异黄酮对前列腺癌细胞的激素受体基因表达的影响

[目的] 通过大豆异黄酮的活性物质染料木黄酮和大豆苷元抑制前列腺癌PG-3和LNCaP细胞增殖和对激素基因表达的影响，探讨大豆异黄酮治疗和预防前列腺癌的可能机制。[方法] 0、10、20、40、60、80和160μmol／L剂量组的染料木黄酮和大豆苷元处理前列腺癌细胞，细胞存活率用MTT方法检测，α雌激素受体(ERα)、β雌激素受体(ERβ)、雄激素受体(AR)和血管上皮生长因子(VEGF)等基因的mRNA表达用RT-PCR进行检测。[结果] 染料木黄酮和大豆苷元对PC-3、LNCaP细胞具有明显的抑制生长作用，在160μmol／L的浓度时，染料木黄酮、大豆苷元作用72h后，PC-3细胞的存活率分别为12．28％和44．88％，LNCaP细胞的存活率分别为25．48％和43．14％，其抑制效应具有时间和剂量依赖性，同时发现对．PC-3细胞的VEGF、ERα和ERβ基因表达下调，AR基因处理前后没有检测到；对LNCaP细胞的VEGF和AR基因表达下调，ERα和ERβ的表达并无影响。[结论] 大豆异黄酮能抑制前列腺癌细胞的增殖效应，存在时间和剂量效应关系，雌激素受体基因可能直接在大豆苷元抑制PC-3细胞的增殖中参与作用，而染料木黄酮抑制PC-3细胞和染料木黄酮及大豆苷元抑制LNCaP细胞可能主要是通过Akt通路影响VEGF和AR等基因而实现。     

Omega-3 Fatty Acid Inhibition of Prostate Cancer Progression to Hormone Independence Is Associated With Suppression of mTOR Signaling and Androgen Receptor Expression

Currently, progression of prostate cancer to androgen independence remains the primary obstacle to improved survival. In order to improve overall survival, novel treatment strategies that are based upon specific molecular mechanisms that prolong the androgen-dependent state and that are useful for androgen-independent disease need to be identified. Both epidemiological as well as preclinical data suggest that omega-3 fatty acids are effective primary tumor prevention agents; however, their efficacy at preventing and treating refractory prostate cancer has not been as thoroughly investigated. We used an in vitro model of androgen ablation to determine the effect of treatment with omega-3 fatty acids on the progression to an androgen-independent state. The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were able to prevent progression of LNCaP cells while the omega-6 fatty acid arachidonic acid (AA) actually promoted cell growth under conditions of hormone depletion. These results correlated with a decrease in the expression of the androgen receptor as well as suppression of the Akt/mTOR signaling pathway. Connecting the mechanisms by which omega-3 fatty acids affect phenotypic outcome is important for effective exploitation of these nutrient agents as a therapeutic approach. Understanding these processes is critical for the development of effective dietary intervention strategies that improve overall survival.     

雄激素受体在雄性激素源性脱发患者的表达观察

目的：了解雄激素受体（AR）在雄性激素源性脱发（AGA）患者顶部表皮、毛囊、皮脂腺、汗腺中的表达情况。方法：选取26例雄性激素源性脱发患者顶部、枕部以及10例非脱发者的顶部头皮标本,用免疫组织化学检测表皮、毛囊、皮脂腺、汗腺中AR的表达。结果：脱发患者头顶部毛囊、皮脂腺、汗腺AR表达均明显强于枕部和非脱发者枕部,差异均有统计学意义（P〈0.05）;脱发患者枕部毛囊、皮脂腺、汗腺AR表达与非脱发者顶部AR表达比较差异均无统计学意义（P〉0.05）;所有标本表皮中AR均为阴性。结论：AR在AGA患者头顶部毛囊、皮脂腺、汗腺的高表达,可能是AGA重要原因之一。     

雄激素及其受体在前列腺癌发生发展中的作用

前列腺发生于泌尿生殖窦上皮 ,是雄激素依赖的器官。雄激素及其受体在前列腺的发生、生长、分化和功能的维持上起着重要的作用。雄激素 (Ｔ)主要由睾丸间质细胞 (ＬｅｙｄｉｇＣｅｌｌ)合成、分泌 ,通过 5α 还原酶 (主要是Ⅱ型 )的作用能转化成更具生物活性的脱氢睾酮 (ＤＨＴ)。除了睾丸 ,肾上腺也能分泌一定量的无活性的甾类激素前体物质如脱氢 (表 )雄甾酮 (ＤＨＥＡ)和雄甾烯二酮等。这些前体物质能在许多组织包括前列腺中被转化生成Ｔ。这些肾上腺来源的雄激素在前列腺及前列腺癌的发生、发展中起到什么作用目前尚未见相关报道。1　前…     

Health-Related Quality of Life and Health Utilities in Metastatic Castrate-Resistant Prostate Cancer: A Survey Capturing Experiences from a Diverse Sample of UK Patients

BackgroundThe collection of preference-based health outcomes data (or utility values) is required to support cost-effectiveness analyses.ObjectiveThis study aimed to collect health-related quality of life (HRQOL) data in men with metastatic castration-resistant prostate cancer (CRPC) stratified by disease states.MethodsMen with metastatic CRPC were recruited via UK patient associations, patient panels, and specialist recruiters and classified into four subgroups reflecting disease state: asymptomatic/mildly symptomatic before chemotherapy, symptomatic before chemotherapy, receiving chemotherapy, and postchemotherapy. HRQOL data (including five-level EuroQol five-dimensional questionnaire [EQ-5D-5L], European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire [EORTC QLQ-C30], and 25-item prostate cancer–specific questionnaire module designed to supplement the EORTC QLQ-C30) along with background and medical history data were collected via an online survey. The EQ-5D-5L and the EORTC-8D (EORTC-8D is an 8 dimensional utility index scored from QLQ-C30 data) were both used to estimate utilities.ResultsData were collected from a total sample of 163 men with metastatic CRPC. Utility values elicited by the EQ-5D-5L ranged from 0.830 for the asymptomatic/mildly symptomatic before chemotherapy disease state (95% confidence interval [CI] 0.795–0.865) to 0.625 for the symptomatic before chemotherapy disease state (95% CI 0.577–0.673). EORTC-8D utilities ranged from 0.856 (95% CI 0.831–0.882) to 0.697 (95% CI 0.664–0.731) for the same disease/treatment states.ConclusionsThis online survey was designed to capture real-world HRQOL data describing men with CRPC. The study estimated utilities using two alternative methods, and the results show good agreement, suggesting that they are robust. This methodology offers a potentially higher quality alternative to vignette-based methods that are commonly used in oncology submissions.     

Effects of Naturally Occurring and Synthetic Organoselenium Compounds on Protein Profiling in Androgen Responsive and Androgen Independent Human Prostate Cancer Cells

Prostate cancer represents a major clinical public health challenge. Both epidemiological and clinical intervention studies support the protective role of selenium against development of prostate cancer. However, the mechanisms responsible for the inhibitory activity by this micronutrient remain elusive. Furthermore, literature reports consistently have shown that the dose and form of selenium are important factors in cancer chemoprevention. Thus, in the present investigation using androgen responsive (AR) lymph node carcinoma of the prostate (LNCaP) and its androgen-independent clone (AI) LNCaP C4-2 human prostate cancer cells, we compared the effects of selenomethionine (SM) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC) on cell growth, DNA synthesis, and on proteomic profiles. p-XSC (5–20 μ M) significantly inhibited cell growth in both cell types in a dose-dependent manner; SM was also effective but at much higher doses (50–100 μ M). We hypothesize that the inhibition of cell growth is due, in part, to selenium interaction with redox-sensitive proteins. Using 2D gel electrophoresis, both organoselenium compounds altered the expression, to a varied extent, of several unrecognized selenium-responsive proteins. Employing matrix-assisted laser-desorption ionization (MALDI) and time-of-flight (TOF; MALDI-TOF) followed by tandem mass spectrometric analysis, we identified the following proteins: cofilin-2, heterogeneous nuclear ribonucleoprotein, single-stranded mitochondrial DNA binding protein, chaperonin 10, nucleoside diphosphate kinase 6, and chain A Horf 6 human peroxidase enzyme. This is the first report showing that SM and p-XSC are capable of altering these proteins; their roles in prostate cancer prevention warrant further investigations.     

Magnolol Causes Alterations in the Cell Cycle in Androgen Insensitive Human Prostate Cancer Cells In Vitro by Affecting Expression of Key Cell Cycle Regulatory Proteins

Prostate cancer, one of the most common cancers in the Western world, affects many men worldwide. This study investigated the effects of magnolol, a compound found in the roots and bark of the magnolia tree Magnolia officinalis, on the behavior of 2 androgen insensitive human prostate cancer cell lines, DU145 and PC3, in vitro. Magnolol, in a 24-h exposure at 40 and 80 μM, was found to be cytotoxic to cells. Magnolol also affected cell cycle progression of DU145 and PC3 cells, resulting in alterations to the cell cycle and subsequently decreasing the proportion of cells entering the G₂/M-phase of the cell cycle. Magnolol inhibited the expression of cell cycle regulatory proteins including cyclins A, B1, D1, and E, as well as CDK2 and CDK4. Protein expression levels of pRBp107 decreased and pRBp130 protein expression levels increased in response to magnolol exposure, whereas p16^INK4a, p21, and p27 protein expression levels were apparently unchanged post 24-h exposure. Magnolol exposure at 6 h did increase p27 protein expression levels. This study has demonstrated that magnolol can alter the behavior of androgen insensitive human prostate cancer cells in vitro and suggests that magnolol may have potential as a novel anti-prostate cancer agent.     

Hepatic Vitamin A Preloading Reduces Colorectal Cancer Metastatic Multiplicity in a Mouse Xenograft Model

Previous research in our laboratory showed that retinol inhibited all-trans retinoic acid (ATRA)-resistant human colon cancer cell invasion via a retinoic acid receptor-independent mechanism in vitro. The objective of the current study was to determine if dietary vitamin A supplementation inhibited metastasis of ATRA-resistant colon cancer cells in a nude mouse xenograft model. Female nude mice (BALB/cAnNCr-nu/nu, n = 14 per group) consumed a control diet (2,400 IU retinyl palmitate/kg diet) or a vitamin A supplemented diet (200,000 IU retinyl palmitate/kg diet) for 1 mo prior to tumor cell injection to preload the liver with vitamin A. HCT-116, ATRA-resistant, human colon cancer cells were intrasplenically injected. Mice continued to consume their respective diets for 5 wk following surgery. Consumption of supplemental vitamin A decreased hepatic metastatic multiplicity to 17% of control. Hepatic and splenic retinol and retinyl ester concentrations were significantly higher in the mice supplemented with vitamin A when compared to mice consuming the control diet. Supplemental vitamin A did not decrease body weight, feed intake, or cause toxicity. Thus, supplemental dietary vitamin A may decrease the overall number of hepatic metastasis resulting from colon cancer.     

单纯去势和完全雄激素阻断治疗晚期前列腺癌的对比分析

目的 对单纯去势以及完全雄激素阻断在晚期前列腺癌的临床效果进行分析和比较.方法 以我院在2008年1月到2012年1月收治的50例晚期前列腺癌患者为研究对象,采用随机分配的方法分为对照组和实验组各25例,对照组在临床上主要采用单纯去势进行治疗,实验组在临床上主要采用完全雄性激素阻断进行治疗.对两组患者的临床治疗效果进行比较.结果 两组患者在总体平均疾病特异性生存时间即DSS以及疾病无进展生存时间即PFS的比较上,P＞0.05,在无转移的晚期前列癌患者中,进行单纯去势治疗的患者与完全雄性激素阻断治疗的患者在DSS和PFS比较上,P＜0.05.对于有转移的晚期前列腺癌患者中,进行完全雄性激素阻断治疗的患者与单纯去势治疗的患者在PFS的比较上,P＜0.05.完全雄性激素阻断患者使用比卡鲁胺进行治疗的患者的PFS为33个月,相比使用氟他胺的患者的PFS要长,P＜0.05.结论 单纯去势以及完全雄性激素阻断治疗在晚期前列腺癌的预后中具有相似的效果.对于无转移的晚期前列腺癌患者,可以进行单纯去势治疗,对于存在转移的患者,最好采用完全雄性激素阻断进行治疗.     

The Use of Dietary Supplements to Alleviate Androgen Deprivation Therapy Side Effects during Prostate Cancer Treatment

Prostate cancer (PCa), the most commonly diagnosed cancer and second leading cause of male cancer death in Western societies, is typically androgen-dependent, a characteristic that underlies the rationale of androgen deprivation therapy (ADT). Approximately 90% of patients initially respond to ADT strategies, however many experience side effects including hot flashes, cardiotoxicity, metabolic and musculoskeletal alterations. This review summarizes pre-clinical and clinical studies investigating the ability of dietary supplements to alleviate adverse effects arising from ADT. In particular, we focus on herbal compounds, phytoestrogens, selenium (Se), fatty acids (FA), calcium, and Vitamins D and E. Indeed, there is some evidence that calcium and Vitamin D can prevent the development of osteoporosis during ADT. On the other hand, caution should be taken with the antioxidants Se and Vitamin E until the basis underlying their respective association with type 2 diabetes mellitus and PCa tumor development has been clarified. However, many other promising supplements have not yet been subjected large-scale clinical trials making it difficult to assess their efficacy. Given the demographic trend of increased PCa diagnoses and dependence on ADT as a major therapeutic strategy, further studies are required to objectively evaluate these supplements as adjuvant for PCa patients receiving ADT.     

TURP联合雄激素阻断治疗晚期前列腺癌伴膀胱出口梗阻疗效观察

目的探讨经尿道前列腺电切（TURP）联合雄激素阻断治疗晚期前列腺癌伴膀胱出口梗阻的临床疗效。方法回顾性分析23例应用TURP联合雄激素阻断治疗晚期前列腺癌伴出口梗阻患者的临床资料,观察患者住院时间、手术时间、留置尿管时间,及手术前后前列腺体积、生活质量评分（QOL）、国际前列腺症状评分（IPSS）、前列腺特异性抗原（PSA）、最大尿流速度（Qmax）、残余尿量（RU）的变化。结果 23例患者手术均成功,1例术后输血400 ml,无前列腺电切综合征现象,住院天数（9.0±3.2）d,手术时间45～120 min,术后留置导尿管时间5～7 d。术前前列腺体积、QOL、IPSS、PSA、Qmax、RU分别为（87.53±18.46）cm3、（3.54±1.16）分、（18.96±3.83）分、（76.32±20.47）μg/L、（9.08±2.76）ml/s、（142.53±34.66）ml,术后1个月前列腺体积（46.52±13.43）cm3、QOL（2.15±1.30）分、IPSS（12.78±3.34）分、PSA（1.82±0.63）μg/L、Qmax（19.20±3.98）ml/s、RU（29.86±16.33）ml,手术前后上述指标比较,差异均有统计学意义（均P〈0.01）,术后第3个月PSA（0.66±0.21）μg/L（P〈0.01）。结论 TURP联合雄激素阻断治疗晚期前列腺癌伴膀胱出口梗阻安全、有效,近期疗效确切,能明显缓解患者尿路梗阻症状,提高患者生活质量,但远期疗效有待进一步研究。     

Effects of Selenomethionine on the Gene Expression Profile of Cloned Human Prostate Cancer Cells Representing a Phenotypic Continuum of Cancer Progression

The cutoff value of critical weight loss is still subject of discussion. In this pilot study, we investigated whether ≥5% weight loss in the past year predicts changes in nutritional status in patients with advanced cancer during treatment with palliative chemotherapy. In 20 patients with advanced cancer undergoing palliative (combination) chemotherapy, body weight, fat free mass (FFM), and cachexia were measured prior to the start and at 9 wk of treatment. History of weight loss was used to test differences in development of nutritional parameters during chemotherapy with use of independent sample t-tests. At baseline, 10 of 20 patients had lost ≥5% body weight during the past year and 5 patients were cachectic. The change in FFM in the first 9 wk of chemotherapy was significantly worse in patients with ≥5% weight loss compared to patients with <5% weight loss [mean difference: 3.5 kg (P = 0.001)]. Data also suggest that ≥5% weight loss predicts shorter survival (P = 0.03). We found that patients with ≥5% weight loss prior to chemotherapy have a deterioration in nutritional status during chemotherapy and may have a shorter survival. These results have to be confirmed in a larger study including a robust survival analysis.     

Adherence to World Cancer Research Fund/American Institute for Cancer Research Lifestyle Recommendations Reduces Prostate Cancer Aggressiveness Among African and Caucasian Americans

The effect of adherence to the World Cancer Research Fund (WCRF) lifestyle recommendations on cancer aggressiveness is unknown. We examined associations between adherence to recommendations and risk of highly aggressive prostate cancer in research subjects enrolled in the North Carolina-Louisiana Prostate Cancer Project (PCaP). We examined associations between adherence to WCRF recommendations and risk of highly aggressive prostate cancer among 2212 newly diagnosed African Americans (AA) or Caucasian Americans (CA) aged 40–70 years in PCaP. Prostate cancer aggressiveness was based on Gleason scores, serum prostate-specific antigens, and TNM stage. Adherence to WCRF recommendations was based on point scores and odds ratios estimated. Results showed that adherence to recommendations was significantly and negatively associated with risk of a highly aggressive prostate cancer. Each additional point in the total adherence score corresponded to a 13% risk reduction. Total adherence score <4 predicted increased risk in both AA (OR = 1.36; 95% CI = 1.01–1.85) and CA (OR = 1.41; 95% CI = 1.01–1.98). Consumption of <500 g red meat per week or ≤125 total kcal/100 g solid food per day is a statistically significant protective factor in the overall cohort. Recommendations aimed at preventing all cancers also may reduce risk of highly aggressive prostate cancer.     

前列腺癌中HSF1蛋白的表达及与临床病理特征的相关性

目的探讨HSF1在前列腺癌组织中的表达及与前列腺癌各项临床病理特征的关系。方法应用免疫组织化学法和图像分析系统研究82例前列腺癌标本中HSF1的表达情况。结果HSF1蛋白在前列腺癌癌细胞胞浆部位染色阳性,阳性表达率为89.2%。HSF1在前列腺癌组织中的表达与Gleason评分呈正相关(r=0.66,P0.001)。HSF1表达与PSA水平随PSA升高而升高,呈正相关(r=0.76,P0.001)。结论HSF1蛋白在前列腺癌中表达增加,可能与调控热休克蛋白家族成员作用机制有关。     

Parenteral Nutrition Rapidly Reduces Hepatic Mononuclear Cell Numbers and Lipopolysaccharide Receptor Expression on Kupffer Cells in Mice

Background: Parenteral nutrition (PN) reduces the number of hepatic mononuclear cell (MNCs) and impairs their function, resulting in poor survival after intraportal bacterial challenge in mice. Our recent animal study demonstrated resumption of enteral nutrition after PN to rapidly restore hepatic MNC numbers (in 12 hours) and lipopolysaccharide (LPS) receptor expression on Kupffer cells (in 48 hours). The present study examined the time courses of hepatic MNC number reductions and LPS receptor expression changes in mice receiving PN. Methods: Male mice (n = 49) from the Institute of Cancer Research were divided into chow (n = 8), PN0.5 (n = 8), PN1 (n = 8), PN2 (n = 9), PN3 (n = 9), and PN5 (n = 7) groups. The chow group was given chow with an intravenous saline infusion. The PN groups were fed parenterally for 0.5, 1, 2, 3, or 5 days following the chow‐feeding courses. After 7 days of nutrition support, hepatic MNCs were isolated and counted. The expression of LPS receptors on Kupffer cells was analyzed by flow cytometry. Results: Hepatic MNC numbers rapidly reached their lowest level in the PN0.5 and PN1 groups but were somewhat restored thereafter and remained stable after the third day, without significant differences between any 2 of the PN groups. CD14 and Toll‐like receptor 4/MD‐2 expressions both showed significant reductions in the PN1 group compared with the chow group and gradually decreased to their lowest levels in the PN5 group. Conclusions: PN administration rapidly reduces hepatic MNC numbers and LPS receptor expression on Kupffer cells.     

HoSAGE: Sarcopenia in Older Patients before and after Treatment with Androgen Deprivation Therapy and Radiotherapy for Prostate Cancer

The journal of nutrition, health & aging - Sarcopenia is a muscle disease defined by a loss of muscle strength associated to a decrease in skeletal muscle mass. In addition to aging, many...     

Family History of Prostate Cancer in a Black Population

Although family history of prostate cancer (PC) is an established risk factor for the disease, few studies have investigated this relationship among men with an African heritage. The Prostate Cancer in a Black Population (PCBP) study is a large, nationwide case–control study conducted in Barbados, West Indies from 2002 to 2011. In the PCBP study, a family history of PC in fathers or brothers was associated with a threefold increased risk of disease (OR = 3.04, 95 % CI (2.18, 4.22)) and a strong positive relationship was noted for the number of affected first degree relatives. Tumor grade did not generally influence the relationship between family history and PC. The magnitude of risks associated with having a father affected with the disease was slightly higher in the PCBP study compared to other populations. It remains unclear whether this finding is the result of an increased genetic susceptibility in African-Barbadian men.