35 resultados para Vaccin anti-cancer

em CentAUR: Central Archive University of Reading - UK


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In previous work we have found that Cp2TiCl2 and its corresponding deriv. of tamoxifen, Titanocene tamoxifen, show an unexpected proliferative effect on hormone dependent breast cancer cells MCF-7. In order to check if this behavior is a general trend for titanocene derivs. we have tested two other titanocene derivs., Titanocene Y and Titanocene K, on this cell line. Interestingly, these two titanocene complexes behave in a totally different manner. Titanocene K is highly proliferative on MCF-7 cells even at low concns. (0.5 .mu.M), thus behave almost similarly to Cp2TiCl2. This proliferative effect is also obsd. in the presence of bovine serum albumin (BSA). In contrast, Titanocene Y alone has almost no effect on MCF-7 at a concn. of 10 .mu.M, but exhibits a significant dose dependent cytotoxic effect of up to 50% when incubated with BSA (20-50 .mu.g/mL). This confirms the crucial role played by the binding to serum proteins in the expression of the in vivo, cytotoxicity of the titanocene complexes. From the hydridolithiation reaction of 6-p-anisylfulvene with LiBEt3H followed by transmetallation with iron dichloride [bis-[(p-methoxy-benzyl)cyclopentadienyl]iron(II)] (Ferrocene Y) was synthesized. This complex, which was characterized by single crystal X-ray diffraction, contains the robust ferrocenyl unit instead of Ti assocd. with easily leaving groups such as chlorine and shows only a modest cytotoxicity against MCF-7 or MDA-MB-231 cells.

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A review. 6-Substituted fulvenes are interesting and easily accessible starting materials for the synthesis of novel substituted titanocenes via reductive dimerization, carbolithiation or hydridolithiation reactions, which are followed by a transmetallation reaction with titanium tetrachloride in the latter two cases. Depending on the substitution pattern, these titanocenes prove to be bioorganometallic anticancer drugs, which have significant potential against advanced or metastatic renal-cell cancer. Patients bearing these stages of kidney cancer have a poor prognosis so far and therefore real progress in the area of metal-based anticancer drugs may come from this simple and effective synthetic approach. This tutorial review provides an insight into the synthesis of fulvene-derived titanocenes and their activity in preclin. expts.

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Colorectal cancer is one of the most common cancers in Western countries. The World Health Organisation identifies diet as a critical risk factor in the development and progression of this disease and the protective role of high levels of fruit and vegetable consumption. Several studies have shown that apples contain several phenolic compounds that are potent anti-oxidants in humans. However, little is known about other beneficial properties of apple phenolics in cancer. We have used the HT29, HT115 and CaCo-2 cell lines as in vitro models to examine the effect of apple phenolics (0.01–0.1% apple extract) on key stages of colorectal carcinogenesis, namely; DNA damage (Comet assay), colonic barrier function (TER assay), cell cycle progression (DNA content assay) and invasion (Matrigel assay). Our results indicate that a crude extract of apple phenolics can protect against DNA damage, improve barrier function and inhibit invasion (p < 0.05). The anti-invasive effects of the extract were enhanced with twenty-four hour pretreatment of cells (p < 0.05). We have shown that a crude apple extract from waste, rich in phenolic compounds, beneficially influences key stages of carcinogenesis in colon cells in vitro.

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From the reaction of Super Hydride (LiBEt3H) with 6-(furyl)fulvene (1a), 6-(thiophenyl)fulvene (1b) or 6-(N-methyl-pyrrole)fulvene (1c) the corresponding lithium cyclopentadienide intermediates (2a-c) were obtained. These intermediates were reacted with titanium tetrachloride and bis-[(furyl-2-cyclopentadienylmethane)] titanium(IV) dichloride (3a) and bis-[(thiophenyl-2-cyclopentadienylmethane)] titanium(IV) dichloride (3b) and bis-[(N-methylpyrrole-2-cyclopentadienylmethane)] titanium(IV) dichloride (3c) were obtained and subsequently characterised by X-ray crystallography. When titanocenes 3a-c were tested against pig kidney (LLC-PK) cells inhibitory concentrations (IC50) of 1.6 x 10(-4) M, 1.5 x 10(-4) M and 9.1 x 10(-5) M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, when compared to their corresponding ansa substituted analogues and also in comparison to unsubstituted titanocene dichloride. (c) 2006 Elsevier Inc. All rights reserved.

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From the carbolithiation of N,N-dimethylamino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and N-methylpyrrole), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4 resulting in dimethylamino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC50 values obtained were of 240, and 28 mu M for titanocenes 5a and 5b, respectively. The most cytotoxic titanocene 5c with an IC50 value of 5.5 mu M is found to be almost as cytotoxic as cis-platin, which showed an IC50 value of 3.3 mu M, when tested on the LLC-PK cell line, and titanocene 5c is approximately 400 times better than titanocene dichloride itself. (c) 2007 Elsevier B.V. All rights reserved.

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From the reaction of tert-butyl lithium or n-butyl lithium with N-methylpyrrole (1a), furan (1b) or 2-bromo-thiophen (1c), 2-N-methylpyrrolyl lithium (2a), 2-furyl lithium (2b) or 2-thiophenyl lithium (2c), respectively, was obtained. When reacted with 6-(2-N-methylpyrrolyl) fulvene (3a), 6-(2-furyl) fulvene (3b) or 6-(2-thiophenyl) fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanocenes (5a-c) were obtained through transmetallation with titanium tetrachloride. When these titanocenes were tested against pig kidney epithelial (LLC-PK) cells, inhibitory concentrations (IC50) of 32 mu M, 140 mu M, and 240 mu M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues. (c) 2006 Elsevier B.V. All rights reserved.

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From the reaction of tert-butyl lithium with p-bromo-N,N-dimethylaniline (1a), p-bromoanisole (1b) or 1-bromo-3,5-dimethoxybenzene (1c), p-N,N-dimethylanityl lithium (2a), p-anisyl lithium (2b) or (3,5-dimethoxyphenyl) lithium (2c), respectively, were obtained. When reacted with 6-(p-N,N-dimethylanilinyl)fulvene (3a), 6-(p-methoxyphenyl)fulvene (3b) or 3,5-(dimethoxyphenyl)fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanium tetrachloride was added "in situ", obtaining titanocenes 5a-C, respectively. When these titanocenes were tested against pig kidney carcinoma (LLC-PK) cells, inhibitory concentrations (IC50) Of 3.8 x 10(-5) M, 4.5 x 10(-5) M, and 7.8 x 10(-5) M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues. (c) 2006 Elsevier Ltd. All rights reserved.

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From the carbolithiation of 6-N,N-dimethylamino fulvene (3a) and different lithiated aryl species [p-N,N-dimethylanilinyl lithium, p-anisyl lithium and 4-lithio-benzo[1.3]dioxole (2a-c)], the corresponding lithium cyclopentadienide intermediates 4a-c were formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4 resulting in dimethylamino-functionalised and aryl-substituted titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC50 values obtained were of 54, 45 and 26 mu M for titanocenes 5a, b and c, respectively. The most cytotoxic titanocene in this paper, 5c is approximately 10 times less cytotoxic than cis-platin, which showed an IC50 value of 3.3 mu M, when tested on the LLC-PK cell line, but approximately 100 times better than titanocene dichloride. (C) 2007 Elsevier Masson SAS. All rights reserved.

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From the carbolithiation of 6-N,N-dimethylamino fulvene (3a) and different ortho-lithiated indole derivatives (5-methoxy-N-methylindole, N-methylindole and N,N-dimethylaminomethylindole), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4 resulting in dimethylamino-functionalised titanocenes (5a-c). When these titanocenes were tested against LLC-PK cells, the IC50 values obtained were of 37 and 71 mu M for titanocenes 5a and 5b respectively. The most cytotoxic titanocene in this paper, 5c showed an IC50 value of 8.4 mu M is found to be almost as cytotoxic as cis-platin, which showed an IC50 value of 3.3 mu M, when tested on the LLC-PK cell line, and titanocene 5c is approximately 250 times better than titanocene dichloride itself.

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Advanced prostate cancer is not curable by current treatment strategies indicating a significant need for new chemotherapeutic options. Highly substituted ansatitanocene compounds have shown promising cytotoxic activity in a range of cancers. The objectives of this study are to examine the effects of these titanocene compounds on prostate cancer cells. Prostate cell lines were treated with three novel titanocene compounds and compared to titanocene dichloride and cisplatin. Percent apoptosis, viability and cell cycle were assessed using propidium iodide DNA incorporation with flow cytometry. Cytochrome C was assessed by western blotting of mitochondrial and cytoplasmic fractions. Apoptosis Inducing Factor was assessed by confocal microscopy. These novel compounds induced more apoptosis compared to cisplatin in a dose dependent manner. Compound Y had the most significant effect on cell cycle and apoptosis. Despite the release of cytochrome C from the mitochondrial fraction there was no inhibition of apoptosis with the pan caspase inhibitor, ZVAD-FMK. AIF was shown to translocate from the cytosol to the nucleus mediating a caspase independent cell death. Bcl-2 over expressing PC-3 cells, which were resistant to cisplatin induced apoptosis, underwent apoptosis following treatment with all the titanocene compounds. This study demonstrates possible mechanisms by which these novel titanocene compounds can mediate their apoptotic effect in vitro. The fact that they can induce more apoptosis than cisplatin in advanced cancer cell lines would confer an advantage over cisplatin. They represent exciting new agents with future potential for the treatment of advanced prostate cancer.

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The traditional Mediterranean diet is thought to represent a healthy lifestyle; especially given the incidence of several cancers including colorectal cancer is lower in Mediterranean countries compared to Northern Europe. Olive oil, a central component of the Mediterranean diet, is believed to beneficially affect numerous biological processes. We used phenols extracted from virgin olive oil on a series of in vitro systems that model important stages of colon carcinogenesis. The effect the extract on DNA damage induced by hydrogen peroxide was measured in HT29 cells using single cell microgel-electrophoresis. A significant anti-genotoxic linear trend (p=0.011) was observed when HT29 cells were pre-incubated with olive oil phenols (0, 5, 10, 25, 50, 75, 100 microg/ml) for 24 hr, then challenged with hydrogen peroxide. The olive oil phenols (50, 100 microg/ml) significantly (p=0.004, p=0.002) improved barrier function of CACO2 cells after 48 hr as measured by trans-epithelial resistance. Significant inhibition of HT115 invasion (p<0.01) was observed at olive oil phenols concentrations of 25, 50, 75, 100 microg/ml using the matrigel invasion assay. No effect was observed on HT115 viability over the concentration range 0, 25, 50 75, 100 microg/ml after 24 hr, although 75 and 100 microg/ml olive oil phenols significantly inhibited HT115 cell attachment (p=0.011, p=0.006). Olive oil phenols had no significant effect on metastasis-related gene expression in HT115 cells. We have demonstrated that phenols extracted from virgin olive oil are capable of inhibiting several stages in colon carcinogenesis in vitro.

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Flavonoids, which are polyphenolic compounds, are a class of plant secondary metabolites possessing a broad spectrum of pharmacological activity including anti-cancer activities. They have been reported to interfere in the initiation, promotion and progression of cancer by modulating different enzymes and receptors in signal transduction pathways related to cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis, metastasis and reversal of multidrug resistance. Due to their multiple molecular mechanisms of action, flavonoids (both natural and synthetic analogs) are being investigated for their potential applications in anti-cancer therapies. In this review article, the main molecular mechanisms of action of flavonoids attributing to their potential anti-cancer activities have been discussed and the key structural features required for their activity are highlighted.

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Although it is known to be a rich source of the putative anti-cancer chemicals isothiocyanates, watercress has not been extensively studied for its cancer preventing properties. The aim of this study was to investigate the potential chemoprotective effects of crude watercress extract toward three important stages in the carcinogenic process, namely initiation, proliferation, and metastasis (invasion) using established in vitro models. HT29 cells were used to investigate the protective effects of the extract on DNA damage and the cell cycle. The extract was not genotoxic but inhibited DNA damage induced by two of the three genotoxins used, namely hydrogen peroxide and fecal water, indicating the potential to inhibit initiation. It also caused an accumulation of cells in the S phase of the cell cycle indicating (possible) cell cycle delay at this stage. The extract was shown to significantly inhibit invasion of HT115 cells through matrigel. Component analysis was also carried out in an attempt to determine the major phytochemicals present in both watercress leaves and the crude extract. In conclusion, the watercress extract proved to be significantly protective against the three stages of the carcinogenesis process investigated.

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The benzyl-substituted unbridged titanocene bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) was tested in vitro against human renal cancer cells (Caki-1), in which it showed an IC50 value of 36 x 10(-6) mol/l. Titanocene Y was then given in vivo in doses of 10, 20, 30, 40 and 50 mg/kg on 5 consecutive days to Caki-1-bearing mice, and it showed concentration-dependent and statistically significant tumor growth reduction with respect to a solvent-treated control cohort. The maximum tolerable dose of Titanocene Y was determined to be 40 mg/kg and it showed significantly better tumor volume growth reduction than cisplatin given at a dose of 2 mg/kg. This superior activity of Titanocene Y with respect to cisplatin will hopefully lead to clinical tests against metastatic renal cell cancer in the near future.

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Doxorubicin is effective against breast cancer, but its major side effect is cardiotoxicity. The aim of this study was to determine whether the efficacy of doxorubicin on cancer cells could be increased in combination with PPARγ agonists or chrono-optimization by exploiting the diurnal cycle. We determined cell toxicity using MCF-7 cancer cells, neonatal rat cardiac myocytes and fibroblasts in this study. Doxorubicin damages the contractile filaments of cardiac myocytes and affects cardiac fibroblasts by significantly inhibiting collagen production and proliferation at the level of the cell cycle. Cyclin D1 protein levels decreased significantly following doxorubicin treatment indicative of a G1 /S arrest. PPARγ agonists with doxorubicin increased the toxicity to MCF-7 cancer cells without affecting cardiac cells. Rosiglitazone and ciglitazone both enhanced anti-cancer activity when combined with doxorubicin (e.g. 50% cell death for doxorubicin at 0.1 μM compared to 80% cell death when combined with rosiglitazone). Thus, the therapeutic dose of doxorubicin could be reduced by 20-fold through combination with the PPARγ agonists, thereby reducing adverse effects on the heart. The presence of melatonin also significantly increased doxorubicin toxicity, in cardiac fibroblasts (1 μM melatonin) but not in MCF-7 cells. Our data show, for the first time, that circadian rhythms play an important role in doxorubicin toxicity in the myocardium; doxorubicin should be administered mid-morning, when circulating levels of melatonin are low, and in combination with rosiglitazone to increase therapeutic efficacy in cancer cells while reducing the toxic effects on the heart.