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1.
Oncogene ; 40(38): 5752-5763, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34341513

RESUMO

Expression of ß-crystallin B2 (CRYßB2) is elevated in African American (AA) breast tumors. The underlying mechanisms of CRYßB2-induced malignancy and the association of CRYßB2 protein expression with survival have not yet been described. Here, we report that the expression of CRYßB2 in breast cancer cells increases stemness, growth, and metastasis. Transcriptomics data revealed that CRYßB2 upregulates genes that are functionally associated with unfolded protein response, oxidative phosphorylation, and DNA repair, while down-regulating genes related to apoptosis. CRYßB2 in tumors promotes de-differentiation, an increase in mesenchymal markers and cancer-associated fibroblasts, and enlargement of nucleoli. Proteome microarrays identified a direct interaction between CRYßB2 and the nucleolar protein, nucleolin. CRYßB2 induces nucleolin, leading to the activation of AKT and EGFR signaling. CRISPR studies revealed a dependency on nucleolin for the pro-tumorigenic effects of CRYßB2. Triple-negative breast cancer (TNBC) xenografts with upregulated CRYßB2 are distinctively sensitive to the nucleolin aptamer, AS-1411. Lastly, in AA patients, higher levels of nucleolar CRYßB2 in primary TNBC correlates with decreased survival. In summary, CRYßB2 is upregulated in breast tumors of AA patients and induces oncogenic alterations consistent with an aggressive cancer phenotype. CRYßB2 increases sensitivity to nucleolin inhibitors and may promote breast cancer disparity.


Assuntos
Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima , Cadeia B de beta-Cristalina/metabolismo , Animais , Aptâmeros de Nucleotídeos/administração & dosagem , Aptâmeros de Nucleotídeos/farmacologia , Nucléolo Celular/efeitos dos fármacos , Nucléolo Celular/metabolismo , Nucléolo Celular/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Invasividade Neoplásica , Transplante de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Cadeia B de beta-Cristalina/genética , Nucleolina
2.
Anticancer Res ; 40(12): 6623-6635, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33288557

RESUMO

BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer (BC) and lacks targeted therapy and alternate therapeutic combinations. There is a necessity to increase disease-free survival in patients particularly within the first 5 years of diagnosis. 2,3-dichloro-5,8-dimethoxy-1,4-naphthoquinone (Z285), a novel 1,4 naphthoquinone analog, has been shown to have cytotoxic activity in BC cell lines and in combination with 4-hydroxytamoxifen (4-OHT). A known metabolite of tamoxifen, was postulated to decrease cell proliferation. Thus, this study investigates the use of Z285 and 4-OHT alone or in combination as a novel therapeutic alternative for TNBC. MATERIALS AND METHODS: Cell proliferation assays were performed on MDA-MB-231, Hs578T, MCF7 and HCC1806 cell lines at varying time points with Z285 and 4-OHT alone and in combination. Furthermore, ROS activity was measured to determine the changes in oxidative stress caused by both drugs. RESULTS: The results showed dose- and time-dependent decreases in proliferation for all cell lines when treated with Z285, 4-OHT and their combination. Combinatorial analysis performed at 72 h using Synergyfinder® showed additive effects in MCF7, HCC1806 and Hs578T and an antagonistic response in MDA-MB-231. Z285 caused a significant increase in ROS production in three cell lines after 8 h, but HCC1806 showed no change in effect. CONCLUSION: These promising results suggest the independent ability of each compound as a stand-alone chemotherapeutic agent, or in combinatorial therapy for the treatment of TNBC.


Assuntos
Apoptose/efeitos dos fármacos , Naftoquinonas/farmacologia , Tamoxifeno/análogos & derivados , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Concentração Inibidora 50 , Espécies Reativas de Oxigênio/metabolismo , Tamoxifeno/farmacologia
3.
Cancer Genomics Proteomics ; 17(6): 739-745, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33099475

RESUMO

BACKGROUND: Prostate cancer (PCa) is a multifactorial disease involving complex interactions between genetic and physiological/environmental factors. Vitamin D receptor (VDR) plays a role in numerous cellular pathways and it has been suggested that VDR genetic variants influence individual susceptibility to PCa. MATERIALS AND METHODS: Logistic regression analysis was used to assess the association of six VDR single nucleotide polymorphisms (SNPs) and factors such as tanning potential and UV sunlight exposure with PCa risk. RESULTS: Marginal significant interactions were found, with a 2-fold increase risk of PCa between SNP 1 (c.278-69G>A) and sunlight UV exposure [odds ratio (OR)=2.02, 95% confidence intervaI (CI)=1.036-4.36; p=0.05]; and a 4-fold increase risk of PCa between SNP 4 (c.907+75C>T) and tanning potential (OR=4.40, 95% CI=0.89-29.12; p=0.0591). In contrast, SNP 5 (rs731236, TaqI) and tanning potential interaction had a protective effect by reducing the risk of PCa by 55% (ß=-0.804; OR=0.448, 95% CI=0.197-9.42; p=0.0427). SNPs 2 (rs61614328) and 6 (rs533037428) did not show any association with PCa even in the presence of UV sunlight exposure. CONCLUSION: The protective effect of SNP 4 from PCa is lost and modified by tanning potential in African Americans. This finding needs to be verified by larger studies in different ethnic populations.


Assuntos
Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Receptores de Calcitriol/genética , Banho de Sol/estatística & dados numéricos , Raios Ultravioleta/efeitos adversos , Adulto , Idoso , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/genética , Fatores de Risco
4.
Cancer Genomics Proteomics ; 16(4): 245-255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31243105

RESUMO

BACKGROUND/AIM: Vitamin D receptor (VDR) is present in numerous cellular pathways and it has been suggested that VDR genetic variants influence individual susceptibility to prostate cancer. Also, analyses of single nucleotide polymorphisms (SNPs) in VDR revealed ethnicity-associated polymorphisms. The aim of this study was to identify VDR SNPs in African American men with and without prostate cancer. MATERIALS AND METHODS: The entire VDR gene was screened for germline mutations in a case-control study by denaturing high performance liquid chromatography and DNA sequencing. Logistic regression was used to estimate the association of SNPs, age, family history, and Gleason score with prostate cancer risk. RESULTS: Six SNPs in the non-coding regions, and one SNP in the coding region, were detected. SNP 1 (c.278-69G>A) and SNP 4 (c.907+75C>T) have not been previously reported. SNP 4 had a significant protective effect (ß=-0.6, p<0.05); whereas, SNP 7 (rs7975232) showed an increase association with prostate cancer risk and high Gleason score (ß=0.32, p<0.05). SNP 4, SNP 7 and age were better predictors of prostate cancer risk than family history with a high degree of sensitivity (74.7%) and specificity (92.4%). CONCLUSION: SNP 4 and SNP 7 could be promising markers for prediction of reduced or increased prostate cancer risk, respectively.


Assuntos
Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Receptores de Calcitriol/genética , Negro ou Afro-Americano , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/patologia
5.
ACS Sens ; 3(8): 1510-1521, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-29979037

RESUMO

A high-throughput multiconstriction microfluidic channels device can distinguish human breast cancer cell lines (MDA-MB-231, HCC-1806, MCF-7) from immortalized breast cells (MCF-10A) with a confidence level of ∼81-85% at a rate of 50-70 cells/min based on velocity increment differences through multiconstriction channels aligned in series. The results are likely related to the deformability differences between nonmalignant and malignant breast cells. The data were analyzed by the methods/algorithms of Ridge, nonnegative garrote on kernel machine (NGK), and Lasso using high-dimensional variables, including the cell sizes, velocities, and velocity increments. In kernel learning based methods, the prediction values of 10-fold cross-validations are used to represent the difference between two groups of data, where a value of 100% indicates the two groups are completely distinct and identifiable. The prediction value is used to represent the difference between two groups using the established algorithm classifier from high-dimensional variables. These methods were applied to heterogeneous cell populations prepared using primary tumor and adjacent normal tissue obtained from two patients. Primary breast cancer cells were distinguished from patient-matched adjacent normal cells with a prediction ratio of 70.07%-75.96% by the NGK method. Thus, this high-throughput multiconstriction microfluidic device together with the kernel learning method can be used to perturb and analyze the biomechanical status of cells obtained from small primary tumor biopsy samples. The resultant biomechanical velocity signatures identify malignancy and provide a new marker for evaluation in risk assessment.


Assuntos
Neoplasias da Mama/diagnóstico , Aprendizado de Máquina , Microfluídica/métodos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Tamanho Celular , Feminino , Humanos , Dispositivos Lab-On-A-Chip , Microfluídica/instrumentação
6.
Cancer Genomics Proteomics ; 15(3): 185-191, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29695400

RESUMO

BACKGROUND/AIM: Prostate cancer is the most common malignancy in US males. African American men have higher incidence and mortality rates than European Americans. Five single nucleotide polymorphisms are associated with PCa. We hypothesized haplotypes inferred from these SNPs are also associated with PCa. PATIENTS AND METHODS: We genotyped SNPs in a case-control admixture mapping study. SNP haplotypes inferred for 157 PCa cases and 150 controls were used in the regression analysis. RESULTS: We found an association between "GTCCC", "ATTCT", and "ACCCC" haplotypes and PCa after ancestry adjustment (OR=3.62, 95%CI=1.42-9.21, p=0.0070; OR=7.89, 95%CI=2.36-26.31, p=0.0008; OR=4.34, 95%CI=1.75-10.78, p=0.0016). The rs615382 variant disrupts the recombination signal binding protein with immunoglobulin kappa J binding site in Rac GTPase activating protein 1 (RACGAP1). CONCLUSION: Disruption of notch 1 mediated-repression of RACGAP1 may contribute to PCa in African Americans.


Assuntos
Negro ou Afro-Americano/genética , Mapeamento Cromossômico/métodos , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Receptor Notch1/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/patologia
7.
BMC Cancer ; 18(1): 274, 2018 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-29523126

RESUMO

BACKGROUND: MYC overexpression is associated with poor prognosis in breast tumors (BCa). The objective of this study was to determine the prevalence of MYC amplification and associated markers in BCa tumors from African American (AA) women and determine the associations between MYC amplification and clinico-pathological characteristics. METHODS: We analyzed 70 cases of well characterized archival breast ductal carcinoma specimens from AA women for MYC oncogene amplification. Utilizing immune histochemical analysis estrogen receptor (ER), progesterone receptor (PR), and (HER2/neu), were assessed. Cases were Luminal A (ER or PR+, Ki-67 < 14%), Luminal B (ER or PR+, Ki-67 = > 14% or ER or PR+ HER2+), HER2 (ER-, PR-, HER2+), and Triple Negative (ER-, PR-, HER2-) with basal-like phenotype. The relationship between MYC amplification and prognostic clinico-pathological characteristics was determined using chi square and logistic regression modeling. RESULTS: Sixty-five (97%) of the tumors showed MYC gene amplification (MYC: CEP8 > 1). Statistically significant associations were found between MYC amplification and HER2-amplified BCa, and Luminal B subtypes of BCa (p < 0.0001), stage (p < 0.001), metastasis (p < 0.001), and positive lymph node status (p = 0.039). MYC amplification was associated with HER2 status (p = 0.01) and tumor size (p = 0.01). High MYC amplification was seen in grade III carcinomas (MYC: CEP8 = 2.42), pre-menopausal women (MYC: CEP8 = 2.49), PR-negative status (MYC: CEP8 = 2.42), and ER-positive status (MYC: CEP8 = 2.4). CONCLUSIONS: HER2 positive BCas in AA women are likely to exhibit MYC amplification. High amplification ratios suggest that MYC drives HER2 amplification, especially in HER2 positive, Luminal B, and subtypes of BCa.


Assuntos
Negro ou Afro-Americano/genética , Neoplasias da Mama/genética , Amplificação de Genes , Proteínas Proto-Oncogênicas c-myc/genética , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos
8.
Cancer Genomics Proteomics ; 14(6): 461-467, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29109096

RESUMO

BACKGROUND/AIM: Denaturing high-performance liquid chromatography (DHPLC) is a technique that is used to detect mutations. The aim of the present study was to determine whether DHPLC elution patterns of vitamin D receptor (VDR) gene PCR products can serve as indicators of susceptibility to prostate cancer (PCa) risk. MATERIALS AND METHODS: DNA samples of PCa cases and controls were screened for mutations and/or polymorphisms in coding exons of VDR gene using DHPLC analysis. Logistic regression, phi-coefficient (ϕ), and Backward Wald models were used to analyze the data. RESULTS: Similar elution patterns of exons 1, 6, 7 and 9 along with higher prevalence of heteroduplex DNA were observed in PCa samples than in controls. Exons 4 and 8 had highly significant protective effects (p<0.05). Whereas, exons 5, 7, and 9 were perfectly positively correlated with PCa risk (ϕ=1), thus presenting candidate exons significantly associated with susceptibility to PCa. CONCLUSION: DHPLC elution patterns of the selected exons could be useful to predict susceptibility to develop PCa.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Reação em Cadeia da Polimerase/métodos , Receptores de Calcitriol/genética , Adulto , Negro ou Afro-Americano , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
9.
In Vivo ; 31(4): 661-668, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28652435

RESUMO

BACKGROUND/AIMS: Breast cancer (BCa) prognostication is a vital element for providing effective treatment for patients with BCa. Studies suggest that ethnicity plays a greater role in the incidence and poor prognosis of BCa in younger women than in their older counterparts. Therefore, the goal of this study was to assess the association between age and ethnicity on the overall final prognosis. MATERIALS AND METHODS: Nottingham Prognostic Index (NPI) was used to analyze BCa prognosis using Howard University Cancer Center Tumor Registry and the National Cancer Institute's Surveillance, Epidemiology, and End Results BCa datasets. Patients were grouped according to their predicted prognosis based on NPI scheme. RESULTS: There was no correlation between the younger patients compared to their older counterparts for any of the prognostic clusters. The significance of ethnicity in poorer prognosis for younger age is not conclusive either. CONCLUSION: An extended prognostic tool/system needs to be evaluated for its usefulness in a clinical practice environment.


Assuntos
Fatores Etários , Neoplasias da Mama/epidemiologia , Etnicidade , Prognóstico , Adulto , Negro ou Afro-Americano , Idoso , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , População Branca/genética
10.
Clin Breast Cancer ; 17(3): 232-238, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28189497

RESUMO

BACKGROUND: Triple negative breast cancer (TNBC) tumors are estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor-negative. TNBC is responsive to chemotherapy, but chemotherapy might be underused in some patient subgroups. The goal of the present study was to characterize the patterns of chemotherapy use (uptake and completion) in TNBC patients. PATIENTS AND METHODS: Women with primary invasive, nonmetastatic breast cancer were recruited in Washington, DC, and Detroit. Data were collected using a standardized telephone survey that captured sociocultural and health care process factors. Clinical data were abstracted from the medical records. We used χ2 tests to access the association between the receipt of chemotherapy use (initiation and completion) and categorical variables, and t tests were used for continuous variables. Logistic regression models were used to evaluate the factors associated with chemotherapy uptake. RESULTS: Women with TNBC (16% of sample) were more likely to be black than white (68% vs. 32%; P < .05). Among women with TNBC, 60% underwent chemotherapy. Chemotherapy uptake was greater for black than for white women (48.3% vs. 11.7%; P = .01) and in women without (vs. with) healthcare discrimination (35% vs. 25%; P = .04). In multivariable models, only race was associated with the receipt of chemotherapy. Black women were more likely to receive chemotherapy than were white women. The odds ratio of receiving chemotherapy by race was 4.1 (95% confidence interval, 1.3-13.1). Each 1-year increase in age was associated with a lower likelihood of chemotherapy completion (odds ratio, 0.9; 95% confidence interval, 0.826-0.981; P = .02). Women with at least some college were less likely to complete chemotherapy than were those with other education levels (P = .02). CONCLUSION: A substantial number of TNBC patients failed to receive and/or complete chemotherapy. Differences in chemotherapy uptake by race and sociocultural factors diminished in multivariable models but age and stage remained significant. Suboptimal treatment among women with TNBC could contribute to adverse outcomes. Future investigations are necessary to assess whether the noninitiation and/or noncompletion of chemotherapy is clinically warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Negro ou Afro-Americano/estatística & dados numéricos , Neoplasias de Mama Triplo Negativas/etnologia , População Branca/estatística & dados numéricos , Biomarcadores Tumorais/metabolismo , Quimioterapia Adjuvante , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
11.
Anticancer Res ; 35(9): 4723-32, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26254362

RESUMO

BACKGROUND/AIM: Prostate cancer is one of the leading causes of death in American males. Emetine, a naturally-derived alkaloid from the Ipecacuanha plant, has been shown to have potential for anti-tumorigenic effects for cancer treatments. The objective of this study was to characterize novel emetine dithiocarbamate (EMTDTC) analogs for potent anti-tumorigenic activity with minimal toxicity to normal prostate cells and identify targeted apoptotic regulatory genes. The leading key compounds, EMTDTC-55 and EMTDTC-56 were studied. MATERIALS AND METHODS: Established methods of cell flow cytometry were used to analyze apoptotic potential in prostate cancer cell lines (DU145, PC3 and LNCaP) and real time-polymerase chain reaction (PCR) for identifying key genes mediating apoptosis. RESULTS: The effect of EMTDTC-55 on DU145, LNCaP and PC3 revealed significant anti-tumorigenic activities. Both compounds showed highly significant apoptotic potential on days 3 and 5 in the prostate cancer cells. Key apoptotic genes were differentially regulated suggestive of cell-cycle arrest and apoptotic induction in androgen-independent cell lines, DU145 and PC3, by both compounds. However, in the androgen-dependent cell line LNCaP, cells were marginally affected by EMTDTC-55, but significant apoptosis was observed by EMTDTC-56 leading to cell-cycle arrest. CONCLUSION: Both dithiocarbamate compounds EMTDTC-55 and EMTDTC-56 have significant chemotherapeutic potential in moderately metastatic DU145 and highly metastatic PC3 cells.


Assuntos
Apoptose/efeitos dos fármacos , Ditiocarb/análogos & derivados , Ditiocarb/farmacologia , Emetina/farmacologia , Neoplasias da Próstata/patologia , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Neoplasias da Próstata/genética
12.
Anticancer Res ; 35(7): 3811-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26124326

RESUMO

BACKGROUND/AIM: Several studies reported that patients with benign prostatic hyperplasia (BPH) experienced a 10% increased incidence of prostate cancer (PCa) after the first 5 years of diagnosis. We investigated the association between single nucleotide polymorphisms (SNPs) in the promoter of Serine Protease Inhibitor Kazal Type 1 (SPINK1) and the increased risk of BPH and PCa. MATERIALS AND METHODS: We genotyped three SNPs in a cases-control study, including BPH and PCa cases. Multiple logistic regression models were applied to analyze clinical and genotypic data. RESULTS: We found an inverse association between SNP rs10035432 and BPH under the log-additive (p=0.007) model. No association was found between these SNPs and PCa risk. However, we observed a possible association between rs1432982 and lower-grade PCa (p=0.05) under the recessive model. CONCLUSION: SPINK1 promoter variants are likely to be associated with the risk of BPH.


Assuntos
Proteínas de Transporte/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/genética , Risco , Inibidor da Tripsina Pancreática de Kazal
13.
Anticancer Res ; 35(3): 1453-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25750297

RESUMO

BACKGROUND/AIM: Roots of Fagara zanthoxyloides and Pseudocedrela kotchyii are used as chewing sticks and as medicinal remedies for diarrhea, cough and fever in West Africa. Extracts of the two plants also possess anti-bacterial, anti-fungal and anti-malarial activities. The aim of the present study was to determine the effects of such extracts on the growth, proliferation and induction of apoptosis in four prostate cancer cell lines. Materials and Methods. Androgen-independent PC3 and DU-145 and androgen-dependent LNCaP and CWR-22 prostate cancer cell lines were cultured for five days with different concentrations of the extracts and examined for growth inhibition and evidence of apoptosis. RESULTS: Irrespective of their androgen dependence, all four cancer cell lines exhibited a dose-dependent decrease in cell proliferation and viability by the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide (MTT) assay and in induction of apoptosis. The results also show that LNCap cells were the most sensitive to the two extracts, with highest inhibition at day 3 and exhibiting the highest rate of apoptosis. Conclusion. These observations suggest that F. zanthoxyloides and P. kotchyii could serve as potential chemopreventive agents in the treatment of prostate cancer.


Assuntos
Extratos Vegetais/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Zanthoxylum , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Fitoterapia , Raízes de Plantas , Neoplasias da Próstata/patologia
14.
Anticancer Res ; 35(3): 1549-58, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25750310

RESUMO

BACKGROUND/AIM: Several studies have revealed an association between single nucleotide polymorphisms (SNPs) in the VDR gene and prostate cancer (PCa) risk in European and Asian populations. To investigate whether VDR SNPs are associated with PCa risk in African-American (AA) men, nine VDR SNPs were analyzed in a case-control study. MATERIALS AND METHODS: Multiple and binary logistic regression models were applied to analyze the clinical and genotypic data. RESULTS: rs731236 and rs7975232 were significantly associated with PCa risk (p<0.05). In the analysis of clinical phenotypes, rs731236, rs1544410 and rs3782905 were strongly associated with high PSA level (p<0.05), whereas rs1544410 and rs2239185 showed a statistically significant association with high Gleason score (p<0.05). Haplotype analysis revealed several VDR haplotypes associated with PCa risk. Additionally, a trend existed, where as the number of risk alleles increased in the haplotype, the greater was the association with risk (p-trend=0.01). CONCLUSION: These results suggest that the VDR SNPs may be associated with PCa risk and other clinical phenotypes of PCa in AA men.


Assuntos
Negro ou Afro-Americano/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/genética , Receptores de Calcitriol/genética , Idoso , Estudos de Casos e Controles , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Risco
15.
In Vivo ; 28(6): 1181-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25398820

RESUMO

BACKGROUND/AIM: Vitamin D deficiency in African-Americans is common due to the high melanin content of the skin that reduces the absorption of UV radiation. To determine if there is a correlation between UV exposure, tanning potential and vitamin D with prostate cancer (PC) risk, we conducted a case-control study of 183 African-American men aged 40 years and older residing in the Washington, DC area. PATIENTS AND METHODS: PC status was described as a binary variable as the presence or absence of cancer and the environmental factors as continuous variables. We used a logistic regression model describing PC as the response, while age, tanning potential, sunlight and vitamin D were treated as the predictors. RESULTS: Men aged 60 years and older had a seven-fold increased risk for developing PC compared to those aged 50 years and less (p<0.003). Tanning potential was a significant (p=0.05) risk factor for PC, while sunlight exposure and vitamin D were not. Tanning potential was also significant (p=0.044) when adjusted for vitamin D and age. However, tanning potential was only marginally significant when adjusted for sunlight exposure (p=0.064) CONCLUSION: The findings of this study indicate that tanning potential may be a predictor for PC risk in African-American men.


Assuntos
Negro ou Afro-Americano , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/etiologia , Bronzeado , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Luz Solar , Raios Ultravioleta , Vitamina D/sangue , Vitamina D/metabolismo
16.
Cancer Genomics Proteomics ; 11(6): 279-94, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25422359

RESUMO

Expression of estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) can subdivide breast carcinomas into clinically meaningful classes. Cancers lacking expression of all three of these receptors (triple-negative breast cancer; TNBC) is of particular interest for molecular research because these tumors currently have no effective targets for therapy. Furthermore, TNBCs are relatively more prevalent among African-American women and can account for some of the health disparities associated with breast cancer. We approached a molecular understanding of how TNBC differs from ER(+) breast cancer through a comprehensive gas chromatography (GC)-mass spectrometry (MS) and liquid chromatography (LC)/MS/MS-based and unbiased metabolomic analysis of a series of breast carcinomas from African-American patients. Remarkably, global metabolomic profiling of tumor tissues identified a total of 418 distinct metabolites, out of which 133 (31.8%) were shown to differ between the ER(+) and TNBC tumors with statistical probability of p<0.05. Specific biochemical pathways affected included those reflecting general increases in energy metabolism and transmethylation in the TNBC tumors when compared to ER(+) tumors. Additionally, biochemicals associated with increased proliferation, redox balance and the recently proposed oncometabolites, sarcosine and 2-hydroxyglutarate, were also detected at higher levels in the TNBC versus ER(+) tumors. These studies demonstrate that TNBC tumors have metabolic signatures that distinguish them from ER(+) tumors and suggest that distinctive metabolic characteristics of these tumors might offer new targets for treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Negro ou Afro-Americano , Metabolômica/métodos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Aminoácidos/metabolismo , Dipeptídeos/metabolismo , Metabolismo Energético , Feminino , Glutationa/metabolismo , Humanos , Redes e Vias Metabólicas , Metaboloma , Metilação , Pessoa de Meia-Idade , NAD/metabolismo , Invasividade Neoplásica , Oxirredução
17.
J Clin Pathol ; 67(2): 153-60, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23986556

RESUMO

BACKGROUND: Fascin, an actin bundling protein, plays a critical role in cell motility due to formation of actin rich protrusions called filopodia, important in cell migration, invasion and metastatic spread. Fascin overexpression has been associated with epithelial to mesenchymal transition and correlates with progression and unfavourable prognosis in breast carcinoma. OBJECTIVE: To evaluate fascin expression by immunohistochemistry and correlate the expression pattern with clinicopathological parameters in breast cancer in African-American (AA) women, in whom triple negative breast cancer (TNBC), an aggressive subtype, is more prevalent. METHODS: Tissue microarrays were constructed from formalin-fixed, paraffin-embedded blocks of tumour tissue from primary breast carcinomas in 202 AA women. Immunohistochemical detection of fascin was correlated with four major subtypes of breast carcinoma (luminal A, luminal B, human epidermal growth factor receptor 2 and triple negative (TN)) and other clinicopathological factors, including age, grade, tumour size, stage, regional lymph node status and survival. RESULTS: We observed a significant association between fascin expression and TN subtype, oestrogen receptor (ER) negativity, progesterone receptor (PR) negativity, Elston-Nottingham (EN) grade 3 and decreased overall survival. There was also a significant association between expression of CK 5/6, a marker of basal-like phenotype, and fascin expression. CONCLUSION: These results suggest that fascin is a marker for TN subtype having a basal-like phenotype and decreased overall survival. Fascin may represent a target for therapy in TNBC in AA women.


Assuntos
Carcinoma Ductal de Mama/metabolismo , Proteínas de Transporte/biossíntese , Proteínas dos Microfilamentos/biossíntese , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Negro ou Afro-Americano , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Proteínas de Transporte/análise , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Proteínas dos Microfilamentos/análise , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Análise Serial de Tecidos , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
18.
Anticancer Res ; 30(2): 519-27, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20332464

RESUMO

BACKGROUND: Worldwide among men, prostate cancer ranks third in cancer occurrence and sixth in cancer mortality. A number of 1, 4-naphthoquinone derivatives have been identified that possess significant pharmacological effects associated with antitumor activities. In this study, the in vitro effects of N-(3-chloro-1,4-dioxo 1,4-dihydro-naphthalen-2-yl)-benzamide (NCDDNB) were evaluated on androgen-dependent (CWR-22) and androgen-independent (PC-3, DU-145) human prostate cancer cell lines, and on a normal bone marrow cell line (HS-5). Specifically, the in vitro activity of this compound on cell cycle regulation and apoptosis was evaluated. MATERIALS AND METHODS: Established methods of cell viability, cell cycle, Western blot and apoptosis were used. RESULTS: The effect of NCDDNB on CWR-22, PC-3, DU-145 and HS-5 cells revealed significant anti-tumor activities with IC(50)s, of 2.5, 2.5, 6.5, and 25 muM respectively. The results of cell cycle analysis showed that NCDDNB arrested PC-3, DU-145, and CWR-22 cells in the G(1)-phase of the cell cycle. The compound showed no effect on the cell cycle progression in the HS-5 bone marrow cell line. These findings were further validated using Western blot analysis. NCDDNB showed the greatest amount of apoptosis in the androgen-independent PC-3 cells in a time-dependent manner with the apoptotic apex at day 5 of treatment. Furthermore, NCDDNB induced-apoptosis in DU-145 and CWR-22 cells peaked at day 3 of treatment. CONCLUSION: Although the mechanism of action of this compound has not been completely elucidated, the effect on the cell cycle and the induction of apoptosis in different prostate cancer cell lines prompted us to carry out a more in-depth preclinical evaluation. This study suggests that NCDDNB may have an impact on treatment of prostate cancer while protecting the bone marrow.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzamidas/toxicidade , Proliferação de Células/efeitos dos fármacos , Naftoquinonas/toxicidade , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos/síntese química , Benzamidas/síntese química , Western Blotting , Ciclo Celular/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Humanos , Técnicas Imunoenzimáticas , Masculino , Naftoquinonas/síntese química , Neoplasias Hormônio-Dependentes/patologia , Neoplasias da Próstata/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
19.
Anticancer Res ; 29(1): 191-9, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19331150

RESUMO

BACKGROUND: Breast cancer is the most frequent cancer and the second leading cause of cancer deaths in women today. A number of 1,4-naphthoquinone derivatives have been found to possess significant pharmacological effects associated with marked antimicrobial and antitumor activities. In the present study, the in vitro effect of 2,3-dichloro-5,8-dimethoxy-1,4-naphthoquinone (DCDMNQ) was evaluated on estrogen-positive MCF-7 and estrogen-negative MDA-MB-436 and Hs-578T human breast cancer cell lines. Moreover, the in vitro activity of this compound on cell cycle regulation and apoptosis were evaluated. MATERIALS AND METHODS: Established methods of cell viability, cell cycle, Western blot and apoptosis were used. RESULTS: The effect of DCDMNQ on MCF-7, MDA-MB-436 and Hs-578T cells revealed significant antitumor activities with IC(50)s, of 0.6 +/- 0.02, 1.4 +/- 0.25 and 3.1 +/- 0.4 microM respectively. Cell cycle analysis showed that DCDMNQ inhibited progression through the cell cycle in MCF-7 and MDA-MB-436 cell lines in a time-dependent manner. DCDMNQ arrested cells in the S-phase of the cell cycle with the greatest proportion of cells in the S-phase by day 5. This cell-cycle arrest was corroborated by inhibition of topoisomerase I induced by DCDMNQ. These findings were further validated using Western blot analysis of retinoblastoma protein time-dependent phosphorylation. Furthermore, DCDMNQ induced apoptosis in both estrogen-positive and -negative cell lines in a time-dependent manner. However, the highest percentages of apoptotic cells were observed in the MDA-MB-436 cell line. CONCLUSION: Although the mechanism of action of DCDMNQ has not been completely elucidated, it appears that this compound can inhibit topoisomerase I in a concentration-dependent manner. These promising results to explore novel naphthoquinone analogues as potential breast cancer agents. This study suggests that DCDMNQ may have an impact on treatment of estrogen-positive and -negative breast cancer while protecting the bone marrow.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Naftoquinonas/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Citometria de Fluxo , Humanos , Inibidores da Topoisomerase I
20.
Anticancer Res ; 27(3B): 1537-46, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17595773

RESUMO

BACKGROUND: Prostate cancer ranks third worldwide in cancer incidence and sixth in cancer mortality among men. A number of 1,4-naphthoquinone derivatives have been found to possess significant pharmacological effects associated with marked antimicrobial and antitumor activities. In the present study the in vitro effect of 2,3-dichloro-5,8-dimethoxy-1,4-naphthoquinone (DCDMNQ) was evaluated on androgen-dependent (LNCaP, CWR-22) and androgen-independent (PC-3. DU-145) human prostate cancer cell lines, and/or a normal bone marrow cell line (HS-5). Moreover, the in vitro activity of this compound on cell cycle regulation and apoptosis was evaluated. MATERIALS AND METHODS: Established methods of cell viability, cell cycle, Western blot and apoptosis were used. RESULTS: The effect of DCDMNQ on LNCaP, CWR-22, PC-3, DU-145 and HS-5 cells revealed significant anti-tumor activities with IC50s, of 1, 3. 1.5, 3 and 10 microM respectively. Cell cycle analysis showed that DCDMNQ inhibited progression through the cell cycle in PC-3 and DU-145 cell lines in a time-dependent manner. The result for the CWR-22 cell line showed that DCDMNQ arrested cells in the G -phase of the cell cycle with the greatest proportion of cells in the G1-phase by day 5; however, the LNCaP cell line was inconsistent. The compound showed no effect on the cell cycle progression in the bone marrow HS-5 cell line. These findings were further validated using Western blot analysis. Furthermore, DCDMNQ induced apoptosis in the androgen-independent cells, preferentially over that of the androgen-dependent cell lines, in a time-dependent manner. CONCLUSION: Although the mechanism of action of this compound has not been completely elucidated, the effect on the cell cycle and the induction of apoptosis in different prostate cancer cell lines prompted us to carry out a more in-depth preclinical evaluation of it. This study suggests that DCDMNQ may have an impact on treatment of prostate cancer while protecting the bone marrow.


Assuntos
Androgênios/metabolismo , Antineoplásicos/farmacologia , Naftoquinonas/farmacologia , Neoplasias da Próstata/metabolismo , Apoptose , Western Blotting , Células da Medula Óssea/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Humanos , Concentração Inibidora 50 , Masculino , Proteína do Retinoblastoma/análise , Proteína do Retinoblastoma/metabolismo
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