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1.
Cancers (Basel) ; 15(15)2023 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-37568816

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) are promising colorectal cancer (CRC) chemopreventive drugs; however, to overcome NSAIDs' associated side effects, there is a need to develop safer and efficacious approaches. The present study was designed to evaluate (i) the efficacy of nitric-oxide releasing (NO)-Sulindac as compared to Sulindac; (ii) whether NO-Sulindac is superior to Sulindac in enhancing low-dose difluoromethylornithine (DFMO)-induced chemopreventive efficacy, and (iii) assessing the key biomarkers associated with colon tumor inhibition by these combinations. In F344 rats, colonic tumors were induced by azoxymethane (AOM). At the adenoma stage (13 weeks post AOM), groups of rats were fed the experimental diets containing 0 ppm, 500 ppm DFMO, 150 ppm Sulindac, and 200 ppm NO-Sulindac, individually or in combinations, for 36 weeks. Colon tumors were evaluated histopathologically and assayed for expression levels of proliferative, apoptotic, and inflammatory markers. Results suggest that (except for NO-Sulindac alone), DFMO, Sulindac individually, and DFMO combined with Sulindac or NO-Sulindac significantly suppressed AOM-induced adenocarcinoma incidence and multiplicities. DFMO and Sulindac suppressed adenocarcinoma multiplicity by 63% (p < 0.0001) and 51% (p < 0.0011), respectively, whereas NO-Sulindac had a modest effect (22.8%, p = 0.09). Combinations of DFMO plus Sulindac or NO-Sulindac suppressed adenocarcinoma incidence (60%, p < 0.0001; 50% p < 0.0004), and multiplicity (81%, p < 0.0001; 62%, p < 0.0001). Rats that were fed the combination of DFMO plus Sulindac showed significant inhibition of tumor cell proliferation and induction of apoptosis. In addition, enhancement of p21, Bax, and caspases; downregulation of Ki-67, VEGF, and ß-catenin; and modulation of iNOS, COX-2, and ODC activities in colonic tumors were observed. These observations show that a lower-dose of DFMO and Sulindac significantly enhanced CRC chemopreventive efficacy when compared to NO-Sulindac alone, and the combination of DFMO and NO-Sulindac was modestly efficacious as compared to DFMO alone.

2.
Cancer Prev Res (Phila) ; 9(1): 53-62, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26577454

RESUMO

Urothelial tumors, accompanied by mutations of the tumor suppressor protein TP53 and dysregulation of mTOR signaling, are frequently associated with aggressive growth and invasiveness. We investigated whether targeting these two pathways would inhibit urothelial tumor growth and progression. Six-week-old transgenic UPII-SV40T male mice (n = 15/group) were fed control diet (AIN-76A) or experimental diets containing mTOR inhibitor (rapamycin, 8 or 16 ppm), p53 stabilizing agent [CP31398 (CP), 150 ppm], or a combination. Mice were euthanized at 40 weeks of age. Urinary bladders were collected and evaluated to determine tumor weight and histopathology. Each agent alone, and in combination, significantly inhibited tumor growth. Treatment with rapamycin alone decreased tumor weight up to 67% (P < 0.0001). Similarly, CP showed approximately 77% (P < 0.0001) suppression of tumor weight. The combination of low-dose rapamycin and CP led to approximately 83% (P < 0.0001) inhibition of tumor weight. There was no significant difference in tumor weights between rapamycin and CP treatments (P > 0.05). However, there was a significant difference between 8 ppm rapamycin and the combination treatment. Tumor invasion was also significantly inhibited in 53% (P < 0.005) and 66% (P < 0.0005) mice after 8 ppm and 16 ppm rapamycin, respectively. However, tumor invasion was suppressed in 73% (P < 0.0001) mice when CP was combined with 8 ppm rapamycin. These results suggest that targeting two or more pathways achieve better treatment efficacy than a single-agent high-dose strategy that could increase the risk of side effects. A combination of CP and rapamycin may be a promising method of inhibiting muscle-invasive urothelial transitional cell carcinoma.


Assuntos
Regulação Neoplásica da Expressão Gênica , Músculos/patologia , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Inflamação , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Invasividade Neoplásica , Neovascularização Patológica , Poliaminas/química , Transdução de Sinais , Sirolimo/química , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
3.
Oncol Rep ; 34(6): 2925-34, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26397133

RESUMO

In tobacco-associated lung cancers, the protein kinase B/mammalian target of rapamycin (Akt/mTOR) pathway frequently is activated by nicotine and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The aim of the present study was to examine the effects of early or late intervention with rapamycin in NNK-induced lung adenoma and progression to adenocarcinoma in female A/J mice. At 7 weeks of age, 40 mice/each carcinogen group received one dose of 10 µmol NNK i.p. Three weeks later, the early intervention groups (25/group) were fed diets containing 0, 8 or 16 ppm rapamycin. The mice were sacrificed after 17 or 34 weeks of drug exposure and tumors were evaluated via histopathology. For late intervention (late adenoma and adenocarcinoma stage), groups of 15 mice were administered diets containing 8 or 16 ppm rapamycin starting 20 weeks after NNK treatment and continuing for 17 weeks before evaluation of tumor progression. Administration of 8 or 16 ppm rapamycin as an early or a late stage intervention significantly suppressed lung adenoma and adenocarcinoma formation (p<0.01-0.0001) after 17 or 34 weeks of exposure. The effect was more pronounced (>50­60% tumor inihibition; p<0.0001) at the early intervention and the size of NNK-induced tumors decreased from >2.10 to <~0.75 mm3 (p=0.0056). Lung tumors harvested from mice exposed to rapamycin showed a significant decrease in p-mTOR, p-S6K1, PCNA and Bcl-xL as compared with controls in the early and late stage intervention studies. These observations suggest that rapamycin is highly effective even with administration after dysplastic adenoma or early adenocarcinoma stages and is useful for high-risk lung cancer patients.


Assuntos
Adenocarcinoma/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Nicotiana/efeitos adversos , Sirolimo/administração & dosagem , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Animais , Carcinógenos/toxicidade , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Nicotina/efeitos adversos , Nitrosaminas/toxicidade , Antígeno Nuclear de Célula em Proliferação/biossíntese , Proteínas Quinases S6 Ribossômicas 90-kDa/biossíntese , Serina-Treonina Quinases TOR/biossíntese , Proteína bcl-X/biossíntese
4.
Cancer Prev Res (Phila) ; 7(7): 708-16, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24795386

RESUMO

Epidemiologic and clinical data suggest that use of anti-inflammatory agents is associated with reduced risk for bladder cancer. We determined the chemopreventive efficacy of licofelone, a dual COX-lipoxygenase (LOX) inhibitor, in a transgenic UPII-SV40T mouse model of urothelial transitional cell carcinoma (TCC). After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm licofelone for 34 weeks. At 40 weeks of age, all mice were euthanized, and urinary bladders were collected to determine urothelial tumor weights and to evaluate histopathology. Results showed that bladders of the transgenic mice fed control diet weighed 3 to 5-fold more than did those of the wild-type mice due to urothelial tumor growth. However, treatment of transgenic mice with licofelone led to a significant, dose-dependent inhibition of the urothelial tumor growth (by 68.6%-80.2%, P < 0.0001 in males; by 36.9%-55.3%, P < 0.0001 in females) compared with the control group. The licofelone diet led to the development of significantly fewer invasive tumors in these transgenic mice. Urothelial tumor progression to invasive TCC was inhibited in both male (up to 50%; P < 0.01) and female mice (41%-44%; P < 0.003). Urothelial tumors of the licofelone-fed mice showed an increase in apoptosis (p53, p21, Bax, and caspase3) with a decrease in proliferation, inflammation, and angiogenesis markers (proliferating cell nuclear antigen, COX-2, 5-LOX, prostaglandin E synthase 1, FLAP, and VEGF). These results suggest that licofelone can serve as potential chemopreventive for bladder TCC.


Assuntos
Antígenos Transformantes de Poliomavirus/metabolismo , Carcinoma in Situ/prevenção & controle , Lipoxigenase/química , Prostaglandina-Endoperóxido Sintases/química , Pirróis/farmacologia , Neoplasias da Bexiga Urinária/prevenção & controle , Uroplaquina II/fisiologia , Animais , Western Blotting , Carcinoma in Situ/genética , Carcinoma in Situ/patologia , Movimento Celular , Proliferação de Células , Feminino , Técnicas Imunoenzimáticas , Lipoxigenase/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Invasividade Neoplásica , Regiões Promotoras Genéticas/genética , Prostaglandina-Endoperóxido Sintases/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
5.
Cancer Prev Res (Phila) ; 6(10): 1140-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23963803

RESUMO

Lung cancer is the leading cause of cancer-related deaths. ß-Escin, a triterpene saponin isolated from horse chestnut seeds, was tested for inhibition of lung adenoma and adenocarcinoma induced by the tobacco carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice; and its possible mode of action was evaluated using the H460 human lung cancer cell line. At 6 weeks of age, 35 mice were fed AIN-76A-modified diet, and one week later, lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 µmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed either control or experimental diets containing 500 ppm for 20 weeks (10 control, 5 ß-escin) or 36 weeks (15 control, 5 ß-escin) and evaluated for lung tumor via histopathologic methods. Administration of 500 ppm ß-escin significantly suppressed lung tumor (adenoma + adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. ß-Escin inhibited NNK-induced lung adenocarcinoma formation by 65% (P < 0.001) at 20 weeks and by 53% (P < 0.0001) at 37 weeks. Immunohistochemical analysis revealed that lung tumors from mice exposed to ß-escin showed significantly reduced aldehyde dehydrogenase (ALDH)1A1 and phospho-Akt (p-Akt) expression when compared with those in mice fed control diet. Aldefluor assay for ALDH revealed that among H460 lung cancer cells treated with different concentrations of ß-escin (0-40 µmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that ß-escin inhibits tobacco carcinogen-induced lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling.


Assuntos
Adenocarcinoma/metabolismo , Aldeído Desidrogenase/metabolismo , Escina/uso terapêutico , Neoplasias Pulmonares/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo , Adenoma/metabolismo , Família Aldeído Desidrogenase 1 , Animais , Carcinogênese , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/induzido quimicamente , Camundongos , Transplante de Neoplasias , Nitrosaminas/efeitos adversos , Extratos Vegetais/química , Reação em Cadeia da Polimerase em Tempo Real , Retinal Desidrogenase , Nicotiana/efeitos adversos , Proteína rhoA de Ligação ao GTP/metabolismo
6.
Nutr Cancer ; 65 Suppl 1: 54-60, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23682783

RESUMO

The present study explored the preventive effects of perilla oil, rich in α-linolenic acid, in rodent models of colon tumorigenesis. Six-week-old male F344 rats were fed diets containing 5% corn oil or 10 or 20% perilla oil. Colonic aberrant crypt foci (ACF) were induced by azoxymethane (AOM) and colonic ACF were evaluated. In familial adenomatous polyposis mode, APC(min) mice fed with 20% corn oil or perilla oil for 80 days and intestines were evaluated for polyps. Multiple colonic mucosal and polyp samples were assayed for the expression and activity of cyclooxygenase COX-isoforms. Dietary perilla oil produced a dose-dependent inhibition of AOM-induced colonic ACF formation (by 35-53%, P < 0.01-0.005) and reduced the number of foci with ≥ 4 crypts/focus (by 38-50%, P < 0.01-0.001) in F344 rats. Dietary perilla oil significantly inhibited development of small intestinal (>69%, P < 0.0001) and colon tumors (>52%, P < 0.03) in APC(min) mice. Administration of perilla oil produced lower levels of type-2 prostaglandins (38-53%) from COX-activities in polyps of APC(min) mice. These observations demonstrate that dietary perilla oil rich in ω-3 fatty acids possesses preventive activity against intestinal neoplastic lesions, both in FAP in genetically-predisposed tissues, as well as against chemically induced preneoplastic lesions in the colon.


Assuntos
Focos de Criptas Aberrantes/patologia , Polipose Adenomatosa do Colo/tratamento farmacológico , Anticarcinógenos/farmacologia , Carcinogênese/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Ácido alfa-Linolênico/farmacologia , Focos de Criptas Aberrantes/induzido quimicamente , Polipose Adenomatosa do Colo/induzido quimicamente , Polipose Adenomatosa do Colo/patologia , Animais , Azoximetano/toxicidade , Carcinogênese/induzido quimicamente , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/patologia , Óleo de Milho/administração & dosagem , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Feminino , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Óleos de Plantas/farmacologia , Ratos , Ratos Endogâmicos F344
7.
Curr Pharm Biotechnol ; 13(1): 147-55, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21466427

RESUMO

Triterpenoids are ubiquitous in the plant kingdom. Recent evidences support the beneficial effects of naturallyoccurring triterpenoids against several types of human diseases, including various cancers. Here, we have summarized the potential of triterpenoids belonging to the lupane, oleanane, ursane, and cucurbitacin groups, and their beneficial effects based on both laboratory and clinical investigations. Anticancer potential of triterpenoids and their anti-inflammatory, anti-proliferative, and pro-apoptotic effects have been discussed both in in vitro and in vivo models. Importantly, a large number of preclinical efficacy studies using chemically-induced, as well as tumor xenograft models provided evidence that both naturally occurring and synthetic derivatives had chemopreventive and therapeutic effects. In this review, we have highlighted several studies on chemopreventive and anticancer potential of triterpenoids based on various preclinical animal models of colon, breast, prostate, and melanoma cancers. Also, we made an attempt in discussing various mechanisms by which triterpenoids regulate various transcription and growth factors, inflammatory cytokines, and intracellular signaling pathways involved in cancer cell proliferation, apoptosis and tumor angiogenesis.


Assuntos
Anticarcinógenos/uso terapêutico , Neoplasias/prevenção & controle , Triterpenos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Anticarcinógenos/farmacologia , Humanos , Inflamação/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Triterpenos/farmacologia
8.
Int J Oncol ; 40(1): 170-5, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21956158

RESUMO

Omeprazole is a proton pump inhibitor, a widely used drug to treat ulcers and gastroesophageal refluxdisease. We have evaluated colon cancer chemopreventive properties of omeprazole using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in male F344 rats and analyzed cell growth inhibition and apoptosis induction in human colon cancer cells. Five-week-old male F344 rats were fed a control or experimental diet containing two doses of omeprazole (200 and 400 ppm). After one week, all animals were s.c. injected with AOM (15 mg/kg body weight, once weekly for two weeks). Rats continued on experimental diets for seven more weeks before being sacrificed. Colons were histopathologically evaluated for ACF. Human colon cancer HCT-116 and HCA-7 cells treated with omeprazole were evaluated for different markers associated with proliferation and apoptotic markers using Western blot technique. Rats fed with 200 and 400 ppm of omeprazole significantly suppressed total colonic ACF formation (~30%, P<0.001) and showed significant suppression of multi-crypt foci (~30-50%, P<0.05-0.001). Omeprazole produced significant dose-response effects on inhibition of multi-crypt foci (≥4). Omeprazole treatment in human colon cancer cell lines HCT-116 and HCA-7 cells resulted in induction of p21waf1/cip1 and decreased the expression of anti-apoptotic proteins Bcl-2, Bcl-XL and survivin in a dose-dependent manner. Anticancer properties observed in colon cancer cell lines suggest that omeprazole may induce key signaling molecules of antiproliferation and inhibition of anti-apoptotic proteins.


Assuntos
Anticarcinógenos/farmacologia , Neoplasias do Colo/prevenção & controle , Omeprazol/farmacologia , Lesões Pré-Cancerosas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Azoximetano , Processos de Crescimento Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Células HCT116 , Humanos , Masculino , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344
9.
Cancer Res ; 69(20): 8175-82, 2009 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-19826045

RESUMO

Tumor suppressor p53 plays a major role in colorectal cancer development. The present study explores the effects of p53-modulating agent CP-31398 alone and combined with celecoxib on azoxymethane-induced aberrant crypt foci (ACF) and colon adenocarcinomas in F344 rats. Maximum tolerated doses were 400 and 3,000 ppm for CP-31398 and celecoxib, respectively. ACF and tumor efficacy endpoints were carried out on azoxymethane-treated 7-week-old rats (48 per group) fed the control AIN-76A diet. Two weeks after carcinogen treatment, rats were fed the diets containing 0, 150, or 300 ppm CP-31398, 300 ppm celecoxib, or 150 ppm CP-31398 plus 300 ppm celecoxib. ACF and colon adenocarcinomas were determined at 8 and 48 weeks after azoxymethane treatment, respectively. Dietary CP-31398 was shown to suppress mean colonic total ACF by 43% and multicrypt ACF by 63%; dietary CP-31398 at 150 and 300 ppm suppressed adenocarcinoma incidence by 30.4% (P < 0.02) and 44% (P < 0.005), respectively, and adenocarcinoma multiplicity by 51% (P < 0.005) and 65% (P < 0.0001), respectively. Dietary celecoxib suppressed colon adenocarcinoma incidence (60%; P < 0.0003) and multiplicity (70%; P < 0.0001). Importantly, combination of low-dose CP-31398 and celecoxib suppressed colon adenocarcinoma incidence by 78% and multiplicity by 90%. Rats that were fed the high-dose CP-31398 or a combination of low-dose CP-31398 and celecoxib showed considerable enhancement of p53 and p21(WAF1/CIP) expression, apoptosis, and reduced tumor cell proliferation in colonic tumors. These observations show, for the first time, that CP-31398 possesses significant dose-dependent chemopreventive activity in a well-established colon cancer model and that a combination of low-dose CP-31398 and celecoxib significantly enhanced colon cancer chemopreventive efficacy.


Assuntos
Adenocarcinoma/prevenção & controle , Azoximetano/toxicidade , Neoplasias Colorretais/prevenção & controle , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/metabolismo , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Carcinógenos/toxicidade , Celecoxib , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/uso terapêutico , Dinoprostona/metabolismo , Quimioterapia Combinada , Técnicas Imunoenzimáticas , Marcação In Situ das Extremidades Cortadas , Masculino , Dose Máxima Tolerável , Proteínas de Membrana/metabolismo , Ratos , Ratos Endogâmicos F344 , Proteína Supressora de Tumor p53/metabolismo
10.
Free Radic Biol Med ; 46(5): 672-9, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19121385

RESUMO

Age-related macular degeneration (AMD) is a complex disease that has potential involvement of inflammatory and oxidative stress-related pathways in its pathogenesis. In search of effective therapeutic agents, we tested curcumin, a naturally occurring compound with known anti-inflammatory and antioxidative properties, in a rat model of light-induced retinal degeneration (LIRD) and in retina-derived cell lines. We hypothesized that any compound effective against LIRD, which involves significant oxidative stress and inflammation, would be a candidate for further characterization for its potential application in AMD. We observed significant retinal neuroprotection in rats fed diets supplemented with curcumin (0.2% in diet) for 2 weeks. The mechanism of retinal protection from LIRD by curcumin involves inhibition of NF-kappaB activation and down-regulation of cellular inflammatory genes. When tested on retina-derived cell lines (661W and ARPE-19), pretreatment of curcumin protected these cells from H(2)O(2)-induced cell death by up-regulating cellular protective enzymes, such as HO-1, thioredoxin. Since, curcumin with its pleiotropic activities can modulate the expression and activation of many cellular regulatory proteins such as NF-kappaB, AKT, NRF2, and growth factors, which in turn inhibit cellular inflammatory responses and protect cells; we speculate that curcumin would be an effective nutraceutical compound for preventive and augmentative therapy of AMD.


Assuntos
Apoptose/efeitos dos fármacos , Curcumina/administração & dosagem , Degeneração Macular/tratamento farmacológico , Fitoterapia , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Animais , Apoptose/fisiologia , Células Cultivadas , Curcumina/farmacologia , Citoproteção/fisiologia , Suplementos Nutricionais , Modelos Animais de Doenças , Eletrorretinografia , Perfilação da Expressão Gênica , Humanos , Luz/efeitos adversos , Degeneração Macular/enzimologia , Degeneração Macular/etiologia , Degeneração Macular/patologia , Camundongos , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/fisiologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos , Ratos Wistar , Células Fotorreceptoras Retinianas Cones/patologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Ativação Transcricional/efeitos dos fármacos
11.
Nutr Cancer ; 60 Suppl 1: 81-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19003584

RESUMO

Pancreatic cancer BxPC-3 cells were exposed to curcumin, docosahexaenoic acid (DHA), or combinations of both and analyzed for proliferation and apoptosis. Pancreatic tumor xenografts were established by injecting BxPC-3 cells into each flank of nude mice. After the tumors reached a size of approximately 190-200 mm(3), animals were fed diets with or without 2,000 ppm curcumin in 18% corn oil or 15% fish oil + 3% corn oil for 6 more wk before assessing the tumor volume and expression of inducible nitric oxide synthase (iNOS), cyclooxygeanse-2 (COX-2), 5-lipoxinase (5-LOX), and p21. A synergistic effect was observed on induction of apoptosis (approximately sixfold) and inhibition of cell proliferation (approximately 70%) when cells were treated with curcumin (5 microM) together with the DHA (25 microM). Mice fed fish oil and curcumin showed a significantly reduced tumor volume, 25% (P < 0.04) and 43% (P < 0.005), respectively, and importantly, a combination of curcumin and fish oil diet showed > 72% (P < 0.0001) tumor volume reduction. Expression and activity of iNOS, COX-2, and 5-LOX are downregulated, and p21 is upregulated in tumor xenograft fed curcumin combined with fish oil diet when compared to individual diets. The preceding results evidence for the first time that curcumin combined with omega-3 fatty acids provide synergistic pancreatic tumor inhibitory properties.


Assuntos
Curcumina/administração & dosagem , Ácidos Graxos Ômega-3/administração & dosagem , Neoplasias Pancreáticas/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Araquidonato 5-Lipoxigenase/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Ciclo-Oxigenase 2/genética , Óleos de Peixe , Humanos , Camundongos , Óxido Nítrico Sintase Tipo II/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cancer Res ; 68(18): 7670-5, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18794156

RESUMO

p53 mutations occur in a large number of human malignancies. Mutant p53 is unable to affect downstream genes necessary for DNA repair, cell cycle regulation, and apoptosis. The styrylquinazoline CP-31398 can rescue destabilized mutant p53 expression and promote activity of wild-type p53. The present study examines chemopreventive effects of CP-31398 on intestinal adenoma development in an animal model of familial adenomatous polyposis. Effects were examined at both early and late stages of adenoma formation. Effects of CP-31398 on early-stage adenomas were determined by feeding 7-week-old female C57BL/6J-APC(min) (heterozygous) and wild-type C57BL/6J mice with American Institute of Nutrition-76A diets containing 0, 100, or 200 ppm of CP-31398 for 75 days. To examine activity toward late-stage adenomas, CP-31398 administration was delayed until 15 weeks of age and continued for 50 days. During early-stage intervention, dietary CP-31398 suppressed development of intestinal tumors by 36% (P < 0.001) and 75% (P < 0.0001), at low and high dose, respectively. During late-stage intervention, CP-31398 also significantly suppressed intestinal polyp formation, albeit to a lesser extent than observed with early intervention. Adenomas in treated mice showed increased apoptotic cell death and decreased proliferation in conjunction with increased expression of p53, p21(WAF1/CIP), cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase. These observations show for the first time that the p53-modulating agent CP-31398 possesses significant chemopreventive activity in vivo against intestinal neoplastic lesions in genetically predisposed APC(min/+) mice. Chemopreventive activity of other agents that restore tumor suppressor functions of mutant p53 in tumor cells is currently under investigation.


Assuntos
Polipose Adenomatosa do Colo/tratamento farmacológico , Pirimidinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/patologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Feminino , Genes APC , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/genética , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Poli(ADP-Ribose) Polimerases/metabolismo , Proteína Supressora de Tumor p53/genética
13.
Int J Oncol ; 33(4): 799-805, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18813794

RESUMO

Nitric oxide-donating aspirin (NO-ASA) represents class of promising chemopreventive NO-NSAIDs. NO-ASA combines the beneficial effects of ASA and the gut-sparing effect of the NO moiety. There is, however, limited information on its pharmacokinetic and pharmacodynamic effects in vivo. Herein, experiments were designed to identify the optimal dose, the effective route of administration, and targeted markers in plasma and colonic tissues of male F344 rats. Seven weeks old male F344 rats were randomized into 9 groups (16/group) and fed the control diet. At eight weeks of age, groups 2-5 were each administered one of four different doses of NO-ASA by gavage (33, 66, 132 and 264 mg/kg) and each of groups 6-9 were fed diets containing NO-ASA (35, 700, 1,400 and 2,800 ppm) for two weeks. Rats were sacrificed 2 and 10 h after completion of the two weeks of treatment with NO-ASA and plasma and colonic mucosa were collected and analyzed for NO-ASA, its metabolites, and PGE2 and TXB2 levels. Our results indicate that NO-ASA is rapidly metabolized, predominantly to salicylic acid; no intact NO-ASA was detected in plasma. Compared to diet-fed NO-ASA, gavaging generated much higher salicylic acid levels over a wide range of doses and a relatively broad time period (10 h). Regardless of its route of administration, NO-ASA lowered the levels of PGE2 in colonic tissues and plasma, as well as TxB2 in plasma in a dose- and time-dependent manner. These findings may have practical utility for the administration of NO-ASA to humans.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/farmacocinética , Aspirina/farmacologia , Aspirina/farmacocinética , Óxido Nítrico/metabolismo , Ração Animal , Animais , Colo/efeitos dos fármacos , Colo/metabolismo , Avaliação Pré-Clínica de Medicamentos , Eicosanoides/metabolismo , Masculino , Ratos , Ratos Endogâmicos F344 , Ácido Salicílico/metabolismo , Tromboxano B2/sangue , Tromboxano B2/metabolismo , Fatores de Tempo
14.
Cancer Res ; 66(14): 7370-7, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16849589

RESUMO

Preclinical and clinical studies have established evidence that cyclooxygenase-2 (COX-2) inhibitors and statins [hydroxy-3-methylglutaryl CoA reductase (HMGR) inhibitors] inhibit colon carcinogenesis. Chronic use of high doses of COX-2 inhibitors may induce side effects, and combining the low doses of agents may be an effective way to increase their efficacy and minimize the side effects. We assessed the chemopreventive efficacy of atorvastatin (Lipitor) and celecoxib individually or in combination in an animal model of familial adenomatous polyposis. Six-week-old male C57BL/6J-APCmin/+ mice were either fed diets containing 0 or 100 ppm atorvastatin or 300 ppm celecoxib, or a combination of both for approximately 80 days. Mice were sacrificed, and their intestines were scored for tumors. Normal-seeming mucosa and intestinal tumors were harvested and assayed for apoptosis (terminal deoxynucleotidyl transferase-mediated nick-end labeling) and HMGR and COX-2 protein expression and activity. We observed that 100 ppm atorvastatin significantly (P < 0.002) suppressed intestinal polyp formation. As anticipated, 300 ppm celecoxib decreased the rate of formation of intestinal polyps by approximately 70% (P < 0.0001). Importantly, the combination of 100 ppm atorvastatin and 300 ppm celecoxib in the diet suppressed the colon polyps completely and small intestinal polyps by >86% (P < 0.0001) compared with the control group. The inhibition of tumor formation by the atorvastatin and celecoxib combination was significant (P < 0.005) when compared with tumor inhibition by celecoxib alone. In addition, increased rates of apoptosis in intestinal tumors (P < 0.01-0.0001) were observed in animals fed with atorvastatin and celecoxib and more so with the combinations. Tumors of animals fed atorvastatin showed a significant decrease in HMGR-R activity. Similarly, tumors of mice exposed to celecoxib showed significantly lower levels of COX-2 activity. These observations show that atorvastatin inhibits intestinal tumorigenesis and that, importantly, when given together with low doses of celecoxib, it significantly increases the chemopreventive efficacy in an APC(min) mice.


Assuntos
Polipose Adenomatosa do Colo/prevenção & controle , Anticarcinógenos/farmacologia , Ácidos Heptanoicos/farmacologia , Pirazóis/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Polipose Adenomatosa do Colo/enzimologia , Polipose Adenomatosa do Colo/patologia , Animais , Apoptose/efeitos dos fármacos , Atorvastatina , Caspase 3 , Caspases/metabolismo , Celecoxib , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Poli(ADP-Ribose) Polimerases/metabolismo
15.
Mol Cancer Ther ; 5(6): 1459-66, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16818504

RESUMO

Extracts of Aesculus hippocastanum (horse chestnut) seed have been used in the treatment of chronic venous insufficiency, edema, and hemorrhoids. Most of the beneficial effects of horse chestnut are attributed to its principal component beta-escin or aescin. Recent studies suggest that beta-escin may possess anti-inflammatory, anti-hyaluronidase, and anti-histamine properties. We have evaluated the chemopreventive efficacy of dietary beta-escin on azoxymethane-induced colonic aberrant crypt foci (ACF). In addition, we analyzed the cell growth inhibitory effects and the induction of apoptosis in HT-29 human colon cancer cell line. To evaluate the inhibitory properties of beta-escin on colonic ACF, 7-week-old male F344 rats were fed experimental diets containing 0%, 0.025%, or 0.05% beta-escin. After 1 week, the rats received s.c. injections of azoxymethane (15 mg/kg body weight, once weekly for 2 weeks) or an equal volume of normal saline (vehicle). Rats were continued on respective experimental diets and sacrificed 8 weeks after the azoxymethane treatment. Colons were evaluated histopathologically for ACF. Administration of dietary 0.025% and 0.05% beta-escin significantly suppressed total colonic ACF formation up to approximately 40% (P < 0.001) and approximately 50% (P < 0.0001), respectively, when compared with control diet group. Importantly, rats fed beta-escin showed dose-dependent inhibition (approximately 49% to 65%, P < 0.0001) of foci containing four or more aberrant crypts. To understand the growth inhibitory effects, HT-29 human colon carcinoma cell lines were treated with various concentrations of beta-escin and analyzed by flow cytometry for apoptosis and cell cycle progression. Beta-escin treatment in HT-29 cells induced growth arrest at the G1-S phase, which was associated with the induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1), and this correlated with reduced phosphorylation of retinoblastoma protein. Results also indicate that beta-escin inhibited growth of colon cancer cells with either wild-type or mutant p53. This novel feature of beta-escin, a triterpene saponin, may be a useful candidate agent for colon cancer chemoprevention and treatment.


Assuntos
Neoplasias do Colo/metabolismo , Neoplasias do Colo/prevenção & controle , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Escina/administração & dosagem , Aesculus/química , Animais , Apoptose/efeitos dos fármacos , Azoximetano/toxicidade , Carcinógenos/toxicidade , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Dieta , Relação Dose-Resposta a Droga , Escina/uso terapêutico , Células HCT116/efeitos dos fármacos , Células HCT116/metabolismo , Células HT29/efeitos dos fármacos , Células HT29/metabolismo , Humanos , Mucosa Intestinal/efeitos dos fármacos , Masculino , Extratos Vegetais , Ratos , Ratos Endogâmicos F344
16.
Mol Cancer Ther ; 5(6): 1530-8, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16818512

RESUMO

Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAID) are promising chemoprevention agents; unlike conventional NSAIDs, they seem free of appreciable adverse effects, while they retain beneficial activities of their parent compounds. Their effect on colon carcinogenesis using carcinoma formation as an end point is unknown. We assessed the chemopreventive properties of NO-indomethacin (NCX 530) and NO-aspirin (NCX 4016) against azoxymethane-induced colon cancer. Seven-week-old male F344 rats were fed control diet, and 1 week later, rats received two weekly s.c. injections of azoxymethane (15 mg/kg body weight). Two weeks after azoxymethane treatment, rats (48 per group) were fed experimental diets containing NO-indomethacin (0, 40, or 80 ppm), or NO-aspirin (1,500 or 3,000 ppm), representing 40% and 80% of the maximum tolerated dose. All rats were killed 48 weeks after azoxymethane treatment and assessed for colon tumor efficacy and molecular changes in colonic tumors and normally appearing colonic mucosa of different dietary groups. Our results suggest that NO-indomethacin at 40 and 80 ppm and NO-aspirin at 3,000 ppm significantly suppressed both tumor incidence (P < 0.01) and multiplicity (P < 0.001). The degree of inhibition was more pronounced with NO-indomethacin at both dose levels (72% and 76% inhibition) than with NO-aspirin (43% and 67%). NO-indomethacin at 40 and 80 ppm and NO-aspirin at 3,000 ppm significantly inhibited the colon tumors' (P < 0.01 to P < 0.001) total cyclooxygenase (COX), including COX-2 activity (52-75% inhibition) and formation of prostaglandin E2 (PGE2), PGF2alpha, and 6-keto-PGF1alpha, and TxB2 from arachidonic acid (53-77% inhibition). Nitric oxide synthase 2 (NOS-2) activity and beta-catenin expression were suppressed in animals given NO-NSAID. In colonic crypts and tumors of animals fed these two NO-NSAIDs, there was a significant decrease in proliferating cell nuclear antigen labeling when compared with animals fed the control diet. The results of this study provide strong evidence that NO-NSAIDs possess strong inhibitory effect against colon carcinogenesis; their effect is associated with suppression of COX and NOS-2 activities and beta-catenin levels in colon tumors. These results pave the way for the rational design of human clinical trials.


Assuntos
Acetatos/administração & dosagem , Antineoplásicos/administração & dosagem , Aspirina/análogos & derivados , Neoplasias do Colo/prevenção & controle , Indóis/administração & dosagem , Animais , Aspirina/administração & dosagem , Azoximetano/toxicidade , Carcinógenos/toxicidade , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dieta , Dinoprostona/metabolismo , Humanos , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Endogâmicos F344 , beta Catenina/metabolismo
17.
Int J Cancer ; 113(5): 798-802, 2005 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-15499611

RESUMO

Epidemiological studies suggest that carotenoids such as beta-carotene and lutein play an important role in reducing the risk for several cancers. However, in colon cancer there is ambiguity with regard to the role of these compounds in that both preventive effects and tumor promotion have been observed. In the present study we observed that male F344 rats were able to tolerate up to 2,500 ppm of beta-carotene as well as of lutein. We have then assessed the chemopreventive efficacy of beta-carotene and lutein at dose levels of approximately 4 and 8% of the 2,500 ppm tolerated dose (TD) and also approximately 40 and 80% of the TD on azoxymethane (AOM)-induced colon carcinogenesis, using aberrant crypt foci (ACF) as a surrogate biomarker for colon cancer. Throughout the experiments, 5-week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing 100 or 200 ppm (approximately 4 or 8% of the 2,500 ppm TD), or 1,000 or 2,000 ppm ( approximately 40 or 80% of the 2,500 ppm TD) of beta-carotene and lutein (n=10 rats/group). After 2 weeks on the experimental or control diets, all animals were injected with AOM (15 mg/kg body wt., once weekly for 2 weeks). At 14 weeks of age, all rats were killed, and their colons were evaluated for ACF. Administration of 100 or 200 ppm of beta-carotene inhibited AOM-induced total colonic ACF formation by 24% (p<0.01) and 36% (p<0.001), respectively, whereas lutein at 200 ppm produced a 27% inhibition (p<0.01) yet had no significant effect at the 100 ppm dose level. Surprisingly, administration of 1,000 or 2,000 ppm of beta-carotene and lutein increased colonic ACF formation in a dose-dependent manner, i.e., to 124% and 144% for the former and 110% and 159% for the latter. These results clearly suggest that further studies are warranted to determine whether the increase in ACF incidence by high doses of beta-carotene and lutein will also lead to an increase in tumor outcome. Taken together these data indicate that the chemopreventive activity of beta-carotene and lutein against colon carcinogenesis depends on the dose level.


Assuntos
Antioxidantes/uso terapêutico , Neoplasias do Colo/prevenção & controle , Luteína/uso terapêutico , Lesões Pré-Cancerosas/prevenção & controle , beta Caroteno/uso terapêutico , Animais , Azoximetano/toxicidade , Carcinógenos/toxicidade , Quimioprevenção , Neoplasias do Colo/induzido quimicamente , Dieta , Relação Dose-Resposta a Droga , Masculino , Lesões Pré-Cancerosas/induzido quimicamente , Ratos , Ratos Endogâmicos F344
18.
Cancer Epidemiol Biomarkers Prev ; 13(8): 1392-8, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15298963

RESUMO

Trigonella foenum graecum (fenugreek) is traditionally used to treat disorders such as diabetes, high cholesterol, wounds, inflammation, and gastrointestinal ailments. Recent studies suggest that fenugreek and its active constituents may possess anticarcinogenic potential. We evaluated the preventive efficacy of dietary fenugreek seed and its major steroidal saponin constituent, diosgenin, on azoxymethane-induced rat colon carcinogenesis during initiation and promotion stages. Preneoplastic colonic lesions or aberrant crypt foci (ACF) were chosen as end points. In addition, we assessed the mechanism of tumor growth inhibition of diosgenin in HT-29 human colon cancer cells. To evaluate the effect of the test agent during the initiation and postinitiation stages, 7-week-old male F344 rats were fed experimental diets containing 0% or 1% fenugreek seed powder (FSP) or 0.05% or 0.1% diosgenin for 1 week and were injected with azoxymethane (15 mg/kg body weight). Effects during the promotional stage were studied by feeding 1% FSP or 0.1% diosgenin 4 weeks after the azoxymethane injections. Rats were sacrificed 8 weeks after azoxymethane injection, and their colons were evaluated for ACF. We found that, by comparison with control, continuous feeding of 1% FSP and 0.05% and 0.1% diosgenin suppressed total colonic ACF up to 32%, 24%, and 42%, respectively (P < or = 0.001 to 0.0001). Dietary FSP at 1% and diosgenin at 0.1% fed only during the promotional stage also inhibited total ACF up to 33% (P < or = 0.001) and 39% (P < or = 0.0001), respectively. Importantly, continuous feeding of 1% FSP or 0.05% or 0.1% diosgenin reduced the number of multicrypt foci by 38%, 20%, and 36% by comparison with the control assay (P < or = 0.001). In addition, 1% FSP or 0.1% diosgenin fed during the promotional stage caused a significant reduction (P < or = 0.001) of multicrypt foci compared with control. Dietary diosgenin at 0.1% and 0.05% inhibited total colonic ACF and multicrypt foci formation in a dose-dependent manner. Results from the in vitro experiments indicated that diosgenin inhibits cell growth and induces apoptosis in the HT-29 human colon cancer cell line in a dose-dependent manner. Furthermore, diosgenin induced apoptosis in HT-29 cells at least in part by inhibition of bcl-2 and by induction of caspase-3 protein expression. On the basis of these findings, the fenugreek constituent diosgenin seems to have potential as a novel colon cancer preventive agent.


Assuntos
Apoptose/efeitos dos fármacos , Diosgenina/farmacologia , Células HT29/efeitos dos fármacos , Extratos Vegetais , Lesões Pré-Cancerosas/tratamento farmacológico , Animais , Apoptose/fisiologia , Azoximetano , Divisão Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/prevenção & controle , Modelos Animais de Doenças , Células HT29/fisiologia , História Pré-Moderna 1451-1600 , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344 , Valores de Referência , Saponinas , Sensibilidade e Especificidade , Trigonella , Células Tumorais Cultivadas
19.
Oncol Rep ; 11(5): 957-63, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15069532

RESUMO

Caveolin-1, -2, and -3 are the principal proteins of caveolae, the vesicular invaginations of the plasma membrane. Recent studies suggest that caveolins play an important role in cellular signaling and, possibly, in tumorigenesis. We examined the expression of the three caveolins in azoxymethane-induced rat colon adenocarcinoma and normal-appearing colonic mucosa, and also in human colon cancer cells with inherently different proliferation rates. Expression of caveolins was assessed in experimental rat colon adenocarcinoma and normal-appearing colonic tissues by RT-PCR, immunoblot and immunohistochemistry. Expression of caveolin-1, -2, and -3 at protein and mRNA levels in human colon cancer cell lines Caco-2, HT-29 and HCT-116 was assessed by immunoblot and RT-PCR, respectively. While caveolin-1 was overexpressed in all experimental adenocarcinoma tissues by comparison to normal-appearing colonic mucosa at both the mRNA and protein level, caveolin-2 was expressed equally only at the mRNA level in both tissues. Immunohistochemical analysis of experimental rat colon tissues also revealed a similar pattern with caveolin-1 being overexpressed in adenocarcinomas as compared to normal-appearing colonic mucosa. Caveolin-1 protein expression was observed in HT-29 and HCT-116 cell lines but not in the Caco-2 cell line or the macrophage Raw 264.7 cell line. Caveolin-1 mRNA expression was evident in all colon carcinoma cell lines tested; however, caveolin-2 mRNA was found only in HT-29 and HCT-116. Caveolin-1 protein and mRNA transcript levels in human colon cancer cell lines were observed to be concordant with the growth rate of the cells, and followed the pattern of HCT-116 > HT-29 > Caco-2. Taken together, our results indicate that caveolin-1 is overexpressed in experimental colon adenocarcinoma by comparison to adjacent normal mucosa, and its expression in human colon cancer cells is directly associated with the growth rate.


Assuntos
Adenocarcinoma/metabolismo , Caveolinas/metabolismo , Neoplasias do Colo/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Experimentais/metabolismo , Adenocarcinoma/genética , Animais , Caveolina 1 , Caveolina 2 , Caveolina 3 , Caveolinas/genética , Divisão Celular , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Humanos , Neoplasias Experimentais/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos
20.
Mol Cancer Ther ; 3(2): 215-21, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14985462

RESUMO

To develop efficient synergistic or additive combinations of chemopreventive and nutritional agents to reduce the risk of colon cancer, experiments were designed to test the application of a selective cyclooxygenase-2 (COX-2) inhibitor together with dietary omega-3 polyunsaturated fatty acids (PUFAs), such as decosahexaenoic acid (DHA). Thus, individual application of celecoxib, a COX-2 inhibitor, DHA, a omega-3 PUFA, and combinations of both were tested for their effectiveness using cell proliferation, apoptosis, and COX-2 expression as markers in the human colon cancer HCA-7 cell line. HCA-7 cells exposed to various subtoxic doses of celecoxib, DHA, or combinations of both were analyzed for inhibition of cell proliferation by trypan blue exclusion and proliferating cell nuclear antigen methods, induction of apoptosis by 4',6-diamidino-2-phenylindole method, and COX-2 by reverse transcription-PCR and Western blot analysis. In addition, we examined the inhibitory potential of celecoxib and DHA on (14)C-arachidonic acid metabolism mediated by COX-2 in the HCA-7 cell line. We found that treatment with celecoxib (50-150 micro M) or DHA (150-225 micro M) individually induces apoptosis and inhibits cell proliferation only at high concentrations in HCA-7 cell lines. A synergistic effect was observed on induction of apoptosis and inhibition of proliferation when cells were exposed to low doses of celecoxib (50-100 micro M) together with DHA (75 micro M). At high concentrations, celecoxib and DHA blocked the increase in COX-2 protein and mRNA expression in HCA-7 cells. Importantly, the inhibition of COX-2 expression was more pronounced in cells treated with low-dose combinations than with individual agents at high concentrations. In addition, celecoxib and DHA at low-dose levels inhibited (14)C-arachidonic acid metabolism (50-85%, P < 0.0001) leading to very low levels of type 2 series prostaglandin formation. These findings provide the basis for the development of combinations of low-dose regimens of a COX-2 inhibitor and omega-3 PUFAs such as DHA for the prevention and treatment of colon cancer. We are currently testing this concept in preclinical models.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/prevenção & controle , Inibidores de Ciclo-Oxigenase/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Sulfonamidas/farmacologia , Apoptose/efeitos dos fármacos , Celecoxib , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Humanos , Proteínas de Membrana , Pirazóis
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