•We reviewed of all anti-carcinogenic effects of soy isoflavones in prostate cancer.•We discussed the traditional growth and apoptotic pathways in prostate cancer cells.•Other new-fangled mechanisms ...were discussed, e.g. autophagy, telomerase, epigenetics.•Effect on cancer milieu, e.g. immune, stem and endothelial cells was also discussed.•These are discussed along with considerations about doses and preclinical models.
Soy isoflavones are dietary components for which an association has been demonstrated with reduced risk of prostate cancer (PCa) in Asian populations. However, the exact mechanism by which these isoflavones may prevent the development or progression of PCa is not completely understood. There are a growing number of animal and in vitro studies that have attempted to elucidate these mechanisms. The predominant and most biologically active isoflavones in soy products, genistein, daidzein, equol, and glycetin, inhibit prostate carcinogenesis in some animal models. Cell-based studies show that soy isoflavones regulate genes that control cell cycle and apoptosis. In this review, we discuss the literature relevant to the molecular events that may account for the benefit of soy isoflavones in PCa prevention or treatment. These reports show that although soy isoflavone-induced growth arrest and apoptosis of PCa cells are plausible mechanisms, other chemo protective mechanisms are also worthy of consideration. These possible mechanisms include antioxidant defense, DNA repair, inhibition of angiogenesis and metastasis, potentiation of radio- and chemotherapeutic agents, and antagonism of estrogen- and androgen-mediated signaling pathways. Moreover, other cells in the cancer milieu, such as the fibroblastic stromal cells, endothelial cells, and immune cells, may be targeted by soy isoflavones, which may contribute to soy-mediated prostate cancer prevention. In this review, these mechanisms are discussed along with considerations about the doses and the preclinical models that have been used.
Testosterone is increasingly prescribed to middle aged and older men, but the safety of this treatment has been called into question, and the possible risk of prostate cancer is unknown. We treated ...Wistar Cpb: WU rats chronically via slow-release Silastic implants with doses of testosterone that increased circulating levels in a dose-related fashion with or without a preceding single injection of the carcinogen N-nitroso-N-methylurea (MNU). Without MNU, testosterone induced prostate carcinomas in 10%–18% of rats, and after MNU injection, testosterone treatment caused prostate cancer in 50%–71% of rats with a very steep dose response, producing a 50% prostatic tumor incidence even at a testosterone dose that did not elevate circulating testosterone levels. Prostate cancers did not occur in rats given MNU or no treatment, whereas testosterone alone induced a low incidence of prostate cancer and increased the number rats bearing tumors at other sites, particularly malignant tumors. Thus, testosterone was shown to be a weak complete carcinogen and a strong tumor promoter for the rat prostate in this study. These findings have potential significant public health implications for the use of testosterone therapy in men.
There is epidemiologic evidence to suggest that arsenic exposure is associated with risk of prostate cancer incidence and mortality. There are no studies indicating that arsenic can induce prostate ...cancer in animals. We evaluated whether drinking water exposure to sodium arsenite would affect prostate carcinogenesis in a rat model that depends on long-term low dose treatment with testosterone. WU rats received a sequential treatment with the antiandrogen flutamide followed by a single androgen administration to stimulate prostatic cell proliferation during which a single injection of N-methyl-N-nitrosourea was given. Two weeks later the animals received subcutaneous slow release testosterone-containing silastic tubing implants and provided with drinking water containing 5 mg/L sodium arsenite or with control drinking water for the duration of the 64 week-long experiment. Arsenite provided in drinking water did not modify the induction of prostate cancer in this rat model compared to control rats or survival. It also did not affect the growth of the animals or their drinking water intake. This animal study with drinking water exposure to 5 mg/L sodium arsenite does not support the notion that arsenic enhances prostate carcinogenesis.
Highlights ► Prostate cancer is likely caused by androgens in concert with estradiol and estrogen metabolites. ► Androgen-receptor mediated activity of androgens is critically involved prostate ...carcinogenesis. ► Estrogen receptor-mediated estradiol effects and genotoxicity of estrogen metabolites are likely both necessary for prostate carcinogenesis.
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.
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.
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).
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.
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.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Blocking the androgen receptor (AR) activity is the main goal of therapies for advanced prostate cancer (PCa). However, relapse with a more aggressive, hormone refractory PCa arises, which harbors ...restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent) activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A) mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L) stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
DDX41 is a tumor suppressor frequently mutated in human myeloid neoplasms, but whether it affects hematopoiesis is unknown. Using a knockout mouse, we demonstrate that DDX41 is required for mouse ...hematopoietic stem and progenitor cell (HSPC) survival and differentiation, particularly of myeloid lineage cells. Transplantation of Ddx41 knockout fetal liver and adult bone marrow (BM) cells was unable to rescue mice from lethal irradiation, and knockout stem cells were also defective in colony formation assays. RNA-seq analysis of Lin−/cKit+/Sca1+Ddx41 knockout cells from fetal liver demonstrated that the expression of many genes associated with hematopoietic differentiation were altered. Furthermore, differential splicing of genes involved in key biological processes was observed. Our data reveal a critical role for DDX41 in HSPC differentiation and myeloid progenitor development, likely through regulating gene expression programs and splicing.
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•DDX41 knockout in HSCs results in neonatal death•DDX41 is required for HSC differentiation, particularly in the myeloid lineage•HSCs lacking DDX41 fail to repopulate the bone marrow•DDX41-deficient fetal HSCs lack expression of genes associated with HSC differentiation
Ma and colleagues show using knockout mice that DDX41 is critical for the development of hematopoietic stem cells and particularly affects differentiation of myeloid lineage cells. This finding suggest that previous work showing that loss of DDX41 leads to hyper-proliferation in stem cells might be the result of decreased or aberrant protein expression, rather than total loss of activity
Background
Androgens are generally thought to cause prostate cancer, but the data from animal studies suggest that they must be aromatized to estrogen and act in concert with genotoxic estrogen ...metabolites. The objective of this study was to determine whether treatment with testosterone (T) combined with a nonestrogenic estrogen metabolite and a nongenotoxic estrogenic compound would all be necessary and sufficient for the induction of a high incidence of prostate cancer in the susceptible NBL rat strain.
Methods
NBL rats were treated with low‐dose testosterone via slow‐release Silastic implants and with the marginally estrogenic genotoxic catechol estrogen 4‐hydroxyestradiol (4OH‐E2) and the nongenotoxic estrogen 2‐fluoroestradiol (2F‐E2) and in one experiment the aromatase inhibitor letrozole via custom‐made slow‐release pellets. Animals were euthanized 52 weeks after implantation and their pituitaries and prostate complexes weighed and fixed in formalin. Hematoxylin and eosin (H&E)‐stained step sections were prepared and examined microscopically for proliferative lesions.
Results
Animals treated with 2F‐E2, with or without the other compounds, had enlarged pituitaries demonstrating its estrogenicity. Animals treated with T, with or without the other compounds, had enlarged prostates consistent with its androgenicity. Rats treated with T plus 2F‐E2 and 4OH‐E2 developed a high incidence of prostatic cancer (89%), while, surprisingly, rats treated with T plus only 2F‐E2 also had a high incidence of prostate cancer (95%) contradicting our initial hypothesis. To test whether the formation of E2 from T by aromatase could lead to estrogen genotoxicity and prostate carcinogenesis we then rats treated with T and 2F‐E2 also with letrozole and found that it reduced prostate cancer incidence by about 50%.
Conclusions
These findings indicate that long‐term treatment with a nongenotoxic estrogen (2F‐E2) and T as well as uninhibited prostatic aromatase activity generating genotoxic E2 are all required for induction of a high incidence of prostatic adenocarcinomas in NBL rats. These and previous data indicate that androgen receptor‐mediated action, estrogen receptor mediation, and estrogen genotoxicity are all required and sufficient for hormonal carcinogenesis in the NBL rat prostate. Interference with the estrogen genotoxicity is a potential approach to prostate cancer chemoprevention.
Background
There is evidence to suggest that green tea soy may have protective effects against prostate cancer, but there are several epidemiologic and clinical studies that did not identify such an ...effect. We tested the notion of protective effects in a rat model of prostate carcinogenesis that has been predictive of the effects of selenium and vitamin E in randomized clinical trials and a human prostate cancer xenograft model in nude mice and rat prostate tumor cells transplanted in immune‐competent syngeneic animals.
Methods
Prostate cancer was induced in rats with methylnitrosourea and testosterone and tumor incidence was determined. Subcutaneous tumor growth was measured resulting from injected cells isolated from rat prostate cancers grafted in syngeneic animals and from the prostate‐specific antigen (PSA)‐producing human prostate cancer PC346 xenografted in nude mice. Brewed decaffeinated green tea infusion or caffeinated green tea extract and the same 300 mg/ml concentration of caffeine were provided in drinking water of the rats and nude mice.
Results
Caffeinated green tea extract and caffeine provided in drinking water did not modify the induction of prostate cancer in the rat model compared with control rats. The same drinking water treatments also did not affect the growth and PSA production of PC346 human prostate cancer xenografts in nude mice and the growth of two transplantable rat prostate cancer tumor lines in Wistar Firth rats. Brewed green tea infusion as drinking water did also not affect tumor growth in these xeno‐ and allograft models.
Conclusion
These animal studies with drinking water exposure to green tea and caffeine do not support the idea that green tea is protective against prostate cancer.
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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