Triacanthine exerts antitumor effects on bladder cancer in vitro and in vivo
Seung-Shick Shin a, Yu-Jin Park b, Byungdoo Hwang b, Sung Lye a, Park b, Sang-Wook Han c, Sung-Soo Park a,Yung Hyun Choi d, Wun-Jae Kim e, Sung-Kwon Moon b
Numerous studies have focused on solvent extracts from locust trees (Gleditsia spp.), which contain diverse bioactive components including saponins, flavonoids, and alkaloids. However, because of the undefined nature of such phytochemicals, their clinical application as chemotherapeutic agents has often been limited.
This study aimed to evaluate the anti-oncogenic activity of triacanthine, an alkaloid obtained from Gleditsia triacanthos L.
The anti-oncogenicity of triacanthine in vitro was evaluated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell-counting kit-8 assay (CCK-8 assay), flow cytometry, imunoblot, migration and invasion assays, zymography, and electrophoretic mobility shift assay in the human bladder carcinoma cell line EJ. The in vivo efficacy of triacanthine was evaluated via oral administration to EJ-xenografted BALB/c nude mice. To identify the side effects of triacanthine, cisplatin was also administered and an acute toxicity test was performed.
Triacanthine significantly inhibited EJ cell proliferation (IC50 600 µM). Flow cytometry analysis revealed that cells were arrested in the G1 phase, and apoptotic cells accumulated in sub-G1 phase in a dose-dependent manner. Triacanthine inhibited the G1–S transition by deterring complex formation between cyclin-dependent kinases and cyclins, thereby up-regulating cell cycle inhibitors p21WAF1 and p27KIP1. In addition, triacanthine induced a caspase-dependent extrinsic pathway of apoptosis and autophagy. Early responsive kinases, extracellular signal-regulated kinase (ERK) and Janus kinase (JNK) were up-regulated by triacanthine. Triacanthine-mediated inhibition of the migratory and invasive potential of EJ cells was attributed to reduction of matrix metalloproteinase (MMP)-9 due to suppression of binding activities of the transcription factors activator protein (AP)-1, specificity protein (Sp)-1, and nuclear factor (NF)-κB. In an in vivo study, triacanthine significantly limited growth of xenografted tumors. Interestingly, while cisplatin resulted in significant weight loss after a 5-mg/kg dose, triacanthine did not cause weight loss, behavioral abnormalities, altered biochemical parameters, or tissue staining. A single oral dose acute-toxicity test (triacanthine 2,000 mg/kg) produced no adverse cytotoxic effects via blood biochemical tests and tissue-organ staining.
To our knowledge, this is the first systematic evaluation of the anti-oncogenic activity of triacanthine. Therefore, we believe that our findings may guide the development of novel chemotherapeutic agents for bladder cancers.
Source : Journal Phytomedicine
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Cruciferous Vegetables, Isothiocyanates, and Bladder Cancer Prevention
Besma Abbaoui Christopher R. Lucas Ken M. Riedl Steven K. Clinton Amir Mortazavi
Bladder cancer is a significant health burden due to its high prevalence, risk of mortality, morbidity, and high cost of medical care. Epidemiologic evidence suggests that diets rich in cruciferous vegetables, particularly broccoli, are associated with lower bladder cancer risk. Phytochemicals in cruciferous vegetables, such as glucosinolates, which are enzymatically hydrolyzed to bioactive isothiocyanates, are possible mediators of an anticancer effect. In vitro studies have shown inhibition of bladder cancer cell lines, cell cycle arrest, and induction of apoptosis by these isothiocyanates, in particular sulforaphane and erucin. Although not yet completely understood, many mechanisms of anticancer activity at the steps of cancer initiation, promotion, and progression have been attributed to these isothiocyanates. They target multiple pathways including the adaptive stress response, phase I/II enzyme modulation, pro‐growth, pro‐survival, pro‐inflammatory signaling, angiogenesis, and even epigenetic modulation. Multiple in vivo studies have shown the bioavailability of isothiocyanates and their antitumoral effects. Although human studies are limited, they support oral bioavailability with reasonable plasma and urine concentrations achieved. Overall, both cell and animal studies support a potential role for isothiocyanates in bladder cancer prevention and treatment. Future studies are necessary to examine clinically relevant outcomes and define guidelines on ameliorating the bladder cancer burden.
Source : Molecular Nutrition and Food Research
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Clarification of the molecular pathway of Taiwan local pomegranate fruit juice underlying the inhibition of urinary bladder urothelial carcinoma cell by proteomics strategy
- Ting-Feng Wu
- Li-Ting Hsu,
- Bo-Xian Tsang,
- Li-Chien Huang,
- Wan-Yin Shih and
- Li-Yi Chen
Pomegranate fruit has been shown to exhibit the inhibitory activity against prostate cancer and lung cancer in vitro and in vivo, which might be a resource for chemoprevention and chemotherapy of cancer. Our previous documented findings indicated that treatment of urinary bladder urothelial carcinoma cell with the ethanol extract isolated from the juice of pomegranate fruit grown in Taiwan could inhibit tumor cell. In this study we intended to uncover the molecular pathway underlying anti-cancer efficacy of Taiwan pomegranate fruit juice against urinary bladder urothelial carcinoma.
We exploited two-dimensional gel electrophoresis coupled with tandem mass spectrometry to find the de-regulated proteins. Western immunoblotting was used to confirm the results collected from proteomics study.
Comparative proteomics indicated that 20 proteins were differentially expressed in ethanol extract-treated T24 cells with 19 up-regulated and 1 down-regulated proteins. These de-regulated proteins were involved in apoptosis, cytoskeleton regulation, cell proliferation, proteasome activity and aerobic glycolysis. Further studies on signaling pathway demonstrated that ethanol extract treatment might inhibit urinary bladder urothelial carcinoma cell proliferation through restriction of PTEN/AKT/mTORC1 pathway via profilin 1 up-regulation. It also might evoke cell apoptosis through Diablo over-expression.
The results of this study provide a global picture to further investigate the anticancer molecular mechanism of pomegranate fruit.
Source BMC Complementary and Alternative Medicine
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PHYSICAL ACTIVITY, OBESITY, AND BLADDER CANCER MORTALITY
Michael Liss, Martha White, Loki Natarajan, J. Kellogg Parsons
Introduction and ObjectivesPhysical activity and obesity are modifiable lifestyle factors that are potential therapeutic targets for bladder cancer prevention and control. However, there are limited data on physical activity, obesity, and bladder cancer mortality. Further analyses of these associations may identify novel prevention and treatment strategies for bladder cancer.
The National Health Information Survey (NHIS) is an annual representative cross-sectional household interview survey. We used baseline data from 1998 through 2004 linked to mortality data reporting deaths through 2006. The primary outcome variable was bladder cancer-specific mortality. The primary exposure variables were self-reported physical activity (dichotomized as “did no exercise” versus “light, moderate or vigorous exercise in >=10 minute-bouts”) and obesity as measured by body mass index (BMI). We utilized multivariable adjusted Cox proportional hazards regression models, with delayed entry to account for age at survey interview. Analyses were adjusted for the complex NHIS multistage sampling methodology using survey weights.
Complete data were available on 222163 participants, of whom 96715 (48%) were men and 146014 (73%) non-Hispanic Whites, and among whom we identified 83 bladder cancer-specific deaths. There were no associations of ethnicity (p=0.43) or gender (p=0.14) with bladder cancer mortality. In multivariate analyses, individuals who reported “any physical activity” were 53% less likely [adjusted hazards ratio (HRadj) 0.53; 95% CI 0.29 to 0.96; p-value = 0.038] to die of bladder cancer than non-exercisers. There were no significant differences in bladder cancer mortality for overweight (BMI 25.0 to 29.9 kg/m2, HRadj 1.06, 95% CI 0.55 to 2.04, p-value = 0.87) or obese (BMI >= 30 kg/m2, HRadj 0.61, 95% CI 0.33 to 1.12, p-value = 0.11) individuals compared to those of normal weight (BMI < 25 kg/m2). Compared to never smokers, former smokers were nearly three times as likely (HRadj 2.95, 95% CI 1.50 to 5.79; p-value<0.001) and current smokers over 4 times as likely (HRadj 4.24, 95% CI 1.86 to 9.65, p-value<0.001) to die of bladder cancer.
Physical activity decreases the risk of bladder cancer mortality. These studies suggest that exercise interventions may potentially prevent bladder cancer death.
Source : Journal Urology
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Lower Bladder cancer Risk Seen in Marijuana Users
Marijuana users had a small but statistically lower risk of bladder cancer compared with people who smoked tobacco or did not smoke, a large retrospective cohort study showed.
The overall cohort had a bladder cancer risk of <1%. Nonetheless, cannabis (marijuana) users had an incidence of 0.3% compared with 0.4% among nonusers. The difference represented a 45% reduction in the hazard ratio (HR) for bladder cancer.
The magnitude of risk reduction appeared to increase with the frequency of cannabis use, Anil A. Thomas, MD, reported at the American Urological Association meeting in San Diego, California, in May.
“The full effects of cannabis use are not known, and Kaiser Permanente does not promote nor condone the use of cannabis,” said Thomas, an endourology fellow at Kaiser Permanente Los Angeles Medical Center. “However, our findings demonstrated a reduced incidence of bladder cancer among cannabis users, which could lead to further investigational studies to determine if cannabinoids, the active components of cannabis, have biologic activity against bladder cancer. Future research may eventually lead to the development of new targeted therapies for patients with bladder cancer.”
Bladder cancer is the fourth most common cancer in men, and tobacco use is a recognized risk factor for developing the disease. Whether that risk extends to cannabis use had not been examined in large epidemiologic studies. To address the issue, Thomas and colleagues analyzed records from the California Men’s Health Study (CMHS), a multiethnic cohort study that focuses primarily on prostate cancer, but also on the etiology of other cancers and non-cancerous conditions.
The bladder cancer study involved 84,170 men from the Northern and Southern Kaiser Permanente health regions participating in the CMHS. After excluding 680 men with a history of bladder cancer, investigators analyzed data for the remaining participants.
According to self-reported information provided by the participants, a total of 71% of the men were smokers (41% cannabis, 57% tobacco and, included in those numbers, 27% both substances). Meanwhile, 29% used neither cannabis nor tobacco. During follow-up for as long as 11 years, 279 study participants (0.3%) developed bladder cancer. Cannabis users accounted for 89 (0.3%) cancers and nonusers (including tobacco users) for 190 cancers (0.4%, P <.0001).
An analysis adjusted for age race/ethnicity, and body mass index showed that exclusive tobacco use was associated with a bladder cancer HR of 1.52 compared with nonusers (P <.007). In contrast, exclusive cannabis use was associated with a reduced risk of bladder cancer (HR=0.55; P =.0484). Men who reported use of tobacco and cannabis had a bladder cancer HR of 1.28, which was not statistically different from that of nonusers (P =.1480).
In another adjusted analysis, men who reported using cannabis once or twice had no reduction in bladder cancer risk (HR=1.07; P =.760), whereas men who reported use in excess of 500 times had a bladder HR of .66, which still did not achieve statistical significance (P =.175).
“While a cause-and-effect relationship has not been established, cannabis use may be inversely associated with bladder cancer risk in this population,” Thomas said. “Additional research is needed to determine if there is indeed a biological effect of cannabis to prevent or delay the development of bladder cancer.”
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Fruit and Vegetable Intakes Are Associated with Lower Risk of Bladder Cancer among Women in the Multiethnic Cohort Study1,2
Song-Yi Park3,7,*,Nicholas J. Ollberding4,7, Christy G. Woolcott5, Lynne R. Wilkens3, Brian E. Henderson6, and Laurence N. Kolonel3
- 3Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI
- 4Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
- 5Departments of Obstetrics, Gynecology, and Pediatrics, Dalhousie University, Halifax, NS, Canada; and
- 6Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
Fruits and vegetables have been examined for their possible effects on the risk of bladder cancer, as they contain numerous nutrients, phytochemicals, and antioxidants with potentially anticarcinogenic properties. In a prospective analysis of 185,885 older adults participating in the Multiethnic Cohort Study, we examined whether the consumption of fruits and vegetables, or of nutrients concentrated in fruits and vegetables, was associated with bladder cancer risk. Cox proportional hazards models were used to calculate HRs and 95% CIs for bladder cancer in relation to dietary intakes. A total of 581 invasive bladder cancer cases (429 men and 152 women) were diagnosed over a mean follow-up period of 12.5 y. In women, total fruits and vegetables [HR = 0.35 (95% CI: 0.22, 0.56); highest vs. lowest quartile], total vegetables [HR = 0.49 (95% CI: 0.29, 0.83)], yellow-orange vegetables [HR = 0.48 (95% CI: 0.30, 0.77)], total fruits [HR = 0.54 (95% CI: 0.34, 0.85)], and citrus fruits [HR = 0.56 (95% CI: 0.34, 0.90)] were inversely associated with the risk of invasive bladder cancer in risk factor-adjusted models. In addition, women with the highest intakes of vitamins A, C, and E; the carotenoids α-carotene, β-carotene, and β-cryptoxanthin; and folate had a lower risk of bladder cancer. For men, no associations for fruits, vegetables, or nutrients were found overall, although inverse associations were observed for vegetable intake among current smokers, and in ethnic-specific analyses, for fruit and vegetable intake among Latinos specifically. Our findings suggest that greater consumption of fruits and vegetables may lower the risk of invasive bladder cancer among women and highlight the need for specific subgroup analyses in future studies.
Source : The Journal of Nutrition
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Green Tea, but Not Black Tea, May Protect against Bladder Cancer
Wang X, Lin Y-W, Wang S, et al.
A meta-analysis of tea consumption and the risk of bladder cancer. Urol Int. 2012; [epub ahead of print]. doi: 10.1159/000342804.
Bladder cancer is the 11th most commonly diagnosed cancer in the world.1 Genetic and environmental factors, as well as aging and smoking, are considered risk factors for bladder cancer. Previous research has suggested that tea (Camellia sinensis) may help protect against several types of cancer, including bladder cancer. Epidemiological studies on the association between tea consumption and bladder cancer have yielded mixed results. A 2001 meta-analysis found no correlation between tea consumption and the occurrence of bladder cancer.2 This new meta-analysis includes more recent multicenter and large sample studies which provide greater statistical power.
The authors identified papers published in English between 1980 and March 2012 by searching PubMed, Web of Science, the Cochrane Library, cited references, and previous meta-analyses. The publications were cohort or case-control studies assessing the association between tea consumption and bladder cancer risk, with results including the relative risk (RR) or odds ratio (OR) and its 95% confidence interval (CI), or with sufficient information to calculate the values.
A total of 17 studies with 8,225 cases were included in the analysis; 4 cohort studies and 13 case-control studies. Seven evaluated Asian populations and the remaining 10 assessed Caucasians. Five studies examined black tea consumption, 4 focused on green tea intake, and the other 8 studies did not distinguish the type of tea.
No significant association was detected between tea consumption and bladder cancer risk in the crude data analysis (OR=0.825; 95% CI, 0.652-1.043). However, as a statistically significant heterogeneity was detected (I2=93.3%), a random-effect analysis was conducted. Similar results were found when potentially confounding variables such as age, gender, and smoking status were excluded (OR=1.12; 95% CI, 0.88-1.43), and there was still significant heterogeneity (I2=64.6%). Sensitivity analysis indicated that no single study could influence the results and no publication bias was found among the studies.
Stratified analyses (by gender, study design, ethnicity, and smoking status) indicated that tea consumption was associated with a decreased risk for bladder cancer, although the results were not significant. However, green tea consumption in Asian countries was associated with a statistically significant protective effect against bladder cancer (OR=0.814; 95% CI, 0.678-0.976), while no such association was noted for black tea.
Interestingly, in the subgroup analysis of ethnicity, tea consumption was not associated with a reduced risk of bladder cancer in Asians. The authors suggest that this may be due to the fact that 2 of the 7 Asian population studies only assessed black tea consumption.
The authors noted that none of the studies conducted in Western countries analyzed the correlation between green tea consumption and bladder cancer risk. They acknowledged that the majority of the included studies analyzed "tea" consumption in general rather than the specific type of tea, which may have resulted in inaccurate estimates. Selection bias, recall bias, and ethnic differences in bladder cancer risk cannot be ruled out. Also, the differences in study design may have biased the results since both cohort and case-control studies were included. Other limitations of this analysis are the exclusion of non-English language publications and studies that the authors deemed to have provided insufficient information.
The authors conclude that their analysis "indicated that green tea may have a protective effect on bladder cancer in Asian people," but that "no such correlation was detected between black tea and bladder cancer."
1Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.
2Zeegers MP, Tan FE, Goldbohm RA, van den Brandt PA. Are coffee and tea consumption associated with urinary tract cancer risk? A systematic review and meta-analysis. Int J Epidemiol. 2001;30(2):353-362.
Source : American Botanical Council
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Study finds painters are 30% more likely to develop cancer of bladder
PAINTERS ARE at significantly increased risk of developing bladder cancer and the danger increases the longer a person works in the trade, a new study has found.
The research, published in Occupational and Environmental Medicine , is based on almost 3,000 cases of the disease in professional painters reported in 41 separate studies.
The study found that plasterers, glaziers, wallpaper hangers, artists and decorators were exposed to the same risk.
Author of the study, Dr Neela Guha, said the risk arises not solely from exposure to paint but to factors that can occur in the environment in which painters work, such as the stripping of old paintwork, sanding or exposure to asbestos.
The study also found that those who had worked in such roles for more than 10 years were more likely to develop bladder cancer than those who had been doing so for less than that time.
The International Agency for Research on Cancer (IARC) has estimated that bladder cancer is the ninth most common cancer worldwide and accounts for 130,000 deaths annually.
While smoking is a key risk, the authors of the study found that after taking tobacco use into account, painters were still 30 per cent more likely to develop bladder cancer than the general population.
The findings are the result of bladder cancer studies carried out from the 1950s to the 1990s.
Dr Guha said that while harmful chemicals like benzene and lead had been reduced or removed from paints in developed countries, it was too soon to say whether new, “greener” paints would reduce the risk of bladder cancer as the disease takes between 10 and 50 years to develop.
Dr Guha advised those working in high-risk environments to wear gloves and keep skin covered, to wear a mask or respirator, not to eat in the area and to ensure the buildings were well ventilated.
Source: Irish Times 20/7/2010
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