fraction, was unaccounted for when examining only plasma. This indicates the importance of analysing whole blood rather than plasma to avoid underestimating polyphenol absorption in bioavailability studies.

Regioselective O-derivatization of quercetin via ester intermediates. An improved synthesis of rhamnetin and development of a new mitochondriotropic derivative.

The regioselective synthesis of several quercetin (3,3',4',5,7-pentahydroxy flavone) tetraesters bearing a single free OH on 5-C was achieved in good yield by proper choice of reaction conditions using common esterification procedures. Tetracetylated quercetin with the free OH on 7-C was selectively obtained instead via imidazole-promoted deacylation of the corresponding pentaester. Unambiguous structural characterization of the two isomeric tetraacetyl quercetin derivatives was obtained by combined HSQC and HMBC 2D-NMR analysis. These molecules can be used as starting materials for the regioselective synthesis of other derivatives. High yield syntheses of the natural polyphenol rhamnetin (7-O-methylquercetin) and of the new mitochondriotropic compound 7-(4-triphenylphosphoniumbutyl) quercetin iodide are reported as examples.

3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763), a glycogen synthase kinase-3 inhibitor, displays therapeutic properties in a mouse model of pulmonary inflammation and fibrosis.

Glycogen synthase kinase (GSK)-3 modulates the production of inflammatory cytokines. Because bleomycin (BLM) causes lung injury, which is characterized by an inflammatory response followed by a fibrotic degeneration, we postulated that blocking GSK-3 activity with a specific inhibitor could affect the inflammatory and profibrotic cytokine network generated in the BLM-induced process of pulmonary inflammation and fibrosis. Thus, here we investigated the effects of the GSK-3 inhibitor 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) on a BLM-induced lung fibrosis model in mice. SB216763 prevented lung inflammation and the subsequent fibrosis when coadministered with BLM. Bronchoalveolar lavage fluid analysis of mice treated with BLM plus SB216763 revealed a significant reduction in BLM-induced alveolitis. Furthermore, SB216763 treatment was associated with a significantly lower production of inflammatory cytokines by macrophages. BLM-treated mice that received SB216763 developed alveolar epithelial cell damage and pulmonary fibrosis to a significantly lower extent compared with BLM-treated controls. These findings suggest that GSK-3 inhibition has a protective effect on lung fibrosis induced by BLM and candidate GSK-3 as a potential therapeutic target for preventing pulmonary fibrosis.

Impact of mitochondriotropic quercetin derivatives on mitochondria.

Mitochondria-targeted polyphenols are being developed with the intent to intervene on the levels of reactive oxygen species (ROS) in mitochondria. Polyphenols being more than just anti-oxidants, the interaction of these derivatives with the organelles needs to be characterised. We have studied the effects of two quercetin derivatives, 3-(4-O-triphenylphosphoniumbutyl)quercetin iodide (Q3BTPI) and its tetracetylated analogue (QTA3BTPI), on the inner membrane aspecific permeability, transmembrane voltage difference and respiration of isolated rat liver mitochondria. While the effects of low concentrations were too small to be reliably defined, when used in the 5-20 microM range these compounds acted as inducers of the mitochondrial permeability transition (MPT), an effect due to pro-oxidant activity. Furthermore, Q3BTPI behaved as an uncoupler of isolated mitochondria, causing depolarisation and stimulating oxygen consumption. When applied to tetramethylrhodamine methyl ester (TMRM)-loaded HepG2 or Jurkat cells uptake of the compounds was predictably associated with a loss of TMRM fluorescence, but there was no indication of MPT induction. A production of superoxide could be detected in some cells upon prolonged incubation of MitoSOX-loaded cells with QTA3BTPI. The overall effects of these model mitochondriotropic polyphenols may thus differ considerably depending on whether their hydroxyls are protected or not and on the experimental system. In vivo assays will be needed for a definitive assessment of their bioactivities.

Absorption and metabolism of resveratrol carboxyesters and methanesulfonate by explanted rat intestinal segments.

Model prodrugs of resveratrol carrying protecting substituents at the hydroxyls have been synthesised and tested. Resveratrol triacetate and resveratrol-tri-mPEG(1900) were formed by linking methyl groups or poly(ethylene glycol) chains, respectively, via carboxyester bonds. Resveratrol trimesylate, a molecule less susceptible to hydrolytic attack, was synthesised as well. This latter compound proved to be stable in vitro, while the carboxyester derivatives were slowly hydrolysed in solutions mimicking the gastric or intestinal environment, and rapidly converted to resveratrol in blood. In ex vivo permeation experiments with explanted intestinal segments, resveratrol and its triacetate derivative appeared in the basolateral compartment essentially as a mixture of Phase II metabolites. When the PEGylated derivative was provided on the apical side, unconjugated resveratrol accounted for about 50% of the compounds in the basolateral-side chamber. The same result was obtained by providing an equivalent physical mixture of resveratrol and PEG polymer, indicating that this behaviour is likely due to an adjuvating effect of PEG rather than to the covalent polymer conjugation. These observations suggest that the ester derivatives are rapidly hydrolysed at the intestinal surface or inside enterocytes, and are then processed as resveratrol. On the other hand, the mesylate was transported from the apical to the basolateral side without modification. It may thus be possible to enhance absorption and hinder metabolism of natural polyphenols by constructing pro-drugs incorporating bonds with appropriate resistance to enzymatic hydrolysis.

Soluble polyphenols: synthesis and bioavailability of 3,4',5-tri(alpha-D-glucose-3-O-succinyl) resveratrol.

We report the development of a chemical modification method of general applicability to polyphenols, which increases solubility to influence absorption. Glucosyl groups were added to the resveratrol kernel via a succinate linker, yielding 3,4',5-tri-(alpha-D-glucose-3-O-succinyl) resveratrol. The construct was only slowly hydrolyzed in acid and at pH 6.8, but it was destroyed by blood esterases in less than 1h. In rats its administration resulted in a blood concentration versus time curve shifted to longer times in comparison to resveratrol, a useful modulation of pharmacokinetics. The area-under-curve parameter and the metabolite mix were similar to those of resveratrol. The method may be advantageously employed to solubilize other polyphenols and to make them more palatable.

Quercetin can act either as an inhibitor or an inducer of the mitochondrial permeability transition pore: A demonstration of the ambivalent redox character of polyphenols.

The Ca(2+)- and oxidative stress-induced mitochondrial permeability transition (MPT) plays an important role in phenomena ranging from tissue damage upon infarction to muscle wasting in some forms of dystrophy. The process is due to the activation of a large pore in the inner mitochondrial membrane. Anti-oxidants are considered a preventive and remedial tool, and mitochondria-targeted redox-active compounds have been developed. Plant polyphenols are generally considered as anti-oxidants, and thus candidates to the role of mitochondria-protecting agents. In patch-clamp experiments, easily oxidizable polyphenols induced closure of the MPT channel. In swelling experiments with suspensions of mitochondria, high (20-50 microM) concentrations of quercetin, the most efficient inhibitor, promoted instead the onset of the MPT. Chelators of Fe(2+/3+) and Cu(+/2+) ions counteracted this effect. Fluorescent indicators of superoxide production confirmed that quercetin potentiates O(2)(*-) generation by isolated mitochondria and cultured cells. Since this was not affected by chelating Fe and Cu ions, the MPT-inducing effect can be ascribed to a "secondary", metal ion-catalyzed production of ROS. These results are a direct demonstration of the ambivalent redox character of polyphenols. Their mode of action in vivo cannot be taken for granted, but needs to be experimentally verified.

Heterogeneity and standardization of phase II metabolism in cultured cells.

Caco-2 cells are widely used for transepithelial transport and metabolism studies. We analysed the metabolites produced from quercetin (Q) during transport of this flavonoid across Caco-2 monolayers and by plastic-adhering cells. We found that the pattern of Phase II metabolic activity varies markedly depending on the particular cell clone, age of the cell culture, and stressful treatment such as freezing/thawing. Prolonged culturing and stress cause a decrease of "detoxifying" conjugating activity. This can be re-established by growing the cells with a low concentration of the transport/metabolism substrate for a few days. We suggest this metabolism-activating procedure be used to make studies with these cells more readily comparable.

Mechanisms of Hyperforin as an anti-angiogenic angioprevention agent.

Hyperforin, the major lipophilic compound contained in extracts of Hypericum perforatum, is responsible for the antidepressant activity associated with the extract. Recently, several other biological properties of Hyperforin have been unveiled including inhibition of tumour invasion and angiogenesis. The mechanism of the anti-angiogenic activity of Hyperforin remains to be fully elucidated. We show that treatment with non-cytotoxic concentrations of Hyperforin restrains, in a dose-dependent manner, the capacity of endothelial cells to migrate towards relevant chemotactic stimuli. Hyperforin inhibits the organisation of HUVE endothelial cells in capillary-like structures in vitro, and potently represses angiogenesis in vivo in the Matrigel sponge assay in response to diverse angiogenic agents. Immunofluorescent staining shows that in cytokine-activated endothelial HUVE cells Hyperforin prevents translocation to the nucleus of NF-kappaB, a transcription factor regulating numerous genes involved in cell growth, survival, angiogenesis and invasion. Under Hyperforin treatment in vivo, the growth of Kaposi's sarcoma - a highly angiogenic tumour - is strongly inhibited, with the resultant tumours remarkably reduced in size and in vascularisation as compared with controls. Hyperforin has also been reported to have anti-inflammatory properties. Here we show that Hyperforin inhibits neutrophil and monocyte chemotaxis in vitro and angiogenesis in vivo induced by angiogenic chemokines (CXCL8 or CCL2). These results highlight the potential for Hyperforin as an anti-inflammatory angioprevention agent, acting as a strong inhibitor of inflammation- or tumour-triggered angiogenesis, and provide new therapeutic approaches to halting pathology-associated angiogenesis.

Curcumin, demethoxycurcumin and bisdemethoxycurcumin differentially inhibit cancer cell invasion through the down-regulation of MMPs and uPA.

Curcumin (Cur), a component of turmeric (Curcuma longa), has been reported to exhibit antimetastatic activities, but the mechanisms remain unclear. Other curcuminoids present in turmeric, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) have not been investigated whether they exhibit antimetastatic activity to the same extent as curcumin. The regulation of matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA) play important role in cancer cell invasion by cleavage of extracellular matrix (ECM). In this line, we comparatively examined the influence of Cur, DMC and BDMC on the expressions of uPA, MMP-2, MMP-9, membrane Type 1 MMP (MT1-MMP), tissue inhibitor of metalloproteinases (TIMP-2), and in vitro invasiveness of human fibrosarcoma cells. The results indicate that the differential potency for inhibition of cancer cell invasion was BDMC> or =DMC>Cur, whereas the cell migration was not affected. Zymography analysis exhibited that curcumin, DMC and BDMC significantly decreased uPA, active-MMP-2 and MMP-9 but not pro-MMP-2 secretion from the cells in a dose-dependent manner, in which BDMC and DMC show higher potency than curcumin. The suppression of active MMP-2 level correlated with inhibition of MT1-MMP and TIMP-2 protein levels involved in pro-MMP-2 activation. Importantly, BDMC and DMC at 10 microM reduced MT1-MMP and TIMP-2 protein expression, but curcumin slightly reduced only MT1-MMP but not TIMP-2. In addition, three forms of curcuminoids significantly inhibited collagenase, MMP-2, and MMP-9 but not uPA activity. In summary, these data demonstrated that DMC and BDMC show higher antimetastasis potency than curcumin by the differentially down-regulation of ECM degradation enzymes.

Development of mitochondria-targeted derivatives of resveratrol.

To target natural polyphenols to the subcellular site where their redox properties might be exploited at best, that is, mitochondria, we have synthesised new proof-of-principle derivatives by linking resveratrol (3,4',5-trihydroxy-trans-stilbene) to the membrane-permeable lipophilic triphenylphosphonium cation. The new compounds, (4-triphenylphosphoniumbutyl)-4'-O-resveratrol iodide and its bis-acetylated derivative, the latter intended to provide transient protection against metabolic conjugation, accumulate into energized mitochondria as expected and are cytotoxic for fast-growing but not for slower-growing cells. They provide a powerful potential tool to intervene on mitochondrial and cellular redox processes of pathophysiological relevance.

A mitochondriotropic derivative of quercetin: a strategy to increase the effectiveness of polyphenols.

Mitochondria-targeted compounds are needed to act on a variety of processes that take place in these subcellular organelles and that have great pathophysiological relevance. In particular, redox-active molecules that are capable of homing in on mitochondria provide a tool to intervene on a major cellular source of reactive oxygen species and on the processes they induce, notably the mitochondrial permeability transition and cell death. We have linked the 3-OH of quercetin (3,3',4',5,7-pentahydroxy flavone), a model polyphenol, and the triphenylphosphonium moiety, a membrane-permeant cationic group, to produce proof-of-principle mitochondriotropic quercetin derivatives. The remaining hydroxyls were sometimes acetylated to hinder metabolism and improve solubility. The new compounds accumulate in mitochondria in a transmembrane potential-driven process and are only slowly metabolised by cultured human colon cells. They inhibit mitochondrial ATPase activity much as quercetin does, and are toxic for fast-growing cells.

Green tea attenuates angiotensin II-induced cardiac hypertrophy in rats by modulating reactive oxygen species production and the Src/epidermal growth factor receptor/Akt signaling pathway.

We previously documented a clear-cut antihypertensive effect of green teat extract (GTE), which was associated with correction of endothelial dysfunction and prevention of left ventricular hypertrophy in an angiotensin II (Ang II)-dependent model of hypertension, but the molecular mechanisms remain to be defined. As several effects of Ang II involve production of reactive oxygen species (ROS) and activation of 2nd messengers, such as mitogen-activated protein kinase (MAPK) and Akt, we investigated the effect of GTE on these signal transduction pathways in Ang II-treated rats. Rats were treated for 2 wk with Ang II infusion (700 mug.kg(-1).d(-1); n = 6, via osmotic minipumps), Ang II plus GTE (6 g/L) dissolved in the drinking water; n = 6), or vehicle (n = 6) to serve as controls. Blood pressure was monitored by telemetry throughout the study. The activation and expression of NAD(P)H oxidase subunits, protein kinase C isoforms, Src, epidermal growth factor receptor (EGFR), Akt, and MAPK were determined in the heart in vitro through immunoprecipitation and western blot analysis with specific antibodies. NAD(P)H oxidase enzymatic activity was measured by cytochrome c reduction assay. GTE blunted Ang II-induced blood pressure increase and cardiac hypertrophy. In Ang II-treated rats, GTE decreased the expression of the NAD(P)H oxidase subunit gp91(phox) and the translocation of Rac-1, as well as NAD(P)H oxidase enzymatic activity. Furthermore, it specifically reduced Ang II-induced Src, EGFR, and Akt phosphorylation. These results show that GTE blunts Ang II-induced cardiac hypertrophy specifically by regulating ROS production and the Src/EGFR/Akt signaling pathway activated by Ang II.

Tetrahydrocurcumin inhibits HT1080 cell migration and invasion via downregulation of MMPs and uPA.

AIM: Tetrahydrocurcumin (THC) is an active metabolite of curcumin. It has been reported to have similar pharmacological activity to curcumin. The proteases that participate in extracellular matrix (ECM) degradation are involved in cancer cell metastasis. The present study investigates the effect of an ultimate metabolite of curcumin, THC, on the invasion and motility of highly-metastatic HT1080 human fibrosarcoma cells. METHODS: The effect of THC on HT1080 cell invasion and migration was determined using Boyden chamber assay. Cell-adhesion assay was used for examining the binding of cells to ECM molecules. Zymography assay was used to analyze the effect of THC on matrix metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) secretion from HT1080 cells. Tissue inhibitor of metalloproteinase (TIMP)-2 and membrane-type 1 matrix metalloproteinase (MT1-MMP) proteins levels were analyzed by Western blotting. RESULTS: Treatment with THC reduced HT1080 cell invasion and migration in a dose-dependent manner. THC also decreased the cell adhesion to Matrigel and laminin-coated plates. Analysis by zymography demonstrated that treatment with THC reduced the levels of MMP-2, MMP-9, and uPA. THC also inhibited the levels of MT1-MMP and TIMP-2 proteins detected by Western blot analysis. CONCLUSION: Our findings revealed that THC reduced HT1080 cell invasion and migration. The inhibition of cancer cell invasion is associated with the downregulation of ECM degradation enzymes and the inhibition of cell adhesion to ECM proteins.

Natural and synthetic agents targeting inflammation and angiogenesis for chemoprevention of prostate cancer.

Prostate cancer is the most common cancer in men and one of the leading causes of cancer-related deaths in Western countries. The extraordinary biological heterogeneity, the increasing incidence of this disease, and the presence of putative premalignant conditions make prostate cancer a crucial pathology to study and test pharmacological or nutritional chemopreventive strategies. It has been demonstrated that the incidence of prostate cancer is lower in Asian people, and that it increases in Asian men living in Western countries; these data point to a pivotal role of diet in the onset of prostate cancer. A large amount of work has been done in investigating chemopreventive properties of dietary compounds widely used in Asian countries (i.e. soy, soybeans, green tea, fish) in respect of the oxidants- and meat-rich diet typical of Western people, particularly of central and northern Europe. Some dietary products appear promising as chemo-preventive agents for prostate cancer, because they display both anti-oxidant and anti-inflammatory activity - and inflammation is crucial for the aetiology of adeno-carcinoma of the prostate. There is increasing evidence for close correlation between inflammation, the microenvironment and tumour-associated neo-angiogenesis causing the adverse outcomes of prostate cancer. It may thus be useful to develop new strategies to couple the treatment of inflammation-related prostate cancer and the generation of angiopreventive or antiinflammatory molecules to prevent this disease. The search for compounds with few or no adverse effects - particularly cardiovascular - as compared with the agents currently in use is therefore of greatest relevance.