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Nathan Goodyear

Differential Effects of Dehydroepiandrosterone and Testosterone in Prostate and Colon C... - 0 views

  • Several studies indicate that DHEA may enhance cancer-promoting activities in several prostate cancer cell lines acting as agonist or antagonist for the intracellular AR
  • the estrogenic metabolites of DHEA, 5a-androstane-3b, 17b-diol (3b-Adiol) and E2 bind to estrogen receptors but not to AR
  • no specific receptor has been identified for DHEA
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  • Different members of neurotrophins are expressed during cancer progression, suggesting their involvement in cell proliferation, anoikis protection, and malignancy
  • Regulation of the apoptotic machinery in prostate and colon cancer cells by testosterone occurs rapidly and is initiated at the plasma membrane level through specific membrane-binding sites not involving the classical cytoplasmic AR
  • testosterone exerts potent regulatory effects on prostate and colon cancer cell apoptosis
  • Testosterone increased cell death in a dose-dependent manner
  • testosterone antagonizes the prosurvival effects of DHEA in neuronal cells, blocking its binding to NGF receptors
  • treatment of cells with DHEA exerted a strong antiapoptotic effect,
  • Androgens hold a central role in prostate and colon cancer biology
  • elevated levels of DHEA or its sulfate ester DHEA-sulfate in young adults are associated to low incidence of androgen-dependent tumors
  • DHEA may play a protective role in young prostate
  • The decline of DHEA with aging may contribute to prostate cancer progression associated with advanced age
  • DHEA is an effective antiapoptotic factor, reversing the serum deprivation-induced apoptosis in prostate cancer cells (DU145 and LNCaP cell lines) as well as in colon cancer cells
  • NGF appears to exert similar antiapoptotic actions in both prostate and color cancer cells
  • exposure of prostate DU145 and colon Caco2 cancer cells to testosterone totally blocked the protective effects of both DHEA and NGF. These findings suggest that testosterone acts as an antagonist of DHEA and NGF
  • These findings support the hypothesis that testosterone may inhibit cancer cell growth by antagonizing the proliferative, antiapoptotic effects of endogenous factors, such as DHEA or NGF, in the case of prostate and colon cancer cells
  • intratumor hormonal microenvironment may play a critical role in tumor progression.
  • The paracrine interactions of androgens with locally produced NGF may define tumor cell fate
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    Full article of previously posted abstract.  Cancers are unique.  Not all cancers are alike.  Whether they are tissue specific or not, cancers are unique.  This article describes the uniqueness of DHEA and Testosterone cancer, with particular attention to colon.
Nathan Goodyear

PLOS ONE: Microbial Dysbiosis in Colorectal Cancer (CRC) Patients - 0 views

  • differences in the colon microbiota in individuals with colon cancer versus those with a normal colonoscopy
  • qPCR revealed significant elevation of the Bacteroides/Prevotella population in cancer patients that appeared to be linked with elevated IL17 producing cells in the mucosa of individuals with cancer.
  • Bacteroides genus populations and more specifically those of Bacteroides fragilis, have recently been shown to produce a metalloprotease in colon cancer patients, but not in controls [12] suggesting this species sub population might favor carcinogenesis
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  • It is noteworthy that among the many mechanisms that may mediate associations between microbiota and human health [21]–[22], pro-inflammatory and immune cell activation in colon mucosa are of great importance in relation to malignancy
  • B. fragilis has been shown to induce mucosal regulatory T-cell responses in the intestine involving TH17 cell recruitment in experimental models
  • the elevations of Bacteroides in the stool and/or IL17 immunoreactive cells in the normal mucosa appear to be promising sensitive markers
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    A relationship between dysbiosis and colon cancer appears to be present.  Particularly an increase in Bacteroidetes and Prevotella species were found in those with colon cancer versus those without.  An inflammatory up regulation of IL-17 appears to be involved.  Whether this is a cause or effect is yet to be determined, but the presence of elevated Bacteroidetes species with increased IL17 could be used as sensitive biomarkers.
Nathan Goodyear

The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pa... - 0 views

  • WNT signaling
  • early colon cancers commonly display loss of function of the tumor suppressor Adenomatous polyposis coli (APC), a key component of the β-CATENIN destruction complex
  • Other cancers also show an active canonical WNT pathway; these include carcinomas of the lung, stomach, cervix, endometrium, and lung as well as melanomas and gliomas
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  • In normal embryogenesis and homeostasis, the canonical WNT pathway is activated by secreted WNT ligands produced in highly controlled context-dependent manners and in precise amounts. WNT activity is transduced in the cytoplasm, inactivates the APC destruction complex, and results in the translocation of activate β-CATENIN to the nucleus, where it cooperates with DNA-binding TCF/LEF factors to regulate WNT-TCF targets and the ensuing genomic response
  • beyond the loss of activity of the APC destruction complex, for instance throughAPC mutation, phosphorylation of β-CATENIN at C-terminal sites is required for the full activation of WNT-TCF signaling and the ensuing WNT-TCF responses in cancer.
  • The WNT-TCF response blockade that we describe for low doses of Ivermectin suggests an action independent to the deregulation of chloride channels
  • involve the repression of the levels of C-terminally phosphorylated β-CATENIN forms and of CYCLIN D1, a critical target that is an oncogene and positive cell cycle regulator.
  • the Avermectin single-molecule derivative Selamectin, a drug widely used in veterinarian medicine (Nolan & Lok, 2012), is ten times more potent acting in the nanomolar range
  • Ivermectin also diminished the protein levels of CYCLIN D1, a direct TCF target and oncogene, in both HT29 and H358 tumor cells
  • Activated Caspase3 was used as a marker of apoptosis by immunohistochemistry 48 h after drug treatment. Selamectin and Ivermectin induced up to a sevenfold increase in the number of activated Caspase3+ cells in two primary (CC14 and CC36) and two cell line (DLD1 and Ls174T) colon cancer cell types (Fig​(Fig2C).2C). All changes were significative
  • The strong downregulation of the expression of the intestinal stem cell genesASCL2 andLGR5 (van der Flieret al, 2009; Scheperset al, 2012; Zhuet al, 2012b) by Ivermectin and Selamectin (Fig​(Fig2D)2D) raised the possibility that these drugs could affect WNT-TCF-dependent colon cancer stem cell behavior
  • Pre-established H358 tumors responded to Ivermectin showing a ˜ 50% repression of growth
  • Ivermectin hasin vivo efficacy against human colon cancer xenografts sensitive to TCF inhibition with no discernable side effects
  • Ivermectin (Campbellet al, 1983), an off-patent drug approved for human use, and related macrocyclic lactones, have WNT-TCF pathway response blocking and anti-cancer activities
  • these drugs block WNT-TCF pathway responses, likely acting at the level of β-CATENIN/TCF function, affecting β-CATENIN phosphorylation status.
  • anti-WNT-TCF activities of Ivermectin and Selamectin
  • Ivermectin has a well-known anti-parasitic activity mediated via the deregulation of chloride channels, leading to paralysis and death (Hibbs & Gouaux, 2011; Lynagh & Lynch, 2012). The same mode of action has been suggested to underlie the toxicity of Ivermectin for liquid tumor cells and the potentiation or sensitization effect of Avermectin B1 on classical chemotherapeutics
  • the specificity of the blockade of WNT-TCF responses we document, at low micromolar doses for Ivermectin and low nanomolar doses for Selamectin, indicate that the blockade of WNT-TCF responses and chloride channel deregulation are distinct modes of action
  • What is key then is to find a dose and a context where the use of Ivermectin has beneficial effects in patients, paralleling our results with xenografts in mice.
  • Cell toxicity appears at doses greater (> 10 μM for 12 h or longer or > 5 μM for 48 h or longer for Ivermectin) than those required to block TCF responses and induce apoptosis.
  • Our data point to a repression of WNT-β-CATENIN/TCF transcriptional responses by Ivermectin, Selamectin and related macrocylic lactones.
  • (i) The ability of Avermectin B1 to inhibit the activation of WNT-TCF reporter activity by N-terminal mutant (APC-insensitive) β-CATENIN as detected in our screen
  • (ii) The ability of Avermectin B1, Ivermectin, Doramectin, Moxidectin and Selamectin to parallel the modulation of WNT-TCF targets by dnTCF
  • (iii) The finding that the specific WNT-TCF response blockade by low doses of Ivermectin and Selamectin is reversed by constitutively active TCF
  • (iv) The repression of key C-terminal phospho-isoforms of β-CATENIN resulting in the repression of the TCF target and positive cell cycle regulator CYCLIN D1 by Ivermectin and Selamectin
  • (v) The specific inhibition ofin-vivo-TCF-dependent, but notin-vivo-TCF-independent cancer cells by Ivermectin in xenografts.
  • These results together with the reduction of the expression of the colon cancer stem cell markersASCL2 andLGR5 (e.g., Hirschet al, 2013; Ziskinet al, 2013) raise the possibility of an inhibitory effect of Ivermectin, Selamectin and related macrocyclic lactones on TCF-dependent cancer stem cells.
  • the capacity of cancer cells to form 3D spheroids in culture, as well as the growth of these, is also WNT-TCF-dependent (Kanwaret al, 2010) and they were also affected by Ivermectin treatment
  • If Ivermectin is specific, it should only block TCF-dependent tumor growth. Indeed, the sensitivity and insensitivity of DLD1 and CC14 xenografts to Ivermectin treatment, respectively, together with the desensitization to Ivermectin actionin vivo by constitutively active TCF provide evidence of the specificity of this drug to block an activated WNT-TCF pathway in human cancer.
  • Ivermectin has a good safety profile since onlyin-vivo-dnTCF-sensitive cancer xenografts are responsive to Ivermectin treatment, and we have not detected side effects in Ivermectin-treated mice at the doses used
  • previous work has shown that side effects from systemic treatments with clinically relevant doses in humans are rare (Yang, 2012), that birth defects were not observed after exposure of pregnant mothers (Pacquéet al, 1990) and that this drug does not cross the blood–brain barrier (Kokozet al, 1999). Similarly, only dogs with mutantABCB1 (MDR1) alleles leading to a broken blood–brain barrier show Ivermectin neurotoxicity (Mealeyet al, 2001; Orzechowskiet al, 2012)
  • Indications may include treatment for incurable β-CATENIN/TCF-dependent advanced and metastatic human tumors of the lung, colon, endometrium, and other organs.
  • Ivermectin, Selamectin, or related macrocyclic lactones could also serve as topical agents for WNT-TCF-dependent skin lesions and tumors such as basal cell carcinomas
  • they might also be useful as routine prophylactic agents, for instance against nascent TCF-dependent intestinal tumors in patients with familial polyposis and against nascent sporadic colon tumors in the general aging population
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    Ivermectin, a common anti-parasitic, found to inhibit WTF-TCF pathway and decrease c-terminal phosophorylaiton of Beta-CATENIN all resulting in increased aptosis and inhibition of cancer growth in colon cancer cell lines and lung cancer cell lines.
Nathan Goodyear

Tumor Repressive Functions of Estrogen Receptor β in SW480 Colon Cancer Cells - 0 views

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    Stimulation of ER-beta provides inhibition of colon cancer cell proliferation.  ER-beta is the prominent ER in the colon.
Jadibuti jadibuti.net

Diet and Herbal Remedies for Ulcerative Colitis - 0 views

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    It is an inflammatory, refractory disease which includes colon, rectum and little part of small intestine. The person who is suffering from Ulcerative colitis in tests shows ulcers inside the colon. Ulcerative colitis comes under the category of ...
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    It is an inflammatory, refractory disease which includes colon, rectum and little part of small intestine. The person who is suffering from Ulcerative colitis in tests shows ulcers inside the colon. Ulcerative colitis comes under the category of ...
Nathan Goodyear

Expression of estrogen receptor beta in colon cancer progression. - Abstract - Europe P... - 0 views

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    ER beta expression is dominant in healthy colon epithelium.  This study found that as colon disease progressed, ER beta expression declined.  So that, early disease was associated with the highest level of ER beta expression.
Nathan Goodyear

Control of Colon Cancer Development and Progression: Role of Estrogens in Colorectal Ca... - 0 views

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    Estrogens decrease colon cancer risk likely via ER beta activity.
Nathan Goodyear

Colonization-Induced Host-Gut Microbial Metabolic Interaction - 0 views

  • he gut microbiota enhances the host’s metabolic capacity for processing nutrients and drugs and modulate the activities of multiple pathways in a variety of organ systems.
  • Acquisition of the gut microbiota was associated with rapid increase in body weight (4%) over the first 5 days of colonization
  • The colonization process stimulated glycogenesis in the liver prior to triggering increases in hepatic triglyceride synthesis
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  • modifications of hepatic Cyp8b1 expression and the subsequent alteration of bile acid metabolites
  • Expression and activity of major drug-metabolizing enzymes (Cyp3a11 and Cyp2c29) were also significantly stimulated
  • The gut microbiota (GM) exhibits a relatively low level of diversity compared to those of most soil ecosystems and in humans it is comprised of usually no more than nine phyla of microorganisms, of which only two are dominant: the Firmicutes and the Bacteroidetes
  • colonization of a germfree gut was rapid and remarkably stable, establishing within only a week after first exposure
  • a study conducted on germfree rats by Nicholls et al. showed that 3 weeks were necessary to obtain a stabilization and “normalization”
  • the microbiota status affects the systemic metabolism of the host, modulating the metabolic fingerprint of topographically remote organs such as the liver and the kidney
  • Gut colonization induces a rapid weight gain associated with stimulation of hepatic glycogenesis and triglyceride synthesis
  • Gut colonization alters bile acid metabolite profiles via modulation of hepatic Cyp8b1 expression
  • Bile acids are well-known contributors to glucose and lipid metabolism in the liver
  • GM is known to alter bile metabolism
  • GM is also known to exert a strong influence on the metabolism of xenobiotics
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    The effects of gut microbiome are not confined to the gut.  They alter bile acid metabolism and thus lipid/glucose metabolism.  They alter CYP450 activity.  They effect metabolism.  They effect the metabolism, and thus effects, of other drugs. 
Nathan Goodyear

Associations between ERα, ERβ, and AR Genotypes and Colon and Rectal Cancer - 0 views

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    Study finds ER-beta plays more significant role in the development of Colon cancer than ER-alpha in women.  HRT in women reduces colon cancer risk in comparison to breast, which is increased.  Shows the different tissue expression of ER-alpha and ER-beta, as well as the HRT itself.
Nathan Goodyear

Diet and Risk of Colorectal Cancer Subtypes Classified by F nucleatum | Colorectal Canc... - 0 views

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    Study finds Diet effect colon cancer risk through gut bacteria. Diet higher in fiber and whole grains found to have lower risk of F nucleatum + colon cancer.
Nathan Goodyear

Curcumin-induced Apoptosis of Human Colon Cancer Colo 205 Cells through the Production ... - 0 views

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    Curcumin found to induce apoptosis, cell death, of colon cancer cells.
Nathan Goodyear

Wernicke's Encephalopathy in Colon Cancer - 0 views

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    Wernicke's encephalopathy in colon cancer relieved with thiamine support
Nathan Goodyear

Oestrogen and colorectal cancer: mechan... [Int J Colorectal Dis. 2013] - PubMed - NCBI - 0 views

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    Estrogen early protects against colon cancer, but estrogen increases proliferation late.  The problem here is the estrogens involved.  If ER beta is shown to be highly expressed in the colon, then Estriol would be of benefit as it preferentially binds to ER beta at a rate of 5:1 and Estradiol at a rate of 1:1.  Estriol is currently used in Europe in advanced breast cancer.
Nathan Goodyear

Estrogen Receptors in Colorectal Cancer: Goalkeepers, Strikers, or Bystanders? - 0 views

  • one can conclude that ERβ has an overall antiproliferative effect, thereby inhibiting cancer cell proliferation and antagonizing ERα function in the breast
  • HRT with estrogen alone did not increase the risk of breast cancer in the Women's Health Initiative clinical trials program
  • colorectal normal or cancer epithelium does not coexpress ERα and ERβ
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  • ERβ expression resulted in the inhibition of proliferation and G1 phase cell-cycle arrest
  • ERβ expression strongly inhibited cMyc and tumor growth in a xenograft mouse model
  • induced ERβ in CRC cells has an antiproliferative, tumor-suppressive function that is independent of ERα
  • ERs also have the ability to bind many other compounds with an estrogen-like structure, including phytoestrogens and xenoestrogens (or endocrine disruptors)
  • Phytoestrogens are a diverse class of natural compounds with structural similarity to estradiol
  • Barone et al. recently found that two ERβ-selective phytoestrogens effectively counteracted CRC tumorigenesis and surprisingly increased ERβ expression in mice with mutations of the tumor-suppressor gene adenomatous polyposis coli
  • We can conclude that estrogens are important in protecting against CRC initiation and progression, and that the protective effect most likely is mediated by ERβ
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    ER beta is a new potential mode of therapy in colon cancer.  ER beta stimulation has been shown to inhibit colon cancer cell growth.
Nathan Goodyear

Oestrogen receptor beta (ERβ) is abundantly expressed in normal colonic mucos... - 0 views

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    ER beta expression is dominantly expressed in normal, healthy colon cells/tissue.  However, like in breast and prostate cancer, ER beta expression is lost in the dedifferentiation of colorectal transformation.
Nathan Goodyear

Loss of expression of oestrogen receptor beta in c... [Oncol Rep. 2005] - PubMed - NCBI - 0 views

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    Loss of ER beta associated with higher risk of colon cancer.  ER beta has been shown to be highly expressed in health colons.  It has been proposed that loss of this ER beta expression is associated with carcinogenesis.
Nathan Goodyear

Chemoprevention of precursors to colon cancer by dehydroepiandroste... - PubMed - NCBI - 0 views

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    Animal study suggests DHEA is preventative in colon cancer.
Nathan Goodyear

Molecular Targeting of H/MDM-2 Oncoprotein in Human Colon Cancer Cells and Stem-like Co... - 0 views

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    PNC-27 selectively kills colon cancer stem cells by binding to membrane H/MDM-2. This was an in vivo study. As with other studies, the result was tumor cell necrosis and associated high LDH release.
Nathan Goodyear

Oestrogen and the colon: potential mechanisms f... [Lancet Oncol. 2008] - PubMed - NCBI - 0 views

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    Estrogen shown to provide protection against colon cancer.  The authors of this study propose that it may be due to ERbeta.
Nathan Goodyear

Estrogen and colon cancer: current issues. [Climacteric. 2002] - PubMed - NCBI - 0 views

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    colon cancer risk reduced in post-menopausal women taking or recently taking estrogen.
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