Publications by authors named "Maarten C Bosland"

87 Publications

Selective progesterone receptor blockade prevents BRCA1-associated mouse mammary tumors through modulation of epithelial and stromal genes.

Cancer Lett 2021 Nov 27;520:255-266. Epub 2021 Jul 27.

Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address:

Pharmacological approaches to breast cancer risk-reduction for BRCA1 mutation carriers would provide an alternative to mastectomy. BRCA1-deficiency dysregulates progesterone signaling, promoting tumorigenesis. Selective progesterone receptor (PR) modulators (SPRMs) are therefore candidate prevention agents. However, their efficacy varies in different BRCA1-deficient mouse models. We examined chemopreventive efficacy of telapristone acetate (TPA), ulipristal acetate (UPA) and mifepristone (MFP) in mice with a conditional knockout of the Brca1 C-terminal domain. The SPRMs displayed a spectrum of efficacy: UPA was most effective, TPA less, and MFP ineffective. Compared to no-treatment controls, UPA reduced tumorigenesis (p = 0.04), and increased tumor latency (p = 0.03). In benign mammary glands, UPA decreased Ki67 (p < 0.001) and increased PR expression (p < 0.0001). RNA sequencing analysis revealed distinct gene expression in response to UPA and MFP. UPA downregulated glycolysis and extracellular matrix-inflammation genes (Fn1, Ptgs2, Tgfb2, Tgfb3) whereas MFP downregulated claudin genes and upregulated amino acid metabolism and inflammation genes. The anti-glucocorticoid effects of MFP appeared not to be tumor-protective, while altering estrogen receptor signaling and NF-kB activation. Our study points to an important role of epithelial PR and its paracrine action on the microenvironment in BRCA1-deficient mammary tumorigenesis, and prevention.
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http://dx.doi.org/10.1016/j.canlet.2021.07.034DOI Listing
November 2021

Prevalence of prostate cancer at autopsy in Nigeria-A preliminary report.

Prostate 2021 Jun 27;81(9):553-559. Epub 2021 Apr 27.

Department of Urology, Northwestern University, Chicago, Illinois, USA.

Background And Objectives: Prostate cancer is the most commonly diagnosed cancer in Nigerian men despite the lack of PSA based screening. Current prevalence estimates in Nigeria are based on cancer registry data obtained primarily from hospital admissions and therefore not truly reflective of prostate cancer incidence. Prior autopsy series did not adhere to modern pathologic quality practices. The aim of this study was to explore the prevalence of asymptomatic prostate cancer among Nigerian men at the time of autopsy.

Methods: Prostates were collected at autopsy at the Universities of Lagos and Calabar Teaching Hospitals from men aged more than 40 who died from causes other than prostate cancer. Thirty-nine prostates from Nigerian men autopsied in 2017 to 2018 were formalin-fixed, weighed, and sliced at 4 mm intervals. Haematoxylin and eosin-stained paraffin sections were prepared from these slices. Presence and Gleason grade of prostatic adenocarcinomas and presence of high-grade prostatic intraepithelial neoplasia (HGPIN) were recorded.

Results: Mean age of cases was 55 ± 11 years and mean prostatic weight was 23.0 ± 10.9 g. The crude prevalence of HGPIN was 20.6%. Overall crude prevalence of prostate cancer was 8.8% (n = 34), increasing from 8.3% for men aged 40-59 (n = 23) to 10.0% for men ≥60 years old (n = 10). Two tumors were small and had Gleason Grade 3 + 3 or 3 + 4, and one large stage T3 tumor with Gleason Grade 4 + 3 disease and neuroendocrine appearance was found in a 54-year-old man.

Conclusions: The 8.8% prevalence of subclinical prostate cancer at autopsy was similar to previously reported Nigerian studies with more limited tissue sampling (6.7%-10%), but considerably lower than estimates in other populations, including African Americans. Our findings suggest that latent, clinically asymptomatic prostate cancer is less frequent in Nigerians than in African Americans, despite shared genetic ancestry. Future studies with increased sample size are warranted to provide insight in the natural history and true prevalence of prostate cancer in West Africa.
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http://dx.doi.org/10.1002/pros.24133DOI Listing
June 2021

Randomized, Placebo-Controlled Six-Month Intervention Study of Soy Protein Isolate in Men with Biochemical Recurrence after Radical Prostatectomy: A Pilot Study.

Nutr Cancer 2021 Mar 25:1-10. Epub 2021 Mar 25.

Departments of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA.

There is evidence to suggest that soy may be beneficial for prostate cancer patients, but few randomized trials have addressed this. We examined the effect of 6-8 mo soy protein supplementation on prostate specific antigen (PSA) serum levels in men who recurred (PSA > 0.1 ng/ml) within three years of prostatectomy. Sixteen men were randomized to 20 g soy protein (∼24-26/day genistein; ∼40-43/day total isoflavones) or casein placebo. PSA was measured at base line and at 1, 2, 4, and 6-8 mo. Serum genistein levels greatly increased from baseline and cholesterol decreased in the soy group. In both treatment arms PSA increased similarly and PSA doubling times were not different over the 6-8 mo study duration. Two subjects in each group had stable PSA. A literature search for clinical studies of soy, isoflavones, and PSA revealed that supplementation with soy or isoflavones did not affect PSA in virtually all clinical studies identified. Although this study is too small to draw a definitive conclusion on the effect of soy protein on PSA in men with biochemical failure, the null finding in this study is consistent with the results of virtually all reports of soy and soy isoflavones in the literature.
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http://dx.doi.org/10.1080/01635581.2021.1903949DOI Listing
March 2021

Soy protein supplementation in men following radical prostatectomy: a 2-year randomized, placebo-controlled clinical trial.

Am J Clin Nutr 2021 04;113(4):821-831

Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA.

Background: Many studies have addressed effects of dietary supplementation with soy protein, but most have been inconsistent and few have been long-term studies in men.

Objectives: This study was a secondary analysis of body weight, blood pressure, thyroid hormones, iron status, and clinical chemistry in a 2-y trial of soy protein supplementation in middle-aged to older men.

Methods: Data were analyzed as secondary outcomes of a randomized controlled trial of dietary supplementation with 20 g/d soy protein isolate, providing 41 mg/d total isoflavones and 23 mg/d genistein, in 44- to 75-y-old men who were at risk of cancer recurrence following prostatectomy randomized to soy (n = 50) or a casein-based placebo (n  = 43). Weight, blood pressure, and blood samples were collected at baseline, every 2 mo in year 1, and every 3 mo in year 2.

Results: Compared with casein, soy supplementation did not affect body weight, blood pressure, serum total cholesterol, calcium, phosphorus, and thyroid hormones. Serum ferritin concentrations doubled over 2 y in both groups (117-129%), whereas hemoglobin and hematocrit increased slightly. In an exploratory subgroup analysis of soy group data, weight increased in subjects producing equol but not in nonproducers. Blood pressure was reduced in nonequol producers but not in producers. Other endpoints were not affected by equol production status.

Conclusions: Soy protein supplementation for 2 y compared with a casein-based placebo did not affect body weight, blood pressure, serum total cholesterol, iron status parameters, calcium, phosphorus, and thyroid hormones. Exploratory analysis suggests that equol production status of subjects on soy may modify effects of soy on body weight and possibly blood pressure. This trial was registered at clinicaltrials.gov as NCT00765479.
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http://dx.doi.org/10.1093/ajcn/nqaa390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024002PMC
April 2021

Impact of 18-Month Soy Protein Supplementation on Steroid Hormones and Serum Biomarkers of Angiogenesis, Apoptosis, and the Growth Hormone/IGF-1 Axis: Results of a Randomized, Placebo-Controlled Trial in Males Following Prostatectomy.

Nutr Cancer 2021 Jan 12:1-12. Epub 2021 Jan 12.

Departments of Oncology and Pathology, Wayne State University, Detroit, MI, USA.

Many studies have addressed the effects of dietary supplementation with soy protein on cancer risk and mortality, but there are only few randomized studies with soy in males. We used serum samples from a two-year trial of soy protein isolate supplementation in middle-aged to older males at risk of recurrence of prostate cancer after radical prostatectomy to determine soy effects on steroid hormones involved in prostate cancer (testosterone, SHBG, and estradiol) and explore the effects on biomarkers of the growth hormone/IGF-1 axis, apoptosis, and angiogenesis. Compared with a casein-based placebo, 18 mo, of consumption of 19.2 g/day of whole soy protein isolate containing 24 mg genistein-reduced circulating testosterone and SHBG, but not free testosterone, and did not affect serum concentrations of estradiol, VEGF, IGF-1, IGFBP-3, IGF-1/IGFBP-3 ratio, soluble Fas, Fas-ligand, and sFas/Fas-ligand ratio. Thus, soy protein supplementation for 18 mo, affected the androgen axis, but the effects on other cancer biomarkers remain to be more definitively determined. The study was registered at clinicaltrials.gov (NCT00765479).
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http://dx.doi.org/10.1080/01635581.2020.1870706DOI Listing
January 2021

The New Zealand white rabbit animal model of acute radiation syndrome: hematopoietic and coagulation-based parameters by radiation dose following supportive care.

Int J Radiat Biol 2020 Oct 26:1-18. Epub 2020 Oct 26.

Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA.

Purpose: Animal models that accurately reflect human responses to radiation injury are needed for advanced mechanistic investigation and development of effective therapeutics. The rabbit is an established animal model accepted by the FDA for studies of cardiovascular disease, lipid metabolism, the development of anticoagulants, testing of bone implants, and the development of treatments for infectious diseases such as HIV. The purpose of this study was to investigate the New Zealand White (NZW) Rabbit model as a model of acute radiation exposure because of its established similarity to human vascular, immune, and coagulation responses.

Materials And Methods: Two sequential studies were performed in a total of 81 male NZW rabbits, 16-20 weeks of age. All animals underwent clinical observations and peripheral blood analyses following a single dose of 0, 6, 7, 8, 8.5, 9, or 10 Gy of total body irradiation via a 6 MV Linear accelerator photon source on day 0. Animals were treated with timed release fentanyl patch (days 0-30), subcutaneous hydration (day 1, Study 2 only), and oral sulfamethoxazole/trimethoprim 30 mg/kg once daily (days 3-30) and were followed for 30 days or to time of mortality.

Results: Study 1 revealed the estimated LD30, -50, -70, and -90 with 95% confidence intervals (CI) at 30 days to be 6.7 (CI: 5.9-7.4), 7.3 (CI: 6.7-7.8), 7.9 (CI: 7.3-8.4), and 8.8 (CI: 7.9-9.7) Gy, respectively. In study 2, a survey of blood coagulation and biochemical parameters were performed over time and necropsy. Complete blood counts taken from animals exposed to 7, 8, or 10 Gy, demonstrated dose-dependent depletion of lymphocytes, neutrophils, and platelets. Platelet counts recovered to baseline levels in survivors by day 30, whereas lymphocyte and neutrophil counts did not. Decedent animals demonstrated grade 3 or 4 neutropenia and lymphopenia at time of death; 64% of the decedents experienced a 30% or greater drop in hematocrit. Decedent animals demonstrated more than 100% increases from serum baseline levels of blood urea nitrogen, creatinine, aspartate aminotransferase, and triglyceride levels at the time of death whereas survivors on average demonstrated modest or no elevation.

Conclusion: This NZW rabbit model demonstrates dose-dependent depletion of hematopoietic parameters. The LD of 7.8 Gy (95% CI: 6.6-8.4) with supportive care appears to be close to the ranges reported for rhesus macaques (5.25-7.44 Gy) and humans (6-8 Gy) with supportive care. These findings support the utility of the NZW rabbit model for further mechanistic investigation of acute radiation exposure and medical countermeasure testing.
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http://dx.doi.org/10.1080/09553002.2020.1820606DOI Listing
October 2020

Eliminating Deaths From Cervical Cancer-Report of a Panel at the 7th Annual Symposium on Global Cancer Research, a Satellite Meeting at the Consortium of Universities for Global Health 10th Annual Meeting.

J Glob Oncol 2019 11;5:1-7

World Health Organization, Geneva, Switzerland.

This is a summary of the presentations addressing approaches and achievements to reach the goal of eliminating cervical cancer as a global public health problem that were delivered at the 7th Annual Symposium on Global Cancer Research at the 10th Annual Consortium of Universities for Global Health Meeting in March 2019. Dr Princess Nothemba Simelela, Assistant Director-General for Family, Women, Children and Adolescents, World Health Organization, gave an introduction to the World Health Organization-led Cervical Cancer Elimination Initiative and the emerging conceptual framework and targets that will shape the global 2020 to 2030 strategy. Subsequent presentations shared experiences from national programs in Rwanda (Agnes Binagwaho), Latin America (Patricia J. Garcia), and Senegal (Babacar Gueye and J. Andrew Dykens. Successes in intensified human papillomavirus vaccination and screening with follow-up treatment of early and advanced lesions detected are highlighted as well as the challenges and obstacles in achieving and maintaining high coverage in Africa and Latin America. With strong political leadership, commitment of national stakeholders, and the use of proven and cost-effective approaches to human papillomavirus vaccination, screening, and treatment, the vision of a world free of cervical cancer and saving women's lives every year by preventing deaths from cervical cancer will be achievable in the next generation in all countries.
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http://dx.doi.org/10.1200/JGO.19.00287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882512PMC
November 2019

Effects of Black Raspberries and Their Constituents on Rat Prostate Carcinogenesis and Human Prostate Cancer Cell Growth In Vitro.

Nutr Cancer 2020 12;72(4):672-685. Epub 2019 Aug 12.

Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

Prostate cancer patients often use dietary supplements, such as black raspberries, which are a rich source of compounds with antioxidant and anticancer activity, particularly on gastrointestinal cancers. Feeding black raspberries inhibited mammary cancer induction in rats and growth of cancer cells in nude mice, indicating systemic bioavailability of bioactive compounds. We tested whether feeding black raspberries and its constituents would inhibit prostate cancer development. However, we did not find preventive effects in two rat prostate carcinogenesis models, even though the berry anthocyanin metabolite protocatechuic acid was detectable in their prostates. Black raspberry extract, the anthocyanin cyanidin-3-rutinoside and protocatechuic acid did not inhibit prostate cancer cell growth in vitro, but ellagic acid and its urolithin A metabolite did at high concentrations. Prostate cancer cell migration was not affected by these agents nor was growth in soft agar, except that ellagic acid reduced colony formation at physiological concentrations and protocatechuic acid at high concentrations. Low bioavailability of bioactive berry compounds and metabolites may limit exposure of tissues such as the prostate, since we found that cyanidin-3-rutinoside was not bioavailable to prostate cancer cells, but its aglycone cyanidin was and inhibited their growth. Thus, black raspberries are unlikely to prevent prostate cancer.
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http://dx.doi.org/10.1080/01635581.2019.1650943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012690PMC
January 2021

Novel insight in estrogen homeostasis and bioactivity in the ACI rat model of estrogen-induced mammary gland carcinogenesis.

Arch Toxicol 2019 07 22;93(7):1979-1992. Epub 2019 May 22.

Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.

Despite being widely used to investigate 17β-estradiol (E2)-induced mammary gland (MG) carcinogenesis and prevention thereof, estrogen homeostasis and its significance in the female August Copenhagen Irish (ACI) rat model is unknown. Thus, levels of 12 estrogens including metabolites and conjugates were determined mass spectrometrically in 38 plasmas and 52 tissues exhibiting phenotypes ranging from normal to palpable tumor derived from a representative ACI study using two different diets. In tissues, 40 transcripts encoding proteins involved in estrogen (biotrans)formation, ESR1-mediated signaling, proliferation and oxidative stress were analyzed (TaqMan PCR). Influence of histo(patho)logic phenotypes and diet on estrogen and transcript levels was analyzed by 2-way ANOVA and explanatory variables influencing levels and bioactivity of estrogens in tissues were identified by multiple linear regression models. Estrogen profiles in tissue and plasma and the influence of Hsd17b1 levels on intra-tissue levels of E2 and E1 conclusively indicated intra-mammary formation of E2 in ACI tumors by HSD17B1-mediated conversion of E1. Proliferation in ACI tumors was influenced by Egfr, Igf1r, Hgf and Met levels. 2-MeO-E1, the only oxidative estrogen metabolite detected above 28-42 fmol/g, was predominately observed in hyperplastic tissues and intra-tissue conversion of E1 seemed to contribute to its levels. The association of the occurrence of 2-MeO-E1 with higher levels of oxidative stress observed in hyperplastic and tumor tissues remained equivocal. Thus, the present study provides mechanistic explanation for previous and future results observed in the ACI model.
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http://dx.doi.org/10.1007/s00204-019-02483-wDOI Listing
July 2019

Role of Estrogen in Androgen-Induced Prostate Carcinogenesis in NBL Rats.

Horm Cancer 2019 06 16;10(2-3):77-88. Epub 2019 Mar 16.

Department of Pathology, University of Illinois at Chicago, Chicago, IL, 60612, USA.

Androgens are thought to cause prostate cancer, but the underlying mechanisms are unclear. Data from animal studies suggest that for androgens to cause prostate cancer, they must be aromatized to estrogen and act in concert with estrogen metabolites. We tested the hypothesis that androgen-receptor and estrogen receptor-mediated effects of androgen and estrogen are necessary, as well as genotoxicity of estrogen metabolites. NBL rats were treated with androgenic and estrogenic compounds for 16-75 weeks through slow-release silastic implants or pellets. Testosterone alone induced cancer in the prostate of 37% of rats. 5α-Dihydrotestosterone, which cannot be converted to estradiol or testosterone, did not cause a significant prostate cancer incidence (4%). Addition of estradiol to 5α-dihydrotestosterone treatment did not markedly enhance prostate cancer incidence (14%), unlike adding estradiol to testosterone treatment which induced a 100% tumor incidence. Testosterone plus estradiol treatment induced a DNA adduct detectable by P-postlabeling, oxidative DNA damage (8-hydroxyguanosine), and lipid peroxidation at the site within the prostate where this treatment causes cancers, preceding later cancer formation. The non-estrogenic 4-hydroxy metabolite of estradiol, when combined with testosterone, induced prostatic dysplasia within 16 weeks and, after long-term treatment, a very low incidence of prostate cancer (21%). When an estrogen that cannot be hydroxylated (2-fluoroestradiol) was added to this combined treatment with testosterone and 4-hydroxyestradiol, dysplasia frequency after 16 weeks was doubled. These results strongly support the hypothesis, but additional definitive studies are needed which may identify new targets to interfere with these mechanisms that are clinically feasible in humans.
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http://dx.doi.org/10.1007/s12672-019-00360-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545235PMC
June 2019

Effects of Black Raspberries and Their Ellagic Acid and Anthocyanin Constituents on Taxane Chemotherapy of Castration-Resistant Prostate Cancer Cells.

Sci Rep 2019 03 13;9(1):4367. Epub 2019 Mar 13.

Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

Cancer patients often use dietary supplements while on therapy, but little is known about interactions of supplements with cancer chemotherapy. Black raspberries (BRB) have anti-cancer effects, but have not been evaluated for interference with chemotherapy for castrate-resistant prostate cancer (CRPC). Here we studied whether BRB and some of their constituents interact with docetaxel and cabazitaxel on CRPC cells in culture and implanted into nude mice. Ellagic acid increased, but BRB extract inhibited, microtubule assembly. Ellagic acid decreased tubulin polymerization by cabazitaxel and bound to tubulin. Ellagic acid, its metabolite urolithin A, BRB extract, and the anthocyanin metabolite protocatechuic acid (PCA) did not alter cytotoxicity of taxanes. Ellagic acid inhibited drug efflux in CRPC cells, but BRB extract and PCA did not. None of these compounds altered CYP3A4 activity. Although dietary ellagic acid did not alter the tumor growth inhibition by docetaxel of xenografted 22Rv1 cells, ellagic acid has the potential to interfere with taxane chemotherapy by reducing tubulin polymerization while inhibiting P-glycoprotein drug efflux. These data are cause for concern of consuming ellagic acid during treatment for CRPC and indicate need for further research, but BRB consumption appears safe.
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http://dx.doi.org/10.1038/s41598-019-39589-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416359PMC
March 2019

Global health and cancer.

Lancet 2019 03;393(10175):983

Center for Global Health and Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(18)33068-XDOI Listing
March 2019

Victor Feron, A life dedicated to toxicology and toxicologic pathology.

Food Chem Toxicol 2019 Mar 29;125:438. Epub 2019 Jan 29.

Professor of Environmental Medicine and Urology, Pathology Department, University of Illinois, 909 South Wolcott Ave, Chicago, USA. Electronic address:

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http://dx.doi.org/10.1016/j.fct.2019.01.006DOI Listing
March 2019

Evaluation of Bisphenol A (BPA) Exposures on Prostate Stem Cell Homeostasis and Prostate Cancer Risk in the NCTR-Sprague-Dawley Rat: An NIEHS/FDA CLARITY-BPA Consortium Study.

Environ Health Perspect 2018 11;126(11):117001

Chicago Center for Health and Environment, University of Illinois at Chicago, Chicago, Illinois, USA.

Background: Previous work determined that early life exposure to low-dose Bisphenol A (BPA) increased rat prostate cancer risk with aging. Herein, we report on prostate-specific results from CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity), which aims to resolve uncertainties regarding BPA toxicity.

Objectives: We sought to ) reassess whether a range of BPA exposures drives prostate pathology and/or alters prostatic susceptibility to hormonal carcinogenesis, and ) test whether chronic low-dose BPA targets prostate epithelial stem and progenitor cells.

Methods: Sprague-Dawley rats were gavaged daily with vehicle, ethinyl estradiol (EE) or [Formula: see text] BPA/kg-BW during development or chronically, and prostate pathology was assessed at one year. One developmentally exposed cohort was given testosterone plus estradiol ([Formula: see text]) implants at day 90 to promote carcinogenesis with aging. Epithelial stem and progenitor cells were isolated by prostasphere (PS) culture from dorsolateral prostates (DLP) of rats continuously exposed for six months to [Formula: see text] BPA/kg-BW. Gene expression was analyzed by quantitative real time reverse transcription polymerase chain reaction (qRT-PCR).

Results: Exposure to BPA alone at any dose did not drive prostate pathology. However, rats treated with EE, 2.5, 250, or [Formula: see text] BPA/kg-BW plus [Formula: see text] showed greater severity of lateral prostate intraepithelial neoplasia (PIN), and DLP ductal adenocarcinoma multiplicity was markedly elevated in tumor-bearing rats exposed to [Formula: see text]-BW. DLP stem cells, assessed by PS number, doubled with chronic EE and [Formula: see text] exposures. PS size, reflecting progenitor cell proliferation, was greater at 25 and [Formula: see text] BPA doses, which also shifted lineage commitment toward basal progenitors while reducing luminal progenitor cells.

Conclusions: Together, these results confirm and extend previous evidence using a rat model and human prostate epithelial cells that low-dose BPA augments prostate cancer susceptibility and alters adult prostate stem cell homeostasis. Therefore, we propose that BPA exposures may contribute to the increased carcinogenic risk in humans that occurs with aging. https://doi.org/10.1289/EHP3953.
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http://dx.doi.org/10.1289/EHP3953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371765PMC
November 2018

Lack of combination effects of soy isoflavones and taxane chemotherapy of castration-resistant prostate cancer.

Prostate 2019 02 21;79(2):223-233. Epub 2018 Oct 21.

Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.

Background: Patients with cancer, including prostate cancer, often use dietary supplements, such as soy or isoflavones, before, during, or after therapy. There is little information about possible interactions between supplements and cancer chemotherapy. There are some reports suggesting enhancement by genistein of taxane chemotherapy for castrate-resistant prostate cancer (CRPC).

Methods: We investigated whether physiologically attainable concentrations of soy isoflavones (≤10 μM) interact with taxanes on growth inhibition of CRPC cells in vitro and in vivo in nude mice exposed via the diet, on microtubule disassembly in vitro, and on P-glycoprotein-mediated drug efflux in 22Rv1 cells and CYP3A4 activity in microsomes.

Results: Genistein, daidzein, and equol did not affect growth of VCaP, 22Rv1, C4-2, and PC-3 CRPC cells or growth inhibition of these cells by docetaxel and cabazitaxel. These isoflavones did not inhibit microtubule disassembly in vitro or inhibit the microtubule effects of taxanes and genistein did not bind substantially to microtubules. Genistein considerably inhibited P-glycoprotein-mediated drug efflux in 22Rv1 cells and CYP3A4 activity in microsomes. However, dietary supplementation with genistein at 250 and 500 ppm did not affect the tumor growth inhibiting effect of docetaxel on 22Rv1 cells xenografted in nude mice.

Conclusions: Our results with relevant cell models and clinically achievable concentrations of soy isoflavones do not support the notion that genistein or other soy isoflavones can enhance the effects of taxane chemotherapy in CRPC cell and xenograft models. Yet, the inhibitory effects of genistein on drug efflux in 22Rv1 cells and on microsomal CYP3A4 activity raise the possibility that genistein can affect taxane effects on CRPC cells in other circumstances than those we studied, which merits further research.
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http://dx.doi.org/10.1002/pros.23727DOI Listing
February 2019

Vitamin K2, a menaquinone present in dairy products targets castration-resistant prostate cancer cell-line by activating apoptosis signaling.

Food Chem Toxicol 2018 May 9;115:218-227. Epub 2018 Feb 9.

Department of Biomedical Sciences, University of Illinois-College of Medicine, Rockford, IL, USA. Electronic address:

The aim of this study was to evaluate the therapeutic effects of vitamin K2 (VK2) on castration-resistant prostate cancer (CRPC) and its anti-cancer mechanisms in a pre-clinical study using a VCaP cell line (ATCC CRL-2876™) which was established from a vertebral bone metastasis from a patient with hormone refractory prostate cancer. Our data showed that VK2 significantly inhibited CRPC VCaP cell proliferation in a dose-dependent manner at 48 h treatment in vitro. In addition, VK2 reduced the migration potential of VCaP cells and inhibited anchorage-independent growth of these cells. Our results also showed that VK2 induces apoptosis in VCaP cells. Furthermore, VK2 enforced growth arrest in VCaP cells by activating cellular senescence. Notably, VK2 treatment elevated the levels of reactive oxygen species in VCaP cells. Western blot analysis revealed that VK2 downregulated the expression of androgen receptor, BiP, survivin, while activating caspase-3 and -7, PARP-1 cleavage, p21 and DNA damage response marker, phospho-H2AX in VCaP cells. In conclusion, our study suggests that VK2 might be a potential anti-cancer agent for CRPC by specifically targeting key anti-apoptotic, cell cycle progression and metastasis-promoting signaling molecules.
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http://dx.doi.org/10.1016/j.fct.2018.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935569PMC
May 2018

A Novel l-Asparaginase with low l-Glutaminase Coactivity Is Highly Efficacious against Both T- and B-cell Acute Lymphoblastic Leukemias .

Cancer Res 2018 03 17;78(6):1549-1560. Epub 2018 Jan 17.

The Jesse Brown VA Medical Center, Chicago, Illinois.

Acute lymphoblastic leukemia (ALL) is the most common type of pediatric cancer, although about 4 of every 10 cases occur in adults. The enzyme drug l-asparaginase serves as a cornerstone of ALL therapy and exploits the asparagine dependency of ALL cells. In addition to hydrolyzing the amino acid l-asparagine, all FDA-approved l-asparaginases also have significant l-glutaminase coactivity. Since several reports suggest that l-glutamine depletion correlates with many of the side effects of these drugs, enzyme variants with reduced l-glutaminase coactivity might be clinically beneficial if their antileukemic activity would be preserved. Here we show that novel low l-glutaminase variants developed on the backbone of the FDA-approved l-asparaginase were highly efficacious against both T- and B-cell ALL, while displaying reduced acute toxicity features. These results support the development of a new generation of safer l-asparaginases without l-glutaminase activity for the treatment of human ALL. A new l-asparaginase-based therapy is less toxic compared with FDA-approved high l-glutaminase enzymes .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856643PMC
March 2018

δ-Tocopherol inhibits the development of prostate adenocarcinoma in prostate specific Pten-/- mice.

Carcinogenesis 2018 02;39(2):158-169

Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, USA.

The PTEN/PI3K/AKT axis plays a critical role in regulating cell growth, differentiation and survival. Activation of this signaling pathway is frequently found in human cancers. Our previous studies demonstrated that δ-tocopherol (δ-T) attenuates the activation of AKT by growth factor in prostate cancer cell lines, leading to inhibition of proliferation and induction of apoptosis. Herein, we investigated whether δ-T inhibits the development of prostate adenocarcinoma in prostate-specific Pten-/- (Ptenp-/-) mice in which the activation of AKT is the major driving force for tumorigenesis. By feeding Ptenp-/- mice with AIN93M or 0.2% δ-T supplemented diet starting at the age of 6 or 12 weeks, we found that δ-T treatment reduced prostate adenocarcinoma multiplicity at the age of 40 weeks by 53.3 and 42.7%, respectively. Immunohistochemical (IHC) analysis demonstrated that the phosphorylation of AKT (T308) was reduced in the prostate of the mice administered the δ-T diet. Consistently, proliferation was reduced and apoptosis was increased in prostate lesions of mice on the δ-T diet. Oxidative stress, as determined by IHC staining of 8-OH-dG, was not altered during prostate tumorigenesis, nor was it affected by administration of δ-T. In contrast, α-tocopherol (α-T) at 0.2% in the diet did not affect prostate adenocarcinoma multiplicity in the Ptenp-/- mice. This finding is consistent with data from our previous study that δ-T, but not α-T, inhibits the activation of AKT and the growth of prostate cancer cells. Together, these results demonstrate that δ-T inhibits the development of prostate adenocarcinoma in Ptenp-/- mice, mainly through inhibition of AKT activation.
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http://dx.doi.org/10.1093/carcin/bgx128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862254PMC
February 2018

Vitamin K and its analogs: Potential avenues for prostate cancer management.

Oncotarget 2017 Aug 19;8(34):57782-57799. Epub 2017 May 19.

Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL, USA.

Epidemiological studies have demonstrated a relationship between cancer incidence and dietary habits. Especially intake of certain essential nutrients like vitamins has been shown to be beneficial in experimental studies and some clinical trials. Vitamin K (VK) is an essential nutrient involved in the blood clotting cascade, and there are considerable experimental data demonstrating its potential anticancer activity in several cancer types including prostate cancer. Previous and studies have focused mainly on anti-oxidative effects as the underlying anticancer mechanism of VK. However, recent studies reveal that VK inhibits the growth of cancer cells through other mechanisms, including apoptosis, cell cycle arrest, autophagy, and modulation of various transcription factors such as Myc and Fos. In the present review, we focus on the anticancer effect of dietary VK and its analogs on prostate cancer, with an emphasis on the signaling pathways that are activated following exposure to these compounds. This review also highlights the potential of VK and its derivatives as an adjuvant treatment in combination with other vitamins or with chemotherapeutic drugs. Based on our recent results and a review of the existing literature, we present evidence that VK and its derivatives can potentially be explored as cancer therapy, especially for prostate cancer.
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http://dx.doi.org/10.18632/oncotarget.17997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593683PMC
August 2017

The common parasite Toxoplasma gondii induces prostatic inflammation and microglandular hyperplasia in a mouse model.

Prostate 2017 Jul 12;77(10):1066-1075. Epub 2017 May 12.

Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana.

Background: Inflammation is the most prevalent and widespread histological finding in the human prostate, and associates with the development and progression of benign prostatic hyperplasia and prostate cancer. Several factors have been hypothesized to cause inflammation, yet the role each may play in the etiology of prostatic inflammation remains unclear. This study examined the possibility that the common protozoan parasite Toxoplasma gondii induces prostatic inflammation and reactive hyperplasia in a mouse model.

Methods: Male mice were infected systemically with T. gondii parasites and prostatic inflammation was scored based on severity and focality of infiltrating leukocytes and epithelial hyperplasia. We characterized inflammatory cells with flow cytometry and the resulting epithelial proliferation with bromodeoxyuridine (BrdU) incorporation.

Results: We found that T. gondii infects the mouse prostate within the first 14 days of infection and can establish parasite cysts that persist for at least 60 days. T. gondii infection induces a substantial and chronic inflammatory reaction in the mouse prostate characterized by monocytic and lymphocytic inflammatory infiltrate. T. gondii-induced inflammation results in reactive hyperplasia, involving basal and luminal epithelial proliferation, and the exhibition of proliferative inflammatory microglandular hyperplasia in inflamed mouse prostates.

Conclusions: This study identifies the common parasite T. gondii as a new trigger of prostatic inflammation, which we used to develop a novel mouse model of prostatic inflammation. This is the first report that T. gondii chronically encysts and induces chronic inflammation within the prostate of any species. Furthermore, T. gondii-induced prostatic inflammation persists and progresses without genetic manipulation in mice, offering a powerful new mouse model for the study of chronic prostatic inflammation and microglandular hyperplasia.
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http://dx.doi.org/10.1002/pros.23362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826344PMC
July 2017

The anti-inflammatory effect of montelukast, a cysteinyl leukotriene receptor-1 antagonist, against estradiol-induced nonbacterial inflammation in the rat prostate.

Naunyn Schmiedebergs Arch Pharmacol 2017 Feb 1;390(2):197-205. Epub 2016 Dec 1.

Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

There is no standard treatment of chronic nonbacterial prostatitis in humans. The current study was aimed to investigate the effect of montelukast, an antagonist of cysteinyl leukotriene receptor-1, against estrogen-induced, nonbacterial lateral lobe-specific prostate inflammation in rats. Male Wistar rats were randomized into five groups of six rats, including sham controls (group 1) and castrated rats (group 2), whereas nonbacterial prostatitis (NBP) was induced in groups 3-5 by castration followed by a daily subcutaneous injection of estradiol (0.25 mg/kg body weight) for 30 days. The rats were left otherwise untreated (group 3) or received a daily oral administration of montelukast (1 and 10 mg/kg body weight for groups 4 and 5, respectively) from the 17th day after castration for two consecutive weeks. Compared with sham controls, induction of NBP led to a significant increase in serum leukotriene B (LTB4), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) levels, along with a significant upregulation in the transcript level of proinflammatory molecules (nuclear factor kappa beta [NF-κβ] and inducible nitric oxide synthase [iNOS]), chemokines (monocyte chemoattractant protein-1 [MCP-1] and eotaxin), and E-selectin in the lateral prostate. Histological examination revealed intense inflammation in the prostate with leukocyte infiltration and acinar degeneration following estradiol treatment of castrated rats. Montelukast significantly suppressed the increase in serum and prostate proinflammatory mediators/chemokines expression and abolished the histologically inflammatory changes in the lateral prostate. These findings indicate that montelukast inhibits estradiol-induced NBP in a rat model through anti-inflammatory mechanisms, suggesting its future beneficial effect for the treatment of clinical chronic NBP.
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http://dx.doi.org/10.1007/s00210-016-1325-4DOI Listing
February 2017

Hepatoma-derived growth factor: A survival-related protein in prostate oncogenesis and a potential target for vitamin K2.

Urol Oncol 2016 11 28;34(11):483.e1-483.e8. Epub 2016 Sep 28.

Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL. Electronic address:

Hepatoma-derived growth factor (HDGF) is a heparin-binding growth factor, which has previously been shown to be expressed in a variety of cancers. HDGF overexpression has also previously been correlated with a poor prognosis in several cancers. The significance of HDGF in prostate cancer, however, has not been investigated. Here, we show that HDGF is overexpressed in both androgen-sensitive LNCaP cells and androgen-insensitive DU145, 22RV1, and PC-3 cells. Forced overexpression enhanced cell viability of RWPE-1 cells, whereas HDGF knockdown reduced cell proliferation in human prostate cancer cells. We also show that HDGF may serve as a survival-related protein as ectopic overexpression of HDGF in RWPE cells up-regulated the expression of antiapoptosis proteins cyclin E and BCL-2, whereas simultaneously down-regulating proapoptotic protein BAX. Western blot analysis also showed that HDGF overexpression modulated the activity of phospho-AKT as well as NF-kB, and these results correlated with in vitro migration and invasion assays. We next assessed the therapeutic potential of HDGF inhibition with a HDGF monoclonal antibody and vitamin k, showing reduced cell proliferation as well as inhibition of NF-kB expression in HDGF overexpressed RWPE cells treated with a HDGF monoclonal antibody and vitamin K. Collectively, our results suggest that HDGF is a relevant protein in prostate oncogenesis and may serve as a potential therapeutic target in prostate cancer.
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http://dx.doi.org/10.1016/j.urolonc.2016.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604255PMC
November 2016

Carnosic acid promotes degradation of the androgen receptor and is regulated by the unfolded protein response pathway in vitro and in vivo.

Carcinogenesis 2016 08 7;37(8):827-838. Epub 2016 Jun 7.

Department of Pharmacy Practice, College of Pharmacy.

Androgen deprivation therapy in prostate cancer is extremely effective; however, due to the continuous expression and/or mutagenesis of androgen receptor (AR), the resistance to antihormonal therapy is a natural progression. Consequently, targeting the AR for degradation offers an alternate approach to overcome this resistance in prostate cancer. In this study, we demonstrate that carnosic acid, a benzenediol diterpene, binds the ligand-binding domain of the AR and degrades the AR via endoplasmic reticulum (ER) stress-mediated proteasomal degradative pathway. In vitro, carnosic acid treatment induced degradation of AR and decreased expression of prostate-specific antigen in human prostate cancer cell lines LNCaP and 22Rv1. Carnosic acid also promoted the expression of ER proteins including BiP and CHOP in a dose-dependent manner. Downregulation of CHOP by small interfering RNA somewhat restored expression of AR suggesting that AR degradation is dependent on ER stress pathway. Future studies will need to evaluate other aspects of the unfolded protein response pathway to characterize the regulation of AR degradation. Furthermore, cotreating cells individually with carnosic acid and proteasome inhibitor (MG-132) and carnosic acid and an ER stress modulator (salubrinal) restored protein levels of AR, suggesting that AR degradation is mediated by ER stress-dependent proteasomal degradation pathway. Degradation of AR and induction of CHOP protein were also evident in vivo along with a 53% reduction in growth of xenograft prostate cancer tumors. In addition, carnosic acid-induced ER stress in prostate cancer cells but not in normal prostate epithelial cells procured from patient biopsies. In conclusion, these data suggest that molecules such as carnosic acid could be further evaluated and optimized as a potential therapeutic alternative to target AR in prostate cancer.
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http://dx.doi.org/10.1093/carcin/bgw052DOI Listing
August 2016

Is There a Future for Chemoprevention of Prostate Cancer?

Cancer Prev Res (Phila) 2016 Aug 20;9(8):642-7. Epub 2016 Apr 20.

Department of Pathology, University of Illinois at Chicago, Chicago, Illinois.

The outcome of the Selenium and Vitamin E Cancer Prevention Trial, demonstrating harm and no preventive activity of selenomethionine and α-tocopherol for prostate cancer, and the lack of approval by the FDA for the use of 5α-reductase inhibitors to prevent prostate cancer have cast doubt about the future of chemoprevention of prostate cancer. This article attempts to critically assess whether the notion that chemoprevention of prostate cancer has no future is warranted. Risk of prostate cancer is modifiable and chemoprevention of prostate cancer, particularly fatal/lethal cancer, is both needed and possible. However, the approach to prostate cancer-chemopreventive agent development has not followed a rational and systematic process. To make progress, the following steps are necessary: (i) identification of intermediate biomarkers predictive of fatal/lethal disease; (ii) development of a rational approach to identification of candidate agents, including high-throughput screening and generation of information on mechanism and biology of candidate agents and potential molecular targets; and (iii) systematic evaluation of the predictive value of preclinical models, phase II trials, and intermediate biomarkers for the outcome of phase III trials. New phase III trials should be based on adequate preclinical and phase II studies. Cancer Prev Res; 9(8); 642-7. ©2016 AACR.
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http://dx.doi.org/10.1158/1940-6207.CAPR-16-0088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970940PMC
August 2016

Interactive effects of 9-cis-retinoic acid and androgen on proliferation, differentiation, and apoptosis of LNCaP prostate cancer cells.

Eur J Cancer Prev 2017 01;26(1):71-77

aDepartment of Pathology, University of Illinois at Chicago, Chicago, Illinois Departments of bEnvironmental Medicine cUrology, New York University School of Medicine, New York, New York, USA dFaculty of Pharmacy, Bezmiâlem Vakif University, Fatih, Istanbul, Turkey.

9-cis-Retinoic acid (9cRA), which binds to both retinoic acid receptors and retinoic X receptors, inhibits prostate cancer induction in rats and reduces growth of prostate cancer cells. However, the nature of this growth inhibition and the interactive influence of androgens are not well defined and are the subject of this report. LNCaP and PC-3 cells were cultured and treated with a range of 9cRA concentrations for 3-6 days in the absence or presence of 5α-dehydrotestosterone. 9cRA inhibited cell proliferation in a dose-dependent manner, plateauing at 10 mol/l. Treatment of cells with 10 mol/l 9cRA inhibited 5α-dihydroxytestosterone (DHT)-stimulated proliferation, the effect of which was maximal at 10 mol/l DHT. Treatment of DHT (10 mol/l)-exposed cells with 9cRA caused a dose-dependent increase in prostate-specific antigen in the medium after 6 days, but not 3 days. 9cRA caused a dose-dependent increase in apoptotic cells stained with H33258 after 3 days, but not 6 days; however, on using flow cytometry, apoptosis was apparent at both 3 and 6 days. Flow cytometry also revealed interference of G0/G1 to S phase transition by 9cRA. Inhibition by 9cRA of anchorage-independent growth of PC-3 cells was also found; LNCaP cells did not grow colonies in soft agar. 9cRA inhibited growth and induced differentiation of human LNCaP prostate cancer cells in vitro and inhibited anchorage-independent growth of PC-3 cells. Because 9cRA and 13-cis-retinoic acid, which is retinoic acid receptor-selective, prevent prostate carcinogenesis in rats, and 13-cis-retinoic acid also inhibits growth of human prostate cancer cells, the RAR is a potential molecular target for prostate cancer prevention and therapy.
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http://dx.doi.org/10.1097/CEJ.0000000000000230DOI Listing
January 2017

Soy isoflavone exposure through all life stages accelerates 17β-estradiol-induced mammary tumor onset and growth, yet reduces tumor burden, in ACI rats.

Arch Toxicol 2016 Aug 9;90(8):1907-16. Epub 2016 Feb 9.

Department of Molecular Cell Physiology and Endocrinology, Institute for Zoology, Technische Universität Dresden, 01062, Dresden, Germany.

There is an ongoing debate whether the intake of soy-derived isoflavones (sISO) mediates beneficial or adverse effects with regard to breast cancer risk. Therefore, we investigated whether nutritional exposure to a sISO-enriched diet from conception until adulthood impacts on 17β-estradiol (E2)-induced carcinogenesis in the rat mammary gland (MG). August-Copenhagen-Irish (ACI) rats were exposed to dietary sISO from conception until postnatal day 285. Silastic tubes containing E2 were used to induce MG tumorigenesis. Body weight, food intake, and tumor growth were recorded weekly. At necropsy, the number, position, size, and weight of each tumor were determined. Plasma samples underwent sISO analysis, and the morphology of MG was analyzed. Tumor incidence and multiplicity were reduced by 20 and 56 %, respectively, in the sISO-exposed rats compared to the control rats. Time-to-tumor onset was shortened from 25 to 20 weeks, and larger tumors developed in the sISO-exposed rats. The histological phenotype of the MG tumors was independent of the sISO diet received, and it included both comedo and cribriform phenotypes. Morphological analyses of the whole-mounted MGs also showed no diet-dependent differences. Lifelong exposure to sISO reduced the overall incidence of MG carcinomas in ACI rats, although the time-to-tumor was significantly shortened.
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http://dx.doi.org/10.1007/s00204-016-1674-2DOI Listing
August 2016

Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges.

Nutr Cancer 2016 23;68(1):1-17. Epub 2015 Nov 23.

c Department of Pathology , University of Illinois at Chicago, College of Medicine, Chicago, Illinois, USA and Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Bezmiâlem Vakif University , Istanbul , Turkey.

The negative efficacy outcomes of double-blinded, randomized, placebo-controlled Phase III human clinical trials with selenomethionine (SeMet) and SeMet-rich selenized-yeast (Se-yeast) for prostate cancer prevention and Se-yeast for prevention of nonsmall cell lung cancer (NSCLC) in North America lead to rejection of SeMet/Se-yeast for cancer prevention in Se-adequate populations. We identify 2 major lessons from the outcomes of these trials: 1) the antioxidant hypothesis was tested in wrong subjects or patient populations, and 2) the selection of Se agents was not supported by cell culture and preclinical animal efficacy data as is common in drug development. We propose that next-generation forms of Se (next-gen Se), such as methylselenol precursors, offer biologically appropriate approaches for cancer chemoprevention but these are faced with formidable challenges. Solid mechanism-based preclinical efficacy assessments and comprehensive safety studies with next-gen Se will be essential to revitalize the idea of cancer chemoprevention with Se in the post-SELECT era. We advocate smaller mechanism-driven Phase I/II trials with these next-gen Se to guide and justify future decisions for definitive Phase III chemoprevention efficacy trials.
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http://dx.doi.org/10.1080/01635581.2016.1105267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822195PMC
December 2016

Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A-humanized mice.

Cancer Lett 2016 Feb 12;371(1):71-8. Epub 2015 Nov 12.

Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Piscataway, NJ, USA; Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA. Electronic address:

Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (α-T), β-T, γ-T and δ-T. The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of α-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than α-T was tested, herein, in a novel prostate carcinogenesis model induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200 mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a γ-T-rich mixture of tocopherols (γ-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified δ-T, γ-T or α-T (0.2% in diet) showed that δ-T was more effective than γ-T or α-T in preventing mPIN formations and p-AKT elevation. These results indicate that γ-TmT and δ-T could be effective preventive agents of prostate cancer.
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http://dx.doi.org/10.1016/j.canlet.2015.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721244PMC
February 2016
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