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F O Andrade,
M K Nagamine,
A De Conti,
L M Chaible,
C C Fontelles,
A A Jordão Junior,
H Vannucchi,
M L Z Dagli,
B K Bassoli, F S Moreno,
T P Ong
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ABSTRACT: The combined treatment with histone deacetylase inhibitors (HDACi) and retinoids has been suggested as a potential epigenetic strategy for the control of cancer. In the present study, we investigated the effects of treatment with butyrate, a dietary HDACi, combined with vitamin A on MCF-7 human breast cancer cells. Cell proliferation was evaluated by the crystal violet staining method. MCF-7 cells were plated at 5 x 10(4) cells/mL and treated with butyrate (1 mM) alone or combined with vitamin A (10 µM) for 24 to 120 h. Cell proliferation inhibition was 34, 10 and 46% following treatment with butyrate, vitamin A and their combination, respectively, suggesting that vitamin A potentiated the inhibitory activities of butyrate. Furthermore, exposure to this short-chain fatty acid increased the level of histone H3K9 acetylation by 9.5-fold (Western blot), but not of H4K16, and increased the expression levels of p21WAF1 by 2.7-fold (Western blot) and of RARβ by 2.0-fold (quantitative real-time PCR). Our data show that RARβ may represent a molecular target for butyrate in breast cancer cells. Due to its effectiveness as a dietary HDACi, butyrate should be considered for use in combinatorial strategies with more active retinoids, especially in breast cancers in which RARβ is epigenetically altered.
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 06/2012; 45(9):841-50. · 1.08 Impact Factor
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ABSTRACT: β-ionone (βI), a cyclic isoprenoid, and geraniol (GO), an acyclic monoterpene, represent a promising class of dietary chemopreventive agents against cancer, whose combination could result in synergistic anticarcinogenic effects. The chemopreventive activities of βI and GO were evaluated individually or in combination during colon carcinogenesis induced by dimethylhydrazine in 48 3-week-old male Wistar rats (12 per group) weighing 40-50 g. Animals were treated for 9 consecutive weeks with βI (16 mg/100 g body weight), GO (25 mg/100 g body weight), βI combined with GO or corn oil (control). Number of total aberrant crypt foci (ACF) and of ACF ≥4 crypts in the distal colon was significantly lower in the GO group (66 ± 13 and 9 ± 2, respectively) compared to control (102 ± 9 and 17 ± 3) and without differences in the βI (91 ± 11 and 14 ± 3) and βI+GO groups (96 ± 5 and 19 ± 2). Apoptosis level, identified by classical apoptosis morphological criteria, in the distal colon was significantly higher in the GO group (1.64 ± 0.06 apoptotic cells/mm²) compared to control (0.91 ± 0.07 apoptotic cells/mm²). The GO group presented a 0.7-fold reduction in Bcl-2 protein expression (Western blot) compared to control. Colonic mucosa concentrations of βI and GO (gas chromatography/mass spectrometry) were higher in the βI and GO groups, respectively, compared to the control and βI+GO groups. Therefore, GO, but not βI, represents a potential chemopreventive agent in colon carcinogenesis. Surprisingly, the combination of isoprenoids does not represent an efficient chemopreventive strategy.
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 03/2011; 44(6):538-45. · 1.08 Impact Factor
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ABSTRACT: The chemopreventive potential of water extracts of the Brassica vegetables cabbage and kale was evaluated by administering their aqueous extracts in drinking water ad libitum to Wistar rats submitted to Ito's hepatocarcinogenesis model (CB group and K group, respectively - 14 rats per group). Animals submitted to this same model and treated with water were used as controls (W group - 15 rats). Treatment with the vegetable extracts did not inhibit (P > 0.05) placental glutathione S-transferase-positive preneoplastic lesions (PNL). The number of apoptotic bodies did not differ (P > 0.05) among the experimental groups. Ex vivo hydrogen peroxide treatment of rat livers resulted in lower (P < 0.05) DNA strand breakage in cabbage- (107.6 +/- 7.8 microm) and kale- (110.8 +/- 10.0 microm) treated animals compared with control (120.9 +/- 12.7 microm), as evaluated by the single cell gel (comet) assay. Treatment with cabbage (2 +/- 0.3 microg/g) or kale (4 +/- 0.2 microg/g) resulted in increased (P < 0.05) hepatic lutein concentration compared with control (0.5 +/- 0.07 microg/g). Despite the absence of inhibitory effects of cabbage and kale aqueous extracts on PNL, these Brassica vegetables presented protection against DNA damage, an effect possibly related to increased hepatic lutein concentrations. However, it must be pointed out that the cause-effect relationship between lutein levels and protection is hypothetical and remains to be demonstrated.
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 03/2010; 43(3):242-8. · 1.08 Impact Factor
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Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 01/2010; · 1.08 Impact Factor
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ABSTRACT: Guarana (Paullinia cupana Mart. var. Sorbilis) is a plant originally from Brazil, which is rich in tannins. Some tannins are known to present protective effects against DNA damage. This study was performed to investigate the anti-genotoxic/cytotoxic properties of guarana in hepatocytes of mice injected with N-nitrosodiethylamine (DEN). The protective effect of guarana was evaluated both by comet assay and DNA smear fragmentation technique in two month-old female BALB/c mice. These were treated previously with 2.0 mg/g bw of guarana for 16 days and then injected with DEN (160 microg/g body weight) to induce DNA damage. The DEN-only treated group presented higher comet image length than the guarana plus DEN and untreated groups (116.06+/-5.0 microm, 104.09+/-3.3 microm and 93.28+/-14.4 microm, respectively; p<0.01). Guarana treatment presented a 52.54% reduction in comet image length when animals were exposed to DEN (p<0.05). DNA samples from the guarana plus DEN group clearly showed less EtBr fluorescence intensity when compared to the DEN-only group, reinforcing the comet assay data. These results show, for the first time, that guarana has a protective effect against DEN-induced DNA damage in mouse liver.
Food and Chemical Toxicology 06/2006; 44(6):862-7. · 3.00 Impact Factor
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ABSTRACT: The effects of vitamin A and all-trans and 9-cis retinoic acids on the progression phase of hepatocarcinogenesis were evaluated in this study. For this purpose, male Wistar rats were first submitted to the resistant hepatocyte model of carcinogenesis (diethylnitrosamine for initiation and 2-acetylaminofluorene for selection/promotion). Ten months after initiation, the animals were distributed into four groups and treated by gavage, every other day and during eight weeks, with corn oil (control group), vitamin A (10 mg/kg of body wt), all-trans retinoic acid (10 mg/kg body wt), or 9-cis retinoic acid (10 mg/kg body wt). After this period, the animals were killed one hour after intraperitoneal administration of 5-bromo-2-deoxyuridine (BrdU, 100 mg/kg body wt). At the time of sacrifice, liver samples were collected for histopathological (hematoxylin-eosin) examination and immunohistochemical detection of glutathione S-transferase and BrdU, as well as for analysis of retinol and retinoic acid concentrations. Histopathological examination showed the lowest incidence of hepatocarcinomas in vitamin A-treated animals. Moreover, groups treated with retinoids demonstrated lower hepatic BrdU labeling indexes in the neoplastic lesions, as well as in their respective surrounding tissues, than controls. Thus vitamin A and all-trans and 9-cis retinoic acid strongly inhibited cell proliferation when administered during the progression phase of hepatocarcinogenesis. Therefore, the anticarcinogenic effects that have been attributed to these retinoids could be partially related to their capacity of inhibiting in vivo cell proliferation.
Nutrition and Cancer 02/2001; 39(2):244-51. · 2.78 Impact Factor
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ABSTRACT: The morphology of livers of Wistar rats treated with beta-carotene (BC), vitamin A (VA, retinol acetate) or corn oil (CO, controls) and submitted to the resistant hepatocyte model of carcinogenesis was studied. Preneoplastic lesions (PNL) were smaller and less numerous in the BC group. The latter group also presented fewer placental glutathione-S-transferase (GST-P) positive and hematoxylin and eosin (H&E) distinguishable PNL, with smaller mean areas and smaller mean areas of the liver occupied by PNL. Clear cell foci predominated in BC livers. In picrosirius-stained liver sections, fibrosis, whether or not accompanying the bile ductular cells, surrounded only 16.67% of PNL in the BC group, as compared to 35.71% in the VA group and 87.72% in the CO group. Moreover, the ductular cell reaction was smaller in the BC group. Smooth muscle actin-positive cells surrounded some PNL, mostly in CO rats, and less frequently in the VA and BC groups. Examination by transmission electron microscopy (TEM) showed that cells with nuclei similar to those of perisinusoidal cells, devoid of cytoplasmic fat globules, probably represented myofibroblasts derived from Ito cells and accompanied the ductular cell reaction. On the basis of these results, we suggest that BC reduced not only the PNL but also the ductular (oval) cell reaction in this experimental model.
Pathology 08/1998; 30(3):259-66. · 2.38 Impact Factor
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ABSTRACT: The inhibitory effects of beta-carotene or vitamin A on preneoplastic lesions induced in rats were compared, when specifically administered during early promotion of hepatocarcinogenesis. Initiation was performed by diethylnitrosamine. During the selection/promotion period 2-acetylaminofluorene was administered, and a partial hepatectomy was performed. Afterwards, the rats were divided into 3 groups. To two groups, beta-carotene or vitamin A were given for five weeks. Another group served as control and received corn oil. At the end of the study, beta-carotene reduced the incidence and total number of hepatocyte nodules. Vitamin A rats exhibited a lower number of nodules, but the incidence was 100%. Moreover, beta-carotene reduced the total number of gamma GT-positive preneoplastic lesions, as well as the morphometric parameters of persistent gamma GT-positive lesions. In contrast, morphometric parameters of persistent lesions remained almost unaffected in vitamin A animals. Furthermore, beta-carotene significantly increased the number of remodeling gamma GT-positive preneoplastic lesions. Vitamin A administration, however, resulted only in a small increase in the number of remodeling lesions. These results suggest that the inhibitory effects of beta-carotene during early promotion of hepatocarcinogenesis can be attributed not only to an inhibitory effect on persistent lesions, but also to a striking stimulatory activity on remodeling gamma GT-positive lesions.
International Journal for Vitamin and Nutrition Research 02/1997; 67(6):415-22. · 0.88 Impact Factor
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ABSTRACT: 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), is a rate-limiting enzyme in the biosynthesis of not only cholesterol but also a variety of non-sterol isoprenoids. It is subjected to multivalent feedback suppression by transcriptional and post-transcriptional control mechanisms mediated by sterols and non-sterol substances. In the present study, the effect of a plant isoprenoid, beta-carotene, on the expression of HMG-CoA reductase in rat liver was investigated. In control rats the hepatic levels of mRNA transcripts of HMG-CoA reductase increased following 2/3 partial hepatectomy with two peaks, one at 8 h and the other at 24 h. Administration of the carotenoid (70 mg/kg, given every alternate day for 3 consecutive weeks) partially inhibited the increase in the transcript level with a 50% reduction at 8 h and 30% reduction at 24 h post partial hepatectomy. Nuclear run-off assays with nuclei isolated from the resting liver and from livers of control rats and rats exposed to beta-carotene for 3 consecutive weeks and killed 8 h after partial hepatectomy indicated that beta-carotene did not inhibit the rate of transcription of HMG-CoA reductase gene. These observations suggest that beta-carotene regulates the expression of HMG-CoA reductase by some post-transcriptional mechanisms.
Cancer Letters 10/1995; 96(2):201-8. · 4.24 Impact Factor
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ABSTRACT: The effects of beta-carotene (beta C) or vitamin A (VA) administration for 8 consecutive weeks were compared in male Wistar rats submitted to the resistant hepatocyte model (RH model) of hepatocarcinogenesis. Animals treated with corn oil (CO), instead of carotenoid or retinoid, served as controls. At the end of the study, beta C treatment resulted in a substantial reduction in the hepatocyte nodule incidence, total number of nodules and in the nodule multiplicity, as well as in the number and size of hepatic gamma-glutamyltranspeptidase (gamma GT)-positive foci. In contrast, animals administered with VA presented a 100% nodule incidence and only a moderate decrease in the total number of hepatocyte nodules. These showed to be in the great majority larger than nodules observed after beta C treatment. Moreover, VA administration resulted in similar number and size of gamma GT-positive foci than controls. In addition, the hepatic concentrations of total VA increased in both, beta C and VA treated animals. However, as expected, increases in the hepatic carotenoid concentrations could be only observed after beta C application. Therefore, changes in the hepatic levels of beta C, and not of VA, resulted in appreciable inhibitory effects on preneoplastic lesions of the liver. The evidence implies that the chemopreventive property of beta C is unrelated to its provitamin A activity.
International Journal for Vitamin and Nutrition Research 02/1995; 65(2):87-94. · 0.88 Impact Factor
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ABSTRACT: The inhibitory effects of beta-carotene (BC) on preneoplastic lesions induced in male Wistar rats by the resistant hepatocyte model was investigated. Rats were divided into six groups. Initiation was performed in all animals by a single injection of diethylnitrosamine. During the selection/promotion period five doses of 2-acetylaminofluorene were administered to the rats and a partial hepatectomy was performed. To three different groups BC was given by gavage throughout the experiment, before the initiation or during the selection/promotion period respectively. Three other groups served as controls and received corn oil instead of the carotenoid. At the end of the study (8 weeks), BC administration throughout the experiment reduced the incidence (P less than 0.005), multiplicity as well as the total number and size of hepatocyte nodules. Furthermore, it significantly decreased the number of foci per cm2 (P less than 0.05), the average focal area (P less than 0.01) and the percentage of liver parenchyma occupied (P less than 0.01). Similar results were observed when BC was given only before the initiation. However, the administration of the carotenoid during the selection/promotion period did not result in significant decreases of these parameters. These results suggest that the inhibitory effects of BC are primarily exerted on the initiation phase of the hepatocarcinogenic process. Nevertheless, continuous long-term exposure to the carotenoid would confer a greater degree of protection. In addition, by means of an analysis of correlation a positive relationship was found between the number of hepatocyte nodules and the hepatic concentration of BC. In contrast, an inverse relationship was observed between the number of nodules and the hepatic concentration of total vitamin A.
Carcinogenesis 11/1991; 12(10):1817-22. · 5.70 Impact Factor
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ABSTRACT: Plasma amino acid concentrations in 33 male alcoholic patients with pellagra (age 20-68 years) were compared with those in 17 healthy male subjects (age 20-45 years). Pellagra diagnosis was made on the basis of the typical clinical skin picture, and low urinary excretion of N'methylnicotinamide and N'methyl-2-pyridone-5-carboxamide (reduced by 70 and 80%, respectively, compared with controls). There were significant differences in body mass index, creatinine/high index and serum albumin between the two groups, indicating that besides pellagra the alcoholic patients had some degree of malnutrition. Of 17 plasma amino acids measured, the following had significantly lower concentrations in the pellagrins: tryptophan (3.65 vs 5.93 mumol/dl, pellagrin vs control), isoleucine (6.31 vs 11.13), leucine (11.54 vs 24.19), lysine (16.25 vs 34.47), methionine (2.61 vs 4.22), phenylalanine (5.71 vs 9.23), threonine (13.29 vs 26.81), valine (17.60 vs 41.06), alanine (42.54 vs 70.87), arginine (5.87 vs 10.09), tyrosine (5.57 vs 9.30). Glutamic acid was significantly higher in the pellagrins (18.45 vs 9.49). There was no difference between the groups of aspartic acid, glycine, histidine, proline and serine concentrations. It is concluded that pellagra is an important factor influencing the amino acid profiles in these patients. This finding should be taken into account when using plasma amino acid levels to assess the clinical status of the pellagrin.
Alcohol and Alcoholism 02/1991; 26(4):431-6. · 2.95 Impact Factor
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ABSTRACT: The effect of zinc supplementation on the metabolism of tryptophan conversion to niacin was studied in 14 alcoholic patients with pellagra and in 7 male control subjects aged 21-45 y. The pellagrins received chemically defined diets based on crystalline amino acids through an enteral tube for 7 d. Patients were divided into two groups (A and B), both receiving a diet from which tryptophan, Zn, and niacin were excluded. Patients in group B, however, received 220 mg Zn sulfate orally. Upon admission the pellagra patients had low plasma Zn levels and low urinary excretion values of N'methylnicotinamide (N'MN) and N'methyl-2-pyridone-5-carboxamide (2-PYR) in relation to the control subjects (p less than 0.01). During the experimental period there was an increase in plasma Zn levels (p less than 0.005) and in urinary N'MN (p less than 0.05) and 2-PYR (p less than 0.05) excretion in the patients receiving Zn supplementation (group B). These results suggest that Zn interacts with niacin metabolism in alcoholic patients with pellagra through a probable mediation by vitamin B-6.
American Journal of Clinical Nutrition 09/1989; 50(2):364-9. · 6.67 Impact Factor
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ABSTRACT: beta-ionone (beta I), a cyclic isoprenoid, and geraniol (GO), an acyclic monoterpene, represent a promising class of dietary chemopreventive agents against cancer, whose combination could result in synergistic anticarcinogenic effects. The chemopreventive activities of beta I and GO were evaluated individually or in combination during colon carcinogenesis induced by dimethylhydrazine in 48 3-week-old male Wistar rats (12 per group) weighing 40-50 g. Animals were treated for 9 consecutive weeks with beta I (16 mg/100 g body weight), GO (25 mg/100 g body weight), beta I combined with GO, or corn oil (control). Number of total aberrant crypt foci (ACF) and of ACF >= 4 crypts in the distal colon was significantly lower in the GO group (66 +/- 13 and 9 +/- 2, respectively) compared to control (102 +/- 9 and 17 +/- 3) and without differences in the beta I (91 +/- 11 and 14 +/- 3) and beta I+GO groups (96 +/- 5 and 19 +/- 2). Apoptosis level, identified by classical apoptosis morphological criteria, was significantly higher in the GO group (1.64 +/- 0.06 apoptotic cells/mm(2)) compared to control (0.91 +/- 0.07 apoptotic cells/mm(2)) in the distal colon. The GO group presented a 0.7-fold reduction in Bcl-2 protein expression (Western blot) compared to control. Colonic mucosa concentrations of beta I and GO (gas chromatography/mass spectrometry) were higher in the beta I and GO groups, respectively, compared to the control and beta I+GO groups. Therefore, GO, but not beta I, represents a potential chemopreventive agent in colon carcinogenesis. Surprisingly, the combination of isoprenoids does not represent an efficient chemopreventive strategy.
BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH. 44(6):538-545.
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[show abstract]
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ABSTRACT: Guarana (Paullinia cupana Mart. var. Sorbilis) is a plant originally from Brazil, which is rich in tannins. Some tannins are known to present protective effects against DNA damage. This study was performed to investigate the anti-genotoxic/cytotoxic properties of guarana in hepatocytes of mice injected with N-nitrosodiethylamine (DEN). The protective effect of guarana was evaluated both by comet assay and DNA smear fragmentation technique in two month-old female BALB/c mice. These were treated previously with 2.0 mg/g bw of guarana for 16 days and then injected with DEN (160 μg/g body weight) to induce DNA damage. The DEN-only treated group presented higher comet image length than the guarana plus DEN and untreated groups (116.06 ± 5.0 μm, 104.09 ± 3.3 μm and 93.28 ± 14.4 μm, respectively; p < 0.01). Guarana treatment presented a 52.54% reduction in comet image length when animals were exposed to DEN (p < 0.05). DNA samples from the guarana plus DEN group clearly showed less EtBr fluorescence intensity when compared to the DEN-only group, reinforcing the comet assay data. These results show, for the first time, that guarana has a protective effect against DEN-induced DNA damage in mouse liver.
Food and Chemical Toxicology.
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[show abstract]
[hide abstract]
ABSTRACT: The inhibitory effects of β-carotene (BC) on preneoplastic lesions induced in male Wistar rats by the resistant hepatocyte model was investigated. Rats were divided into six groups. Initiation was performed in all animals by a single injection of diethylnitrosamine. During the selection/promotion period five doses of 2-acetylaminofluorene were administered to the rats and a partial hepatectomy was performed. To three different groups BC was given by gavage throughout the experiment, before the initiation or during the selection/ promotion period respectively. Three other groups served as controls and received corn oil instead of the carotenoid. At the end of the study (8 weeks), BC administration throughout the experiment reduced the incidence ( P < 0.005), multiplicity as well as the total number and size of hepatocyte nodules. Furthermore, it significantly decreased the number of foci per cm2 ( P < 0.05), the average focal area ( P < 0.01) and the percentage of liver parenchyma occupied (P < 0.01). Similar results were observed when BC was given only before the initiation. However, the administration of the carotenoid during the selection/promotion period did not result in significant decreases of these parameters. These results suggest that the inhibitory effects of BC are primarily exerted on the initiation phase of the hepatocarcinogenic process. Nevertheless, continuous long-term exposure to the carotenoid would confer a greater degree of protection. In addition, by means of an analysis of correlation a positive relationship was found between the number of hepatocyte nodules and the hepatic concentration of BC. In contrast, an inverse relationship was observed between the number of nodules and the hepatic concentration of total vitamin A.
