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1.  Erythrocyte Omega-6 and Omega-3 Fatty Acids and Mammographic Breast Density 
Nutrition and cancer  2013;65(3):410-416.
Diets low in omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and high in omega-3 (n-3) PUFAs may protect against breast cancer development. Associations of PUFA intake with mammographic density, an intermediate marker of breast cancer risk, have been inconsistent; however, prior studies have relied on self-reported dietary PUFA intake. We examined the association between circulating erythrocyte n-6 and n-3 PUFAs with mammographic density in 248 postmenopausal women who were not taking exogenous hormones. PUFAs in erythrocytes were measured by gas-liquid chromatography, and mammographic density was assessed quantitatively by planimetry. Spearman’s correlation coefficients and generalized linear models were used to evaluate the relationships between PUFA measures and mammographic density. None of the erythrocyte n-6 or n-3 PUFA measures were associated with percent density or dense breast area.
PMCID: PMC3657737  PMID: 23530640
2.  Dietary influence on MAPK-signaling pathways and risk of colon and rectal cancer 
Nutrition and cancer  2013;65(5):729-738.
Mitogen-activated protein kinase (MAPK) pathways regulate cellular functions including cell proliferation, differentiation, migration, and apoptosis. Associations between genes in the DUSP, ERK1/2, JNK, and p38 MAPK-signaling pathways and dietary factors associated with growth factors, inflammation, and oxidative stress and risk of colon and rectal cancer were evaluated. Data include colon cases (n=1555) and controls (n=1956) and rectal cases (n=754) and controls (n=959). Statistically significant interactions were observed for the MAPK-signaling pathways after adjustment for multiple comparisons. DUSP genes interacted with carbohydrates, mutagen index, calories, calcium, vitamin D, lycopene, dietary fats, folic acid, and selenium. MAPK1, MAPK3, MAPK1 and RAF1 within the ERK1/2 MAPK-signaling pathway interacted with dietary fats and cruciferous vegetables. Within the JNK MAPK-signaling pathway, interactions between MAP3K7 and protein, vitamin C, iron, folic acid, carbohydrates, and cruciferous vegetables; MAP3K10 and folic acid; MAP3K9 and lutein/zeaxanthin; MAPK8 and calcium; MAP3K3 and calcium and lutein; MAP3K1 and cruciferous vegetables. Interaction within the p38-signaling pathway included: MAPK14 with calories, carbohydrates saturated fat, selenium, vitamin C; MAP3K2 and carbohydrates, and folic acid. These data suggest that dietary factors involved in inflammation and oxidative stress interact with MAPK-signaling genes to alter risk of colorectal cancer.
PMCID: PMC3971867  PMID: 23859041
Colorectal Cancer; MAPK; JNK; p38; ERK1/2; diet; inflammation; stress
3.  Ginger phytochemicals exhibit synergy to inhibit prostate cancer cell proliferation 
Nutrition and cancer  2013;65(2):263-272.
Dietary phytochemicals offer non-toxic therapeutic management as well as chemopreventive intervention for slow-growing prostate cancers. However, the limited success of several single-agent clinical trials suggest a paradigm shift that the health benefits of fruits and vegetables are not ascribable due to individual phytochemicals rather may be ascribed to but to synergistic interactions among them. We recently reported growth-inhibiting and apoptosis-inducing properties of ginger extract (GE) in in vitro and in vivo prostate cancer models. Nevertheless, the nature of interactions among the constituent ginger biophenolics, viz. 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogoal, remains elusive. Here we show antiproliferative efficacy of the most-active GE biophenolics as single-agents and in binary combinations, and investigate the nature of their interactions using the Chou-Talalay combination-index (CI) method. Our data demonstrate that binary combinations of ginger phytochemicals synergistically inhibit proliferation of PC-3 cells with CI values ranging from 0.03-0.88. To appreciate synergy among phytochemicals present in GE, the natural abundance of ginger biophenolics was quantitated using LC-UV/MS. Interestingly, combining GE with its constituents (in particular, 6-gingerol) resulted in significant augmentation of GE’s antiproliferative activity. These data generate compelling grounds for further preclinical evaluation of GE alone and in combination with individual ginger biophenols for prostate cancer management.
PMCID: PMC3925258  PMID: 23441614
antiproliferative; ginger; phytochemicals; prostate cancer; synergy
4.  Chemopreventive and Anti-cancer Efficacy of Silibinin against Growth and Progression of Lung Cancer 
Nutrition and cancer  2013;65(0 1):3-11.
The use of systemic chemotherapeutic drugs and molecular-targeted therapies in the treatment of patients with locally advanced or metastatic lung cancer has its limitations due to the associated acute and cumulative dose limiting toxicities and acquisition of drug resistance. Prevention and therapeutic intervention by dietary agents including nutraceuticals which are non-toxic, cost-effective, and physiologically bioavailable, are emerging approaches in lung cancer management. In this regard, silibinin, a natural flavonolignan, has been rigorously evaluated for the prevention and growth control of lung cancer through extensive in vitro and in vivo studies. Successful studies conducted so far, have established that silibinin is effective both alone and in combination with other agents (e.g. chemotherapeutic and epigenetic agents) in significantly inhibiting the growth of lung cancer cells. In vivo, its effects have been shown to be mediated through inhibition of proliferation, angiogenesis and epigenetic-related events. Therefore, the present review focuses on encompassing the efficacy and mechanisms of silibinin against lung cancer.
PMCID: PMC3924887  PMID: 23682778
Lung cancer; Silibinin; Phytochemicals; Chemoprevention
5.  Reality check: no such thing as a miracle food 
Nutrition and cancer  2013;65(2):165-168.
PMCID: PMC3635479  PMID: 23441603
6.  Partial Associations of Dietary Iron, Smoking and Intestinal Bacteria with Colorectal Cancer Risk 
Nutrition and cancer  2013;65(2):169-177.
Smoking and high red meat intake have been associated with colorectal cancer (CRC) risk. Increased iron exposure may be a common factor, favoring the colonization of certain bacterial pathogens that preferentially grow in an iron-rich luminal environment. We analyzed the data from a population-based case-control study of CRC and measured antibody levels against flagelin of Salmonella (FliC), one of the irontrophic bacteria, in two independent blood collections. The risk of CRC synergistically increased by combined exposures to heme iron intake and pack-years (PY) of cigarette smoking (P-value for the interaction = 0.039 on the continuous scale). There was a marginally significant interaction between heme iron intake and PY in increasing FliC antibody in the US control subjects (P=0.055), although no iron or smoking data were available for Dutch samples. Furthermore, FliC antibody levels were significantly higher in patients with colorectal polyps and cancer than in controls in both Dutch (3.93 vs. 2.23) (P=0.014) and US samples (6.65 vs. 4.37) (P<0.001). Potential roles of iron from cigarette smoking and dietary heme in CRC through altering irontrophic luminal bacterial population may warrant further investigation.
PMCID: PMC3655765  PMID: 23441604
smoking; iron; intestinal bacteria; colorectal cancer; Salmonella
7.  Evaluation of the Clinical Relevance of Body Composition Parameters in Patients with Cancer Metastatic to the Liver Treated with Hepatic Arterial Infusion Chemotherapy 
Nutrition and cancer  2012;64(2):10.1080/01635581.2012.638433.
The association between body composition parameters and toxicity associated with hepatic arterial infusion (HAI) chemotherapy regimens has not been analyzed. We analyzed data from patients with advanced cancer and liver metastases treated on a clinical trial of HAI oxaliplatin combination regimen. Patient characteristics, response and toxicities were analyzed in relevance with body composition data from CT images. Forty-eight of 57 patients (mean age 57 years; 60% women) had available CT scans. The most common diagnosis was colorectal cancer (22/48, 46%); 30/48 patients (63%) had body mass index (BMI) ≥ 25 kg/m2. Twenty of 48 patients were sarcopenic (42%). Grade 3–4 adverse events did not differ among patients with and without sarcopeniaor according to BMI. The median survival (95% confidence interval [CI]) was 167 (128–206) days for sarcopenic and 280 (214–346) days for non-sarcopenic patients (p=0.271). Among patients treated at the maximum tolerated dose, the median survival was 103 days for sarcopenic and 312 days for non-sarcopenic patients (p=0.173). Sarcopenia was present in 30% (6/20) of patients with reduction in tumor size post-treatment, and in 52% (14/27) of patients with increased tumor size (p=0.171). In conclusion, body composition was not associated with toxicities. Sarcopenia might be associated with shorter survival.
PMCID: PMC3886552  PMID: 22229660
neoplasms; antineoplastic combined chemotherapy protocols; adverse effects; treatment outcome; survival; sarcopenia
8.  In Vitro and In Vivo Effects of Phenethyl Isothiocyanate Treatment on Vimentin Protein Expression in Cancer Cells 
Nutrition and cancer  2013;65(0 1):61-67.
We have shown previously that cancer prevention by cruciferous vegetable constituent phenethyl isothiocyanate (PEITC) in a transgenic mouse model of prostate cancer is associated with induction of E-cadherin protein expression. Because suppression of E-cadherin protein concomitant with induction of mesenchymal markers (e.g., vimentin) is a biochemical hallmark of epithelial-mesenchymal transition, a process implicated in cancer metastasis, we hypothesized that PEITC treatment was likely to suppress vimentin protein expression. Contrary to this prediction, exposure of human breast (MDA-MB-231) and prostate cancer cells (PC-3 and DU145) to PEITC resulted in a dose-dependent increase in vimentin protein level, which was observed as early as 6 hours post-treatment and persisted for the duration of the experiment (24 hours). RNA interference of vimentin resulted in a modest augmentation of PEITC-mediated inhibition of MDA-MB-231 and PC-3 cell migration as well as cell viability. Furthermore, the PEITC-induced apoptosis was moderately increased upon siRNA knockdown of vimentin protein in MDA-MB-231 and PC-3 cells. To our surprise, PEITC treatment caused a marked decrease in vimentin protein expression in breast and prostate carcinoma in vivo in transgenic mouse models; although the difference was statistically significant only in the breast carcinomas. The present study highlights the importance of in vivo correlative studies for validation of the in vitro mechanistic observations.
PMCID: PMC3671484  PMID: 23682784
Phenethyl isothiocyanate; Vimentin; Cancer chemoprevention
9.  The effect of gartanin, a naturally- occurring xanthone in mangosteen juice, on the mTOR pathway, autophagy, apoptosis and the growth of human urinary bladder cancer cell Lines 
Nutrition and cancer  2013;65(0 1):68-77.
Garcinia mangostana, often referred to as “mangosteen,” is a fruit grown in Southeast Asia, and has been used for centuries as a local beverage and natural medicine. Its bioactive compounds, xanthones (i.e. gartanin, α-mangostin, etc), have reported effects on ailments ranging from skin infections and inflammation, to urinary tract infections. We demonstrate that mangosteen xanthones (i.e. gartanin and α-mangostin) at pharmacologically achievable concentrations inhibit the growth of cancer cell lines from different stages of human urinary bladder cancer. The growth inhibitory effects of gartanin in mouse embryonic fibroblasts (MEFs) are at least in part dependent on the existence of p53 or TSC1. Indeed, further studies have shown that gartanin treatment of bladder cancer cell lines T24 and RT4 resulted in a marked suppression of p70S6 and 4E-BP1 expression and induction of autophagy, suggesting the inhibition of the mTOR pathway. In addition, gartanin down-regulated the expression of Bcl-2 and activated the p53 pathway leading to apoptosis induction. Together, these results suggested that gartanin is a multiple targeting agent that is suitable for further study into its chemopreventive properties for human urinary bladder cancer.
PMCID: PMC3671488  PMID: 23682785
Gartanin; human urinary bladder cancer; the mTOR pathway; autophagy
10.  Peri-gestational Dietary Folic Acid Deficiency Protects Against Medulloblastoma Formation in a Mouse Model of Nevoid Basal Cell Carcinoma Syndrome 
Nutrition and cancer  2013;65(6):857-865.
Hereditary nevoid basal cell carcinoma syndrome (NBCCS) is caused by PTCH1 gene mutations that result in diverse neoplasms including medulloblastoma (MB). Epidemiological studies report reduced pediatric brain tumor risks associated with maternal intake of prenatal vitamins containing folic acid (FA) and FA supplements specifically. We hypothesized that low maternal FA intake during the peri-gestational period would increase MB incidence in a transgenic NBCCS mouse model, which carries an autosomal dominant mutation in the Ptch1 gene. Female wild-type C57BL/6 mice (n=126) were randomized to one of three diets with differing FA amounts: 0.3 mg/kg (low), 2.0 mg/kg (control), and 8.0 mg/kg (high) one month prior to mating with Ptch1+/− C57BL/6 males. Females were maintained on the diet until pup weaning; the pups were then aged for tumor development. Compared to the control group, offspring MB incidence was significantly lower in the low FA group (Hazard Ratio (HR)=0.47; 95% confidence interval (CI) 0.27–0.80) at one year. No significant difference in incidence was observed between the control and high FA groups. Low maternal peri-gestational FA levels may decrease MB incidence in mice genetically predisposed to tumor development. Our results could have implications for prenatal FA intake recommendations in the presence of cancer syndromes.
PMCID: PMC3771499  PMID: 23909730
11.  Are diet quality scores after breast cancer diagnosis associated with improved breast cancer survival? 
Nutrition and cancer  2013;65(6):820-826.
Previous studies have found that diets rich in fruits and vegetables are associated with reduced breast cancer mortality. However, these eating patterns do not necessarily reflect overall diet quality. The association of breast cancer mortality with a priori defined dietary scores, which are based on recommended dietary guidelines and reflect diet quality, has not been evaluated. We hypothesized that diet quality indices based on recommended guidelines are associated with decreased risk of breast cancer and non-breast cancer mortality in breast cancer survivors.
We examined the association between the Dietary Approaches to Stop Hypertension (DASH) score, and the Alternative Healthy Eating Index (AHEI)-2010, and the risk of breast cancer mortality and total mortality among women from the Nurses’ Health Study diagnosed with breast cancer.
Adherence to DASH-style and AHEI-2010 diets were associated with reduced risk of non-breast cancer mortality (comparing the fifth quintile with the first quintile RR = 0.72, 95% CI: 0.53–0.99, p-trend = 0.03 for DASH, and RR = 0.57, 95% CI: 0.42–0.77, p-trend <0.0001 for AHEI-2010). Diet scores were not significantly associated with breast cancer mortality.
Our findings suggest that adherence to a higher quality diet after breast cancer diagnosis does not considerably change the risk of breast cancer death and recurrence. However, healthy dietary choices after breast cancer were associated with reduced risk of non-breast cancer mortality in women with breast cancer.
PMCID: PMC3776311  PMID: 23909725
12.  Special issue on Molecular Basis for Cancer Prevention with Bioactive Food Components in Nutrition and Cancer – An International Journal 
Nutrition and cancer  2013;65(0 1):10.1080/01635581.2013.785012.
PMCID: PMC3808077  PMID: 23682777
Biomarkers; Cancer Prevention; Cell cycle checkpoint; Cell signaling; Apoptosis; Angiogenesis
13.  The Effects of Soy Consumption before Diagnosis on Breast Cancer Survival: the Multiethnic Cohort Study 
Nutrition and cancer  2013;65(4):10.1080/01635581.2013.776694.
This study tested the hypothesis that prediagnostic soy intake was inversely associated with all-cause and breast cancer-specific mortality. The analyses included 3,842 female in the Multiethnic Cohort (MEC) study of African Americans, Native Hawaiians, Japanese Americans, Latinos, and Caucasians, who completed a quantitative food frequency questionnaire, aged ≥50 years at cohort entry, and diagnosed with primary invasive breast cancer following cohort entry (1993-2007). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated from Cox proportional hazards regression with adjustment for known clinical and lifestyle factors. During a mean follow-up after diagnosis of invasive breast cancer of 6.2±3.8 years, there were 804 deaths including 376 breast cancer-specific deaths. The HR (95%CI) for all-cause and breast cancer-specific morality comparing the highest versus lowest tertiles were 1.03 (0.81-1.33) and 1.03 (0.71-1.50) for soy products and 0.99 (0.82-1.20) and 0.95 (0.71-1.28) for total isoflavones, respectively (Ptrend > 0.60 for all). There was limited evidence of differences by hormone receptor status, tumor stage, or ethnic group. Prediagnostic soy intake was unrelated to mortality in postmenopausal women. Our findings are consistent with the literature that soy consumption does not adversely affect breast cancer survival in women.
PMCID: PMC3821969  PMID: 23659444
Breast neoplasms; ethnic groups; soy foods; isoflavones; survival; postmenopause
14.  Dietary Antioxidants and Prostate Cancer: A Review 
Nutrition and cancer  2013;65(6):10.1080/01635581.2013.806672.
Prostate cancer is the most common non-cutaneous cancer in men in the United States. Several studies have examined the relationship between prostate cancer and antioxidants; however, the results of these studies are inconsistent. This article provides a systematic review of studies on prostate cancer and antioxidant intake from diet and supplements. Tea and coffee appear to offer protection against advanced prostate cancer. Different forms of vitamin E appear to exert different effects on prostate cancer, with alpha-tocopherol potentially increasing and gamma-tocopherol potentially decreasing risk of the disease. There is no strong evidence for a beneficial effect of selenium, vitamin C, or beta-carotene, while lycopene appears to be negatively associated with risk of the disease. The effect of dietary antioxidants on prostate cancer remains undefined and inconclusive, with different antioxidants affecting prostate cancer risk differentially. Further studies are needed to clarify the relationship between antioxidants and prostate cancer risk and to delineate the underlying mechanisms.
PMCID: PMC3823537  PMID: 23909722
15.  Differential Effect of Grape Seed Extract against Human Non-Small-Cell Lung Cancer Cells: the role of Reactive Oxygen Species and Apoptosis Induction 
Nutrition and cancer  2013;65(0 1):10.1080/01635581.2013.785003.
Present study examines grape seed extract (GSE) efficacy against a series of Non-small-cell lung cancer (NSCLC) cell lines which differ in their Kras and p53 status to establish GSE potential as a cytotoxic agent against a wide-range of lung cancer cells. GSE suppressed growth and induced apoptotic death in NSCLC cells irrespective of their k-Ras status, with more sensitivity towards H460 and H322 (wt k-Ras) than A549 and H1299 cells (mutated k-Ras). Mechanistic studies in A549 and H460 cells, selected, based on comparative efficacy of GSE at higher and lower doses, respectively, showed that apoptotic death involves cytochrome c release associated caspases 9 and 3 activation, and PARP cleavage, strong phosphorylation of ERK1/2 and JNK1/2, down regulation of cell survival proteins, and up regulated pro-apoptotic Bak expression. Importantly, GSE treatment caused a strong superoxide radical-associated oxidative stress, significantly decreased intracellular reduced glutathione levels, suggesting, for the first-time, the involvement of GSE-caused oxidative stress in its apoptotic inducing activity in these cells. Since GSE is a widely-consumed dietary agent with no known untoward effects, our results support future studies to establish GSE efficacy and usefulness against NSCLC control.
PMCID: PMC3859370  PMID: 23682782
Apoptosis; chemoprevention; reactive oxygen species; grape seed extract; lung cancer; natural products
16.  Nutrient Pathways and Breast Cancer Risk: The Long Island Breast Cancer Study Project 
Nutrition and cancer  2013;65(3):10.1080/01635581.2013.767364.
The relative importance of biochemical pathways has not been previously examined when considering the influence of diet on breast cancer risk. To address this issue, we utilized interview data from a population-based sample of 1,463 breast cancer cases and 1,500 controls. Dietary intake was assessed shortly after diagnosis using a 101-item food frequency questionnaire. Age- and energy-adjusted odds ratios (ORs) for individual micro- and macronutrients were estimated with logistic regression. Hierarchical modeling was employed to account for biologically plausible nutrient pathways (one-carbon metabolism, oxidative stress, glycemic control and phytoestrogens). Effect estimates from hierarchical modeling were more precise and plausible compared to those from multivariable models. The strongest relationship observed was for the glycemic control pathway, but confidence intervals (CI) were wide [OR (95% CI): 0.86 (0.62, 1.21)]. Little or no effect was observed for the one-carbon metabolism, oxidative stress and phytoestrogen pathways. Associations were similar when stratified by supplement use. Our approach that emphasizes biochemical pathways, rather than individual nutrients, revealed that breast cancer risk may be more strongly associated with glycemic control factors than those from other pathways considered. Our study emphasizes the importance of accounting for multiple nutrient pathways when examining associations between dietary intake and breast cancer.
PMCID: PMC3875325  PMID: 23530633
diet; nutrient pathways; hierarchical regression; glycemic control; breast cancer; epidemiology
17.  Soy food consumption and lung cancer risk: a meta-analysis using a common measure across studies 
Nutrition and cancer  2013;65(5):10.1080/01635581.2013.795983.
A published meta-analysis pooled individual studies by using the study-specific odds ratio (OR) or relative risk (RR) for the highest versus lowest category of soy or isoflavone intake from each study, but it should be problematic to make comparison between studies/populations for lung cancer risk as the quantiles are so different from different studies/populations. Therefore, we conducted a meta-analysis to explore the association between exposure of estimated daily soy protein intake in grams and lung cancer risk. We extracted ORs or RRs and 95% confidence intervals (CIs), converted them to the estimated ones for daily soy protein intake and pooled them using fixed or random effects models from 11 epidemiologic studies. Overall, the inverse association between daily grams of soy protein intake and risk of lung cancer was borderline statistically significant (OR=0.98, 95% CI=0.96 to 1.00); the inverse association was statistically significant in nonsmokers (0.96; 0.93–0.99) and stronger than in smokers (P for difference<0.05). No statistical significance for the associations was observed between genders, the origin of the participants, study design and types of soy intake. This study suggests a borderline reduction in risk of lung cancer with daily soy protein intake in grams, and a significant inverse association in nonsmokers.
PMCID: PMC3858084  PMID: 23859029
soy intake; lung cancer; meta-analysis
18.  Soy Isoflavones in Conjunction With Radiation Therapy in Patients With Prostate Cancer 
Nutrition and cancer  2010;62(7):10.1080/01635581.2010.509839.
Soy isoflavones sensitize prostate cancer cells to radiation therapy by inhibiting cell survival pathways activated by radiation. At the same time, soy isoflavones have significant antioxidant and anti-inflammatory activity, which may help prevent the side effects of radiation. Therefore, we hypothesized that soy isoflavones could be useful when given in conjunction with curative radiation therapy in patients with localized prostate cancer. In addition to enhancing the efficacy of radiation therapy, soy isoflavones could prevent the adverse effects of radiation. We conducted a pilot study to investigate the effects of soy isoflavone supplementation on acute and subacute toxicity (≤6 mo) of external beam radiation therapy in patients with localized prostate cancer. Forty-two patients with prostate cancer were randomly assigned to receive 200 mg soy isoflavone (Group 1) or placebo (Group 2) daily for 6 mo beginning with the first day of radiation therapy, which was administered in 1.8 to 2.5 Gy fractions for a total of 73.8 to 77.5 Gy. Adverse effects of radiation therapy on bladder, bowel, and sexual function were assessed by a self-administered quality of life questionnaire at 3 and 6 mo. Only 26 and 27 patients returned completed questionnaires at 3 and 6 mo, respectively. At each time point, urinary, bowel, and sexual adverse symptoms induced by radiation therapy were decreased in the soy isoflavone group compared to placebo group. At 3 mo, soy-treated patients had less urinary incontinence, less urgency, and better erectile function as compared to the placebo group. At 6 mo, the symptoms in soy-treated patients were further improved as compared to the placebo group. These patients had less dripping/leakage of urine (7.7% in Group 1 vs. 28.4% in Group 2), less rectal cramping/diarrhea (7.7% vs. 21.4%), and less pain with bowel movements (0% vs. 14.8%) than placebo-treated patients. There was also a higher overall ability to have erections (77% vs. 57.1%). The results suggest that soy isoflavones taken in conjunction with radiation therapy could reduce the urinary, intestinal, and sexual adverse effects in patients with prostate cancer.
PMCID: PMC3856358  PMID: 20924975
19.  Bioavailability of Phytochemical Constituents From a Novel Soy Fortified Lycopene Rich Tomato Juice Developed for Targeted Cancer Prevention Trials 
Nutrition and cancer  2011;65(6):10.1080/01635581.2011.630156.
Studies suggest that tomato and soy foods may contribute to a lower risk of certain cancers. We developed a novel soy germ tomato juice to be used in controlled cancer prevention trials. This study describes an initial test of compliance, phytochemical bioavailability, and effects on biomarkers of blood lipids. Healthy men and women (n = 18) consumed a soy germ-fortified juice daily (300 mL supplying 66 mg isoflavones and 22 mg lycopene) for 8 wk. A single-dose bioavailability study was completed on day 1 and isoflavones in plasma and urine, and lycopene in the plasma, were measured. All subjects completed the trial, with 97.7% ± 3.5% (mean ± SD) of the scheduled juice consumed. No adverse effects were documented. The postprandial study indicated that 3.1% ± 2.3% of lycopene was absorbed and that 49.3% ± 12.1% isoflavones ingested were recovered in 24-h urines. Lycopene plasma concentration changed from 0.60 ± 0.22 to 1.24 ± 0.30 μmol/L during 8 wk of consumption. Juice consumption significantly improved resistance of LDL+VLDL-C to Cu2+-mediated oxidation (P = 0.039), HDL-C (47.3 ± 15.8 to 51.7 ± 14.8 mg/dL, P < 0.001), and the ratio of total-C/HDL-C (4.25 ± 1.59 to 3.63 ± 1.16, P < 0.001) at 8 wk. A well-characterized soy-fortified tomato juice can be produced in large scale for multiinstitutional long-term cancer prevention trials and showed excellent compliance with no toxicity, while demonstrating absorption of biologically active phytochemicals.
PMCID: PMC3850031  PMID: 22098224
20.  Sulforaphane Potentiates the Efficacy of 17-Allylamino 17-Demethoxygeldanamycin Against Pancreatic Cancer Through Enhanced Abrogation of Hsp90 Chaperone Function 
Nutrition and cancer  2011;63(7):10.1080/01635581.2011.596645.
Heat shock protein 90 (Hsp90), an essential molecular chaperone that regulates the stability of a wide range of oncogenic proteins, is a promising target for cancer therapeutics. We investigated the combination efficacy and potential mechanisms of sulforaphane, a dietary component from broccoli and broccoli sprouts, and 17-allylamino 17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, in pancreatic cancer. MTS assay demonstrated that sulforaphane sensitized pancreatic cancer cells to 17-AAG in vitro. Caspase-3 was activated to 6.4-fold in response to simultaneous treatment with sulforaphane and 17-AAG, whereas 17-AAG alone induced caspase-3 activity to 2-fold compared to control. ATP binding assay and coimmunoprecipitation revealed that sulforaphane disrupted Hsp90-p50Cdc37 interaction, whereas 17-AAG inhibited ATP binding to Hsp90. Concomitant use of sulforaphane and 17-AAG synergistically downregulated Hsp90 client proteins in Mia Paca-2 cells. Co-administration of sulforaphane and 17-AAG in pancreatic cancer xenograft model led to more than 70% inhibition of the tumor growth, whereas 17-AAG alone only suppressed the tumor growth by 50%. Our data suggest that sulforaphane potentiates the efficacy of 17-AAG against pancreatic cancer through enhanced abrogation of Hsp90 function. These findings provide a rationale for further evaluation of broccoli/broccoli sprout preparations combined with 17-AAG for better efficacy and lower dose-limiting toxicity in pancreatic cancer.
PMCID: PMC3850054  PMID: 21875325
21.  Dietary Fat, Tamoxifen Use and Circulating Sex Hormones in Postmenopausal Breast Cancer Survivors 
Nutrition and cancer  2010;62(2):10.1080/01635580903305359.
Evidence is inconsistent regarding whether dietary fat influences sex hormone concentrations. This issue is important for breast cancer survivors since clinical recommendations suggest maintaining low hormone levels primarily via pharmacologic agents. This study examines associations between dietary fat and circulating sex hormones among participants in the HEAL (Health, Eating, Activity and Lifestyle) Study, a cohort of breast cancer survivors (n=511). During a post-diagnosis interview, detailed data were collected on diet, physical activity, lifestyle habits, and medication use (including tamoxifen). Staff measured height and weight and collected fasting bloods. Multivariate linear regression modeled associations of dietary fat with serum sex hormones. Among women using tamoxifen, we observed modest inverse associations of dietary fat with estrone (p< 0.01), estradiol (p< 0.05), testosterone (p< 0.01), free testosterone (p< 0.01), and DHEA (p< 0.01) for higher vs. lower fat intake, but there was no evidence for a trend. Associations were consistent across measures (percent energy from fat, total, saturated and polyunsaturated fat) and modest effect modification was observed between fat intake and tamoxifen in relation to hormones. Among women not using tamoxifen, fat intake was not associated with hormone concentrations. Further work is needed to confirm the findings and to understand the clinical implications of these observations.
PMCID: PMC3846524  PMID: 20099190
Diet; dietary fat; sex steroid hormones; estrogen; testosterone; postmenopausal breast cancer; tamoxifen
22.  Colorectal Cancer: Chemopreventive Role of Curcumin and Resveratrol 
Nutrition and cancer  2010;62(7):10.1080/01635581.2010.510259.
Colorectal cancer (CRC) is a second leading cause of cancer deaths in the Western world. Currently there is no effective treatment except resection at a very early stage with or with-out chemotherapy. Of various epithelial cancers, CRC in particular has a potential for prevention, since most cancers follow the adenoma-carcinoma sequence, and the interval between detection of an adenoma and its progression to carcinoma is usually about a decade. However no effective chemopreventive agent except COX-2 inhibitors, limited in their scope due to cardiovascular side effects, have shown promise in reducing adenoma recurrence. To this end, natural agents that can target important carcinogenic pathways without demonstrating discernible adverse effects would serve as ideal chemoprevention agents. In this review, we discuss merits of two such naturally occurring dietary agents—curcumin and resveratrol—for chemoprevention of CRC.
PMCID: PMC3837545  PMID: 20924971
23.  Promoter methylation of E- cadherin, p16, and RAR-β2 genes in breast tumors and dietary intake of nutrients important in one-carbon metabolism 
Nutrition and cancer  2011;63(7):10.1080/01635581.2011.605982.
Aberrant DNA methylation plays a critical role in carcinogenesis, and the availability of dietary factors involved in one carbon metabolism may to contribute to aberrant DNA methylation. We investigated the association of intake of folate, vitamins B2, B6, B12, and methionine with promoter methylation of E- cadherin, p16, and RAR-β2 genes in archived tumor tissues from incident, primary breast cancer cases in a population-based case-control study. Real time methylation-specific PCR was performed on 803 paraffin-embedded samples; usual dietary intake was queried from a food frequency questionnaire. Unconditional logistic regression was used to derive adjusted odds ratios (OR) and 95% confidence intervals (CI) for likelihood of promoter methylation for high compared to low intake of those one-carbon nutrients. Overall, in case-case comparisons, dietary intakes of folate, vitamins B2, B6, B12, and methionine were not associated with likelihood of promoter methylation of E- cadherin, p16, and RAR-β2 for all cases combined or within strata defined by menopausal status and ER status in this study. This finding, however, does not exclude the possibility that intake of such nutrients might have the ability to modulate promoter methylation in normal, or pre-malignant (dysplastic) breast tissue.
PMCID: PMC3834353  PMID: 21916701
one-carbon nutrient; breast cancer; epidemiology; epigenetics; promoter methylation
24.  Hepatic vitamin A preloading reduces colorectal cancer metastatic multiplicity in a mouse xenograft model 
Nutrition and cancer  2012;64(5):10.1080/01635581.2012.687425.
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 (RAR)-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 (2400 IU retinyl palmitate/kg diet) or a vitamin A supplemented diet (200,000 IU retinyl palmitate/kg diet) for one month 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 wks 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.
PMCID: PMC3829719  PMID: 22642873
colon cancer; vitamin A; chemoprevention; metastasis
25.  Dietary intake of specific fatty acids and breast cancer risk among postmenopausal women in the VITAL cohort 
Nutrition and cancer  2012;64(8):1131-1142.
Studies of dietary fat intake and breast cancer have been inconsistent and few have examined specific fatty acids. We examined the association between specific monounsaturated (MUFA), polyunsaturated (PUFA), saturated (SFA), and trans-fatty acids (TFA) and breast cancer risk. Participants, 50–76y, were female members of the VITamins And Lifestyle (VITAL) Cohort, who were postmenopausal at baseline. In 2000–2002, participants completed a food frequency questionnaire. 772 incident, primary breast cancer cases were identified using a population-based cancer registry. Cox proportional hazard models estimated hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between fatty acid intake and breast cancer risk. Intake of total MUFAs (Highest vs. lowest quintile: HR=1.61, 95% CI: 1.08–2.38, P-trend=0.02), particularly myristoleic and erucic acids, was associated with increased breast cancer risk. Whereas total SFA was suggestive of an increased risk (HR=1.47, 95% CI: 1.00–2.15, P-trend=0.09), strong associations were observed for palmitic, margaric, and stearic acids. Total TFA and PUFA intake were not associated with breast cancer. However, among TFAs, linolelaidic acid was positively associated with risk; among PUFAs, intake of eicosapentaenoic and docosahexaenoic acids were inversely associated with risk. Our findings show that fatty acids are heterogeneous in their association with postmenopausal breast cancer risk.
PMCID: PMC3633593  PMID: 23137008

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