Phytoestrogens in common herbs regulate prostate cancer cell growth in vitro

Prostate cancer is an important public health problem in the United States. Seven phytoestrogens found in common herbal products were screened for estrogen receptor binding and growth inhibition of androgen-insensitive (PC-3) and androgen-sensitive (LNCaP) human prostate tumor cells. In a competitive 3H-estradiol ligand binding assay using mouse uterine cytosol, 2.5 M quercetin, baicalein, genistein, epigallocatechin gallate (EGCG), and curcumin displaced > 85% of estradiol binding, whereas apigenin and resveratrol displaced > 40%. From growth inhibition studies in LNCaP cells, apigenin and curcumin were the most potent inhibitors of cell growth, and EGCG and baicalein were the least potent. In PC-3 cells, curcumin was the most potent inhibitor of cell growth, and EGCG was the least potent. In both cell lines, significant arrest of the cell cycle in S phase was induced by resveratrol and EGCG and in G2M phase by quercetin, baicalein, apigenin, genistein, and curcumin. Induction of apoptosis was induced by all of the 7 compounds in the 2 cell lines as shown by TUNEL and DNA fragmentation assays. Androgen responsiveness of the cell lines did not correlate with cellular response to the phytoestrogens. In conclusion, these 7 phytoestrogens, through different mechanisms, are effective inhibitors of prostate tumor cell growth.     

In vitro effects of epidermal growth factor, follicle stimulating hormone and testosterone on mouse spermatogonial cell colony formation

The complex process of spermatogenesis is regulated by various factors. In the present study, the in vitro effects of epidermal growth factor (EGF), follicle stimulating hormone (FSH) and testosterone on spermatogonial cell colony formation were investigated, and the best colonising factor was chosen for treating cells before transplantation. Sertoli and spermatogonial cells were isolated from neonatal mouse testes. The identity of the cells was confirmed through analysis of morphology, alkaline phosphatase activity, immunoreactivity and transplantation. Co-cultured Sertoli and spermatogonial cells were treated with EGF, FSH and testosterone before colony assay. Results indicated that EGF is the best factor for in vitro colonisation of spermatogonial cells, but transplantation of the EGF-treated group did not show any significant change compared with the control groups. In conclusion, EGF increased in vitro colonisation of spermatogonial cells, but, as a result of differential effects, did not influence transplantation efficiency.     

CD147对LNCaP-AI细胞生长影响

目的 观察RNA干扰白细胞分化抗原147（CD147）基因对雄激素非依赖性前列腺癌LNCaP-AI细胞增殖、细胞周期和凋亡影响。方法 脂质体2000转染靶向CD147基因的shRNA质粒到LNCaP-AI细胞中,通过G418筛选获得稳定低表达CD147细胞株。利用溴化四氮唑蓝法和流式细胞术检测CD147基因沉默后对细胞增殖、细胞周期和凋亡的影响。结果 与对照组比较,沉默CD147表达后明显抑制LNCaP-AI细胞增殖（P<0.05）;细胞周期出现在G₀/G₁期细胞百分率从（69.76±3.83）%增加到（79.40±4.02）%,差异有统计学意义（P<0.05）;S期和G₂/M期细胞百分率分别从（23.51±2.58）%、（6.73±0.70）%减少到（17.03±2.02）%和（3.57±0.21）%,差异有统计学意义（P<0.05）,呈现G₀/G₁期细胞阻滞;但不引起细胞凋亡。结论 RNA干扰CD147基因能够抑制LNCaP-AI细胞增殖,诱导细胞周期异常。     

瘦素、雌二醇和睾酮在女性青春期中的变化规律及相互关系

为研究瘦素在女性从青春期前到整个青春期发育过程中作用 ,及瘦素、雌二醇和睾酮在此过程中的变化规律和相互关系 ,检测 7～ 1 7岁不同营养状况 (1 50名肥胖、1 50名正常和 1 50名营养不良 )女性血中瘦素、雌二醇和睾酮水平 ,并调查了月经初潮时间。结果显示 7～ 1 7岁女性瘦素变化规律 :逐渐升高→出现第一个高峰 (肥胖组、正常组和营养不良组峰值分别为 1 4 46μg ml;8 85μg ml;8 60 μg ml)→下降→出现突增(第二高峰 )→突降 (1 3～ ,P <0 0 1 )→缓慢上升→下降的趋势 ;不同营养状况女性瘦素突增时间不同 ,第一高峰与青春期发育开始时间相一致 ,第二高峰出现在青春期后期。三组雌二醇水平从 1 1岁开始迅速增长 ,并随年龄的增长而升高 ,瘦素与雌二醇无相关性。三组睾酮在 1 0岁均出现增长高峰 ,之后下降 ,在 1 2岁均出现迅速升高。瘦素与睾酮无相关性。提示瘦素可能是调控女性青春期发育过程的决定因素 ,瘦素第一增长高峰可能是青春期启动信号 ,第二增长高峰可能是青春期结束信号     

Beta-carotene modulates human prostate cancer cell growth and may undergo intracellular metabolism to retinol

Epidemiologic and animal studies provide support for a relationship between high intakes of carotenoids from fruits and vegetables with reduced risk of several malignancies including prostate cancer. The highly controlled environments of in vitro systems provide an opportunity to investigate the cellular and molecular effects of carotenoids. The effects of beta-carotene (BC) on in vitro growth rates, p21(WAF1) and p53 gene expression, as well as the conversion of BC to retinol were investigated in three human prostate adenocarcinoma cell lines: PC-3, DU 145 and LNCaP. In these experiments, media concentrations of 30 micromol BC/L for 72 h significantly (P < 0.05) slowed in vitro growth rates in all three cell lines, independently of p53 or p21(WAF1) status or expression. (14)C-labeled retinol was detected in prostate tumor cells incubated with (14)C-labeled BC, suggesting metabolic conversion of BC to retinol. Conversely, no (14)C-labeled retinol was detected in media incubated without prostate cancer cells. These studies support a hypothesis that in vitro biological effects of BC on prostate cells may result in part from the conversion of BC to retinol or other metabolites. The possibility that prostate cancer cells in vivo locally metabolize provitamin A carotenoids to retinol and other related metabolites may have implications for our understanding of prostate cancer etiology and the design of future prevention studies.     

Lycopene inhibits the growth of human androgen-independent prostate cancer cells in vitro and in BALB/c nude mice

Lycopene is a promising chemopreventive agent for human prostate cancer. To test the hypothesis that the effect of lycopene on prostate cancer is stage specific in the process of carcinogenesis, inhibitory effects of natural lycopene on the proliferation of 3 different human prostate carcinoma cell lines were examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Lycopene more potently inhibited the growth of the androgen-independent DU145 and PC-3 cells than androgen-dependent LNCaP cells. The 50% inhibitory concentration of lycopene for these cell lines was 26.6 micromol/L for DU145, 40.3 micromol/L for PC-3, and 168.5 micromol/L for LNCaP. We also studied the inhibitory effect of lycopene on the growth rate of DU145 tumor xenografts in BALB/c male nude mice. The tumor growth rate was inhibited by 55.6 and 75.8% in mice treated with 100 and 300 mg/kg lycopene, respectively, compared with controls. In addition, no tumors formed in 1 mo in mice treated with DU145 cells that had been pretreated with 20 micromol/L lycopene; however, they did form when DU145 cells were not pretreated. Flow cytometry revealed that lycopene caused DU145 cells to accumulate in the G(0)/G(1) phase and to undergo apoptosis in a dose-dependent manner. The rate of apoptosis was up to 42.4% lower in DU145 cells treated with 32 micromol/L lycopene compared with the untreated control cells. These results suggest that lycopene may specifically inhibit the growth of androgen-independent prostate cancers.     

Role of transurethral resection of the prostate in population-based prostate cancer incidence rates.

The extensive pool of asymptomatic prostate disease in the population, which increases substantially with age, suggests that the frequent use of transurethral resection of the prostate (TURP) in recent decades has had a large effect on prostate cancer incidence. The authors identified the effect of TURP-detected prostate cancer on the observed incidence rates between 1973 and 1993 for men aged 65 years and older. They linked population-based cancer registry data from the Surveillance, Epidemiology, and End Results Program to Medicare records between 1986 and 1993 to determine whether a TURP occurred sufficiently close to the time of a prostate cancer diagnosis for them to assume that it led to the diagnosis. TURP-detected cases prior to 1986 were calculated using an indirect method that involved multiplying the TURP procedure rate in the general population (from the National Hospital Discharge Survey) by estimates of the proportion of TURPs resulting in a prostate cancer diagnosis (from Medicare data and the literature). TURP explained much of the observed increase in overall prostate cancer incidence between 1973 and 1986 and possibly all of it in men aged 70 years and older. However, its influence on the trend and overall magnitude of the rates diminished between 1987 and 1993. The changing role of TURP in detecting prostate cancer is attributed to changes in medical technology and screening practices. The declining influence of TURP on prostate cancer incidence is likely to have continued beyond the study period due to the recent introduction and increasing use of medications for treating obstructive uropathy.     

叶酸对体外人胃腺癌细胞SGC-7901生长的作用

目的 以体外培养的人胃癌细胞株SGC—7901为材料，观察叶酸的抑癌防癌作用。方法 采用生长曲线法、MTT法观察叶酸对细胞的增殖和功能的影响；采用FCM进行细胞周期分析，观察叶酸对细胞凋亡的影响。结果 在叶酸浓度为375，750和1875nmol／L时对人胃癌细胞株的增殖和功能有抑制作用，浓度为375nmol／L时引起的凋亡率可达33．1％。结论 叶酸对人胚肌腱细胞无抑制作用，表明叶酸对正常人体细胞无不良影响而对癌细胞有抑制作用。     

Milk stimulates growth of prostate cancer cells in culture

Concern has been expressed about the fact that cows' milk contains estrogens and could stimulate the growth of hormone-sensitive tumors. In this study, organic cows' milk and two commercial substitutes were digested in vitro and tested for their effects on the growth of cultures of prostate and breast cancer cells. Cows' milk stimulated the growth of LNCaP prostate cancer cells in each of 14 separate experiments, producing an average increase in growth rate of over 30%. In contrast, almond milk suppressed the growth of these cells by over 30%. Neither cows' milk nor almond milk affected the growth of MCF-7 breast cancer cells or AsPC-1 pancreatic cancer cells significantly. Soy milk increased the growth rate of the breast cancer cells. These data indicate that prostate and breast cancer patients should be cautioned about the possible promotional effects of commercial dairy products and their substitutes.     

Role of mammalian lignans in the prevention and treatment of prostate cancer

Prostate cancer is poised to become the most prevalent male cancer in the Western world. In Japan and China, incidence rates are almost 10-fold less those reported in the United States and the European Union. Epidemiological data suggest that environmental factors such as diet can significantly influence the incidence and mortality of prostate cancer. The differences in lifestyle between East and West are one of the major risk factors for developing prostate cancer. Traditional Japanese and Chinese diets are rich in foods containing phytoestrogenic compounds, whereas the Western diet is a poor source of these phytochemicals. The lignan phytoestrogens are the most widely occurring of these compounds. In vitro and in vivo reports in the literature indicate that lignans have the capacity to affect the pathogenesis of prostate cancer. However, their precise mechanism of action in prostate carcinogenesis remains unclear. This article outlines the possible role of lignans in prostate cancer by reviewing the current in vitro and in vivo evidence for their anticancer activities. The intriguing concept that lignans may play a role in the prevention and treatment of prostate cancer over the lifetime of an individual is discussed.     

Tomato and soy polyphenols reduce insulin-like growth factor-I-stimulated rat prostate cancer cell proliferation and apoptotic resistance in vitro via inhibition of intracellular signaling pathways involving tyrosine kinase

We examined the ability of polyphenols from tomatoes and soy (genistein, quercetin, kaempferol, biochanin A, daidzein and rutin) to modulate insulin-like growth factor-I (IGF-I)-induced in vitro proliferation and apoptotic resistance in the AT6.3 rat prostate cancer cell line. IGF-I at 50 micro g/L in serum-free medium produced maximum proliferation and minimized apoptosis. Polyphenols exhibited different abilities to modulate IGF-I-induced proliferation, cell cycle progression (flow cytometry) and apoptosis (Annexin V/propidium iodide and terminal deoxynucleotidyltransferase-mediated deoxyuridine 5'-triphosphate nick end labeling). Genistein, quercetin, kaempferol and biochanin A exhibited dose-dependent inhibition of growth with a 50% inhibitory concentration (IC(50)) between 25 and 40 micro mol/L, whereas rutin and daidzein were less potent with an IC(50) of >60 micro mol/L. Genistein and kaempferol potently induced G(2)/M cell cycle arrest. Genistein, quercetin, kaempferol and biochanin A, but not daidzein and rutin, counteracted the antiapoptotic effects of IGF-I. Human prostate epithelial cells grown in growth factor-supplemented medium were also sensitive to growth inhibition by polyphenols. Genistein, biochanin A, quercetin and kaempferol reduced the insulin receptor substrate-1 (IRS-1) content of AT6.3 cells and prevented the down-regulation of IGF-I receptor beta in response to IGF-I binding. IGF-I-stimulated proliferation was dependent on activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) and phosphatidylinositide 3-kinase pathways. Western blotting demonstrated that ERK1/2 was constitutively phosphorylated in AT6.3 cells with no change in response to IGF-I, whereas IRS-1 and AKT were rapidly and sensitively phosphorylated after IGF-I stimulation. Several polyphenols suppressed phosphorylation of AKT and ERK1/2, and more potently inhibited IRS-1 tyrosyl phosphorylation after IGF-I exposure. In summary, polyphenols from soy and tomato products may counteract the ability of IGF-I to stimulate proliferation and prevent apoptosis via inhibition of multiple intracellular signaling pathways involving tyrosine kinase activity.     

Dietary acrylamide intake and the risk of renal cell, bladder, and prostate cancer

BACKGROUND: Acrylamide, a probable human carcinogen, was recently detected in various heat-treated carbohydrate-rich foods. Epidemiologic studies on the relation with cancer have been few and largely negative. OBJECTIVE: We aimed to prospectively examine the association between dietary acrylamide intake and renal cell, bladder, and prostate cancers. DESIGN: The Netherlands Cohort Study on diet and cancer includes 120,852 men and women aged 55-69 y. At baseline (1986), a random subcohort of 5000 participants was selected for a case-cohort analysis approach using Cox proportional hazards analysis. Acrylamide intake was assessed with a food-frequency questionnaire at baseline and was based on chemical analysis of all relevant Dutch foods. RESULTS: After 13.3 y of follow-up, 339, 1210, and 2246 cases of renal cell, bladder, and prostate cancer, respectively, were available for analysis. Compared with the lowest quintile of acrylamide intake (mean intake: 9.5 microg/d), multivariable-adjusted hazard rates for renal cell, bladder, and prostate cancer in the highest quintile (mean intake: 40.8 microg/d) were 1.59 (95% CI: 1.09, 2.30; P for trend = 0.04), 0.91 (95% CI: 0.73, 1.15; P for trend = 0.60), and 1.06 (95% CI: 0.87, 1.30; P for trend = 0.69), respectively. There was an inverse nonsignificant trend for advanced prostate cancer in never smokers. CONCLUSIONS: We found some indications for a positive association between dietary acrylamide and renal cell cancer risk. There were no positive associations with bladder and prostate cancer risk.     

Reduction of corticosterone-induced muscle proteolysis and growth retardation by a combined treatment with insulin, testosterone and high-protein-high-fat diet in rats.

An experiment was conducted to clarify the combined effect of simultaneous administrations of insulin (Ins, 4 units/100 g body weight/day) and testosterone propionate (TP, 2 mg/100 g body weight/day) and feeding a high-protein-high-fat (HPHF) diet (50% protein, 36% fat) on corticosterone (CTC, 10 mg/100 g body weight/day)-induced muscle proteolysis or growth retardation in young growing male rats. After 6 days prefeeding of the standard (STD) diet (25% protein, 9% fat) and the HPHF diet, hormones were injected subcutaneously for 4 days. Urine was collected every day for the 4-day experimental period to measure N tau-methylhistidine excretions. The results were as follows. The growth was markedly inhibited and muscle proteolysis was accelerated by the CTC treatment. Feeding HPHF diet reduced CTC-induced muscle proteolysis and the growth retardation, and administrations of Ins and TP further reduced the proteolysis and the growth retardation. From these results, it is thought that administrations of Ins and TP and feeding HPHF diet minimize the muscle protein wasting by counteracting insulin resistance caused by CTC, and masking the CTC receptor.     

Rye whole grain and bran intake compared with refined wheat decreases urinary C-peptide, plasma insulin, and prostate specific antigen in men with prostate cancer

Rye whole grain and bran intake has shown beneficial effects on prostate cancer progression in animal models, including lower tumor take rates, smaller tumor volumes, and reduced prostate specific antigen (PSA) concentrations. A human pilot study showed increased apoptosis after consumption of rye bran bread. In this study, we investigated the effect of high intake of rye whole grain and bran on prostate cancer progression as assessed by PSA concentration in men diagnosed with prostate cancer. Seventeen participants were provided with 485 g rye whole grain and bran products (RP) or refined wheat products with added cellulose (WP), corresponding to ~50% of daily energy intake, in a randomized controlled, crossover design. Blood samples were taken from fasting men before and after 2, 4, and 6 wk of treatment and 24-h urine samples were collected before the first intervention period and after treatment. Plasma total PSA concentrations were lower after treatment with RP compared with WP, with a mean treatment effect of -14% (P = 0.04). Additionally, fasting plasma insulin and 24-h urinary C-peptide excretion were lower after treatment with RP compared with WP (P < 0.01 and P = 0.01, respectively). Daily excretion of 5 lignans was higher after the RP treatment than after the WP treatment (P < 0.001). We conclude that whole grain and bran from rye resulted in significantly lower plasma PSA compared with a cellulose-supplemented refined wheat diet in patients with prostate cancer. The effect may be related to inhibition of prostate cancer progression caused by decreased exposure to insulin, as indicated by plasma insulin and urinary C-peptide excretion.     

Effects of dietary fatty acids on DU145 human prostate cancer cell growth in athymic nude mice

The purpose of this study was to examine the effects of diets containing different unsaturated fatty acids (FAs) on DU145 human prostate cancer cell growth in nude mice. In Experiment 1, groups of 25 mice were fed 23% (wt/wt) fat diets containing 18% corn oil (CO)‐5% linseed oil (18: 2n‐6 FA‐rich), 18% linseed oil (LO)‐5% CO (18: 3n‐3 FA‐rich), or 18% menhaden oil (MO)‐5% CO (20: 5 and 22: 6n‐3 FA‐rich), and seven days later they were injected subcutaneously with 1 × 10⁶ DU145 cells. The diets were continued for six weeks. The growth rates and final weights of tumors from the 18% CO‐5% LO and 18% LO‐5% CO mice were similar; there was a 30% reduction in tumor growth in the 18% MO‐5% CO group (p < 0.001). The tumor phospholipid FA patterns suggested that the inhibitory effect of the high‐MO diet was due, at least in part, to a reduction of arachidonic acid available for prostaglandin biosynthesis. In Experiment 2, groups of 25 mice were injected with 5 × 10⁵ or 1×10⁶ DU145 cells directly into the prostate gland and fed a high‐fat linoleic acid (n‐6 FA)‐rich or a low‐fat diet for 10 weeks. At necropsy, macroscopic cancers and microscopic intraprostatic tumors were evaluated. When the initial tumor load was 1 × 10⁶ cells, all but 7 of the 50 mice had developed large macroscopic tumors; the mean tumor weight in the high‐fat group was twice that in the low‐fat group (p = 0.047). A stimulatory effect of dietary n‐6 FA on DU145 prostate cancer cell growth may require a critical initial tumor cell mass.     

重组人生长激素体外干预人肝癌细胞生长及受体表达

24、9.40±0.51、8.33±0.31,明显多于空白对照组的7.51±0.54(P＜0.05).细胞株SMMC7721弱表达GHR,细胞株QGY-7701未表达GHR,与未处理组比,rhGH干预组生长率、CFSE荧光强度、下游蛋白IGF-1、GHR表达差异均无统计学意义(P＞0.05).结论 体外环境下,rhGH可以促进GHR高表达人肝癌细胞株HepG-2增殖,提高其IGF-1的表达量和增加其胞膜GHR密度;但不促进人肝癌细胞株QGY-7701、SMMC7721增殖,不能使其GHR表达状态发生改变.     

雌二醇和睾酮与缺氧缺血性脑损伤的研究进展

近年来研究发现类固醇激素 ,如雌二醇和睾酮同缺氧缺血性脑损伤关系密切。在神经细胞缺氧缺血状态下 ,不仅外源性雌二醇和睾酮可减轻神经组织受损程度 ,并且大脑自身也上调雌二醇和受损处雌二醇受体的表达。目前认为在发生缺氧缺血性脑损伤后 ,雌二醇和睾酮可通过抗氧化作用 ,保护神经元免受兴奋性氨基酸的毒性作用 ,调节星形胶质细胞和小胶质细胞形态、结构和功能 ,以及抗神经细胞凋亡而发挥保护作用。对雌二醇和睾酮在神经系统的保护作用进一步深入研究 ,有望为临床缺氧缺血性脑损伤的治疗提供新的途径     

Changes in sexual function and serum testosterone levels in patients with prostate cancer after image-guided proton therapy

Since sexual function and testosterone levels after image-guided proton therapy (IGPT) have not yet been examined in detail, we prospectively evaluated changes before and after IGPT. Among patients treated with IGPT with or without combined androgen blockade (CAB) therapy between February 2013 and September 2014, patients who agreed to participate in the study and were followed up for >3 years after IGPT were evaluated. Serum testosterone levels were regularly measured together with prostate-specific antigen (PSA) levels before and after IGPT. The Erection Hardness Score (EHS) and the sexual domain summary, function subscale and bother subscale of the sexual domain in the Expanded Prostate Cancer Index Composite (EPIC) were assessed. There were 38 low-risk, 46 intermediate-risk and 43 high- or very-high-risk patients (NCCN classification). Although serum testosterone levels in low-risk patients did not decrease after IGPT, reductions were observed in the average EHS and the sexual domain summary score of the EPIC. In intermediate-, high- and very-high-risk patients, testosterone and PSA levels both increased following the termination of CAB after IGPT, and the average EHS increased. The sexual domain summary score gradually increased, but not above minimally important differences. In intermediate-risk patients, the function subscale increased from 4.4 to 14.8 (P < 0.05) 12 months after IGPT and reached a plateau after 60 months. The results of the present study would suggest the potential of IGPT, and further prospective studies to directly compare IGPT with other modalities are warranted.