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Nathan Goodyear

Postmenopausal circulating levels of 2- and 16α-hydroxyestrone and risk of en... - 0 views

www.ncbi.nlm.nih.gov/...PMC3241553

estrogen metabolism 2-hydroxyestrone 4-hydroxyestrone estrogen metabolites cancer uterine cancer endometrial cancer hormones 2:16alpha-OHE1 2:16

shared by Nathan Goodyear on 07 Oct 15 - No Cached
  • our results do not support the hypothesis that greater metabolism of oestrogen via the 2-OH pathway, relative to the 16α-OH pathway, protects against endometrial cancer. Indeed our results are more suggestive of an increase in risk, rather than a decrease, with higher levels of 2-OHE1
  • women with a higher 2-OHE1 : 16α-OHE1 ratio did not have a decreased risk of endometrial cancer as compared with women with a lower ratio
  • The findings from this first prospective epidemiological study of oestrogen metabolites and endometrial cancer are in line with results from prospective studies on breast cancer, another oestrogen-related cancer. None of the seven studies on breast cancer reported significant associations overall
  • ...4 more annotations...
  • On the whole, prospective epidemiological data do not support the hypothesis that the 2-hydroxyestrogen pathway is protective, and the 16α-hydroxyestrogen pathway harmful, in hormone-dependent cancers
  • Both 2- and 4-hydroxyestrogens are catecholestrogens, and it has been suggested that catecholestrogens increase risk of oestrogen-mediated cancers through direct genotoxic effects, rather than through stimulation of cell proliferation via binding to oestrogen receptors
  • the evidence is stronger for 4-hydroxyestrogens than for 2-hydroxyestrogens
  • a significant increase in risk of breast cancer with levels of 2-OHE1 has also been reported previously, although it was limited to hormone receptor-negative tumours
  • Nathan Goodyear on 07 Oct 15
     
    2:16 hydroxyestrone ratio not associated with uterine cancer risk.
Nathan Goodyear

Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC2567082

cancer dichloroacetate dichloracetic acid DCA

shared by Nathan Goodyear on 07 Nov 18 - No Cached
  • The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis
  • The most important reason for the poor performance of cancer drugs is the remarkable heterogeneity and adaptability of cancer cells. The molecular characteristics of histologically identical cancers are often dissimilar and molecular heterogeneity frequently exists within a single tumour.
  • Because GO is far more efficient in generating ATP compared with GLY (producing 36 vs 2 ATP per glucose
  • ...9 more annotations...
  • molecule), cancer cells upregulate glucose receptors and significantly increase glucose uptake in an attempt to ‘catch up
  • early carcinogenesis often occurs in a hypoxic microenvironment, the transformed cells have to rely on anaerobic GLY for energy production.
  • Hypoxia-inducible factor (HIF) is activated in hypoxic conditions
  • evidence suggests that transformation to a glycolytic phenotype offers resistance to apoptosis
  • non-small cell lung cancer, breast cancer and glioblastoma
  • Dichloroacetate activated the pyruvate dehydrogenase, which resulted in increased delivery of pyruvate into the mitochondria
  • DCA increased GO and depolarised the mitochondria, returning the membrane potential towards the levels of the non-cancer cells, without affecting the mitochondria of non-cancerous cells
  • induction of apoptosis by DCA in non-small cell lung cancer, breast cancer and glioblastoma cell lines
  • DCA was shown to induce apoptosis in endometrial (Wong et al, 2008) and prostate (Cao et al, 2008) cancer cells
  • Nathan Goodyear on 07 Nov 18
     
    DCA as targeted therapy in cancer.
Nathan Goodyear

Dichloroacetate induces apoptosis in endometrial cancer cells - 0 views

Dichloroacetate induces apoptosis in endometrial cancer cells

DCA dichloracetic acid dichloroacetate cancer

shared by Nathan Goodyear on 07 Nov 18 - No Cached
  • Nathan Goodyear on 07 Nov 18
     
    DCA induces apoptosis of endometrial cancer cells in cell line study. DCA is a pyruvate dehydrogenase kinase inhibitor which will increase apoptosis and decrease proliferation. DCA serves to recapture the mitochondrial kreb's cycle and ETC coupling potential.
Nathan Goodyear

New use of microsatellite instability analysis in endometrial cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC5587995

endometrial cancer "uterine cancer" MSI MMR

shared by Nathan Goodyear on 16 Jan 19 - No Cached
  • Nathan Goodyear on 16 Jan 19
     
    Nice look at MSI in endometrial cancer. Present in approximately 30%. MSI are the result of MMR defects.
Nathan Goodyear

Sugar-Sweetened Beverage Intake and the Risk of Type I and Type II Endometrial Cancer a... - 0 views

cebp.aacrjournals.org/...2384

sugar soda coke uterine endometrial cancer postmenopausal women nutrition diet

shared by Nathan Goodyear on 25 Feb 14 - No Cached
  • Nathan Goodyear on 25 Feb 14
     
    intake of sugar drinks i.e. coke associated with increased risk of type I endometrial cancer in postmenopausal women.
Nathan Goodyear

Relative Expression of Progesterone Receptors A and B in Endometrioid Cancers of the En... - 0 views

cancerres.aacrjournals.org/...4576.long

progesterone receptor progesterone receptors A B PR-A PR-B endometrial cancer uterine progesterone receptor receptors

shared by Nathan Goodyear on 26 Nov 12 - No Cached
  • Nathan Goodyear on 26 Nov 12
     
    Balance of progesterone receptors A and B in the development of endometrial cancer.
Nathan Goodyear

Intravenous Ascorbate as a Tumor Cytotoxic Chemotherapeutic Agent - 0 views

www.seanet.com/...d_hypotheses_1995-v44-p207.htm

vitamin C cancer IV vitamin C ascorbic acid

shared by Nathan Goodyear on 05 Mar 18 - No Cached
  • There is a 10 — 100-fold greater content of catalase in normal cells than in tumor cells
  • induce hydrogen peroxide generation
  • Ascorbic acid and its salts (AA) are preferentially toxic to tumor cells in vitro (6 — 13) and in vivo
  • ...36 more annotations...
  • related to intracellular hydrogen peroxide generation
  • only be obtained by intravenous administration of AA
  • Preferentially kills neoplastic cells
  • Is virtually non-toxic at any dosage
  • Does not suppress the immune system, unlike most chemotherapy agents
  • Increases animal and human resistance to infectious agents by enhancing lymphocyte blastogenesis, enhancing cellular immunity, strengthening the extracellular matrix, and enhancing bactericidal activity of neutrophils and modulation of complement protein
  • Strengthens the structural integrity of the extracellular matrix which is responsible for stromal resistance to malignant invasiveness
  • 1969, researchers at the NCI reported AA was highly toxic to Ehrlich ascites cells in vitro
  • In 1977, Bram et al reported preferential AA toxicity for several malignant melanoma cell lines, including four human-derived lines
  • Noto et al reported that AA plus vitamin K3 had growth inhibiting action against three human tumor cell lines at non-toxic levels
  • Metabolites of AA have also shown antitumor activity in vitro
  • The AA begins to reduce cell proliferation in the tumor cell line at the lowest concentration, 1.76 mg/dl, and is completely cytotoxic to the cells at 7.04 mg/dl
  • the normal cells grew at an enhanced rate at the low dosages (1.76 and 3.52 mg/dl)
  • preferential toxicity of AA for tumor cells. >95% toxicity to human endometrial adenocarcinoma and pancreatic tumor cells (ATCC AN3-CA and MIA PaCa-2) occurred at 20 and 30 mg/dl, respectively.
  • No toxicity or inhibition was demonstrated in the normal, human skin fibroblasts (ATCC CCD 25SK) even at the highest concentration of 50 mg/dl.
  • the use of very high-dose intravenous AA for the treatment of cancer was proposed as early as 1971
  • Cameron and Pauling have published extensive suggestive evidence for prolonged life in terminal cancer patients orally supplemented (with and without initial intravenous AA therapy) with 10 g/day of AA
  • AA, plasma levels during infusion were not monitored,
  • the long-term, oral dosage used in those experiments (10 g/day), while substantial and capable of producing immunostimulatory and extracellular matrix modulation effects, was not high enough to achieve plasma concentrations that are generally cytotoxic to tumor cells in culture
  • This low cytotoxic level of AA is exceedingly rare
  • 5 — 40 mg/dl of AA is required in vitro to kill 100% of tumor cells within 3 days. The 100% kill levels of 30 mg/dl for the endometrial carcinoma cells and 40 mg/dl for the pancreatic carcinoma cells in Figure 2 are typical
  • normal range (95% range) of 0.39-1.13 mg/dl
  • 1 h after beginning his first 8-h infusion of 115 g AA (Merit Pharmaceuticals, Los Angeles, CA), the plasma AA was 3.7 mg/dl and at 5 h was 19 mg/dl. During his fourth 8-h infusion, 8 days later, the 1 h plasma level was 158 mg/dl and 5 h was 185 mg/dl
  • plasma levels of over 100 mg/dl have been maintained in 3 patients for more than 5 h using continuous intravenous infusion
  • In rare instances of patients with widely disseminated and rapidly proliferating tumors, intravenous AA administration (10 — 45 g/day) precipitated widespread tumor hemorrhage and necrosis, resulting in death
  • Although the outcomes were disastrous in these cases, they are similar to the description of tumor-necrosis-factor-induced hemorrhage and necrosis in mice (52) and seem to demonstrate the ability of AA to kill tumor cells in vivo.
  • toxic effects of AA on one normal cell line were observed at 58.36 mg/dl and the lack of side effects in patients maintaining >100 mg/dl plasma levels
  • Although it is very rare, tumor necrosis, hemorrhage, and subsequent death should be the highest priority concern for the safety of intravenous AA for cancer patients.
  • Klenner, who reported no ill effects of dosages as high as 150 g intravenously over a 24-h period
  • Cathcart (55) who describes no ill effects with doses of up to 200 g/d in patients with various pathological conditions
  • following circumstances: renal insufficiency, chronic hemodialysis patients, unusual forms of iron overload, and oxalate stone formers
  • Screening for red cell glucose-6-phosphate dehydrogenase deficiency, which can give rise to hemolysis of red blood cells under oxidative stress (57), should also be performed
  • any cancer therapy should be started at a low dosage to ensure that tumor hemorrhage does not occur.
  • patient is orally supplementing between infusions
  • a scorbutic rebound effect can be avoided with oral supplementation. Because of the possibility of a rebound effect, measurement of plasma levels during the periods between infusions should be performed to ensure that no such effect takes place
  • Every effort should be made to monitor plasma AA levels when a patient discontinues intravenous AA therapy.
  • Nathan Goodyear on 05 Mar 18
     
    Older study, 1995, but shows the long-standing evidence that IVC preferentially is cytotoxic to cancer cells.`
Nathan Goodyear

The current state and future perspectives of cannabinoids in cancer biology - 0 views

www.ncbi.nlm.nih.gov/...PMC5852356

Cancer CBD THC cannabinoids

shared by Nathan Goodyear on 19 Sep 18 - No Cached
hoangkimchi liked it
  • The activation of each of them leads to an inhibition of adenylyl cyclase via G proteins (Gi/o), which in turn activates many metabolic pathways such as mitogen‐activated protein kinase pathway (MAPK), phosphoinositide 3‐kinase pathway (PI3K), cyclooxygenase‐2 pathway (COX‐2), accumulation of ceramide, modulation of protein kinase B (Akt), and ion channels
  • phytocannabinoids, endocannabinoids, and synthetic cannabinoids
  • Action of THC in human organism relies on mimicking endogenous agonists of CB receptors—endocannabinoids
  • ...8 more annotations...
  • The upregulated expression of CB receptors and the elevated levels of endocannabinoids have been observed in a variety of cancer cells (skin, prostate, and colon cancer, hepatocellular carcinoma, endometrial sarcoma, glioblastoma multiforme, meningioma and pituitary adenoma, Hodgkin lymphoma, chemically induced hepatocarcinoma, mantel cell lymphoma)
  • concentration of endocannabinoids, expression level of their receptors, and the enzymes involved in their metabolism frequently are associated with an aggressiveness of cancer
  • CB2 receptor contributes to human epidermal growth factor receptor (HER2) pro‐oncogenic signaling and an overexpression of CB2 increases susceptibility for leukemia development after leukemia viral infection
  • endocannabinoid‐degrading enzymes are upregulated in cancer cell lines and in human tumors
  • Many cannabinoids, ranging from phytocannabinoids (THC, CBD), endocannabinoids (2‐arachidonoylglycerol, anandamide), to synthetic cannabinoids (JWH‐133, WIN‐55,212‐2), have shown ability to inhibit proliferation, metastasis, and angiogenesis in a variety of models of cancer
  • Despite some inconsistent data, the main effect of cannabinoids in a tumor is the inhibition of cancer cells’ proliferation and induction of cancer cell death by apoptosis
  • CB1 and CB2 receptor agonists stimulate apoptotic cell death in glioma cells by induction of de novo synthesis of ceramide, sphingolipid with proapoptotic activity
  • process of autophagy is upstream of apoptosis in mechanism of cell death induced by cannabinoids
Nathan Goodyear

Antitumor activity of dichloroacetate on C6 glioma cell: in vitro and in vivo evaluation - 0 views

www.ncbi.nlm.nih.gov/...PMC3601023

cancer DCA

shared by Nathan Goodyear on 12 Nov 14 - No Cached
  • the oral bioavailability of DCA is nearly 100%
  • the oral bioavailability of DCA is almost 100%.
  • DCA can penetrate into the traditional chemotherapy sanctuary sites. Interestingly, it was reported that DCA could penetrate across the BBB,30 exhibiting the potential activity for brain therapy.
  • ...23 more annotations...
  • Clinical studies of DCA have shown reduced lactate levels
  • It has been reported that DCA activates the PDH by inhibition of PDK in a dose-dependent manner, and results in increased delivery of pyruvate into the mitochondria
  • The antitumor activity of DCA on nonsmall cell lung cancer, breast cancer, glioblastomas, and endometrial and prostate cancer cells has been demonstrated
  • It is well known that many chemotherapeutic agents have a low therapeutic index in brain tumors.
  • The most common metabolic hallmark of cancer cells is their propensity to metabolize glucose to lactic acid at a high rate even in the presence of oxygen
  • Pyruvate dehydrogenase kinase (PDK) is a gate-keeping enzyme that regulates the flux of carbohydrates (pyruvate) into the mitochondria
  • In the presence of activated PDK, pyruvate dehydrogenase (PDH), a critical enzyme that converts pyruvate to acetyl-CoA instead of lactate in glycolysis, is inhibited, limiting the entry of pyruvate into the mitochondria.
  • the level of Hsp70 was significantly decreased
  • DCA can penetrate the BBB
  • It has been reported that DCA treatment resulted in an increase in the proportion of tumor cells in the S phase, showing a decrease in proliferation as well as the induction of apoptosis
  • Heat shock proteins (HSPs) are involved in protein folding, aggregation, transport, and/or stabilization by acting as a molecular chaperone, leading to the inhibition of apoptosis by both caspase-dependent and/or independent pathways
  • HSPs are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, and metastasis
  • Considering the fact that high expression of HSPs is essential for cancer survival, the inhibition of HSPs is an important strategy of anticancer therapy.
  • In addition, after 5 years of continued treatment with oral DCA at a dose of 25 mg/kg, the serum DCA levels are only slightly increased compared with the levels after the first several doses, also showing its safety for oral administration at this dose.
  • DCA can enter the circulation rapidly after oral administration and then generate the stimulation of PDH activity generally within minutes.
  • Our in vivo results in tumor tissues indicated that DCA significantly induced ROS production and decreased MMP in tumor tissues
  • The numbers of microvessels in the DCA treatment groups were significantly decreased, suggesting the potential antiangiogenic effect of DCA
  • Under hypoxic conditions, hypoxia-inducible factor (HIF-1α) is activated and induces angiogenesis
  • In addition, HIF-1α can also induce the expression of PDK,48 which can inhibit the activity of PDH
  • The inhibition effect of DCA on HIF-1α would decrease vascular endothelial growth factor and inhibit angiogenesis
  • the antiangiogenic effect in the 25 mg/kg treatment group was lower than that in 75 mg/kg or 125 mg/kg treatment groups
  • In conclusion, DCA induces the apoptosis of C6 cells through the activation of the mitochondrial pathway, arresting the cell cycle of C6 cells in S phase and down-regulating Hsp70 expression.
  • DCA significantly induced the ROS production and decreased the MMP in tumor tissues. Our in vivo antitumor activity results also indicated that DCA has an antiangiogenic effect
  • Nathan Goodyear on 12 Nov 14
     
    DCA as proposed therapy in cancer.
Nathan Goodyear

Estradiol-17β Upregulates Pyruvate Kinase M2 Expression to Coactivate Estroge... - 0 views

press.endocrine.org/...jc.2013-2639

Estradiol ER alpha ER-alpha women female hormone hormones aerobic glycolysis Warburg effect estrogen

shared by Nathan Goodyear on 07 Oct 14 - No Cached
  • Nathan Goodyear on 07 Oct 14
     
    This is an important study.  Study found that Estradiol increased the transcription of pyruvate kinase M (PKM2)production in endometrial stromal cells.  This increase in PKM2 shifted metabolism to a aerobic glycolysis pattern similar to the Warburg effect described in cancer.  Additionally, increased PKM2 via Estradiol increased ER alpha transcription and functioned as a ER alpha coactivator.
Nathan Goodyear

Survival implications of time to surgical treatment of endometrial cancers - American J... - 0 views

www.ajog.org/...fulltext

uterine cancer endometrial cancer surgery

shared by Nathan Goodyear on 05 Sep 19 - No Cached
  • Nathan Goodyear on 05 Sep 19
     
    Study finds that early (defined as 1-2 weeks after diagnosis) surgery after diagnosis of uterine cancer is associated with increased complications including death. This compared to lower postoperative death rates in delay out to 3-4 weeks.
Nathan Goodyear

The role of androst-5-ene-3β,17β-diol (androstenedi... [Steroids. 2014] - Pub... - 0 views

www.ncbi.nlm.nih.gov/...25065586

DHT metabolite 3-beta androstanediol 3-beta-diol 3 beta androstanediol PCOS endometrial proliferation cancer women hormone hormones Testosterone

shared by Nathan Goodyear on 30 Jul 14 - No Cached
  • Nathan Goodyear on 30 Jul 14
     
    The DHT metabolite 3beta-androstanediol found to increase proliferation of endometrial tissue in women with PCOS.  In contrast, Testosterone repressed proliferation.  
Nathan Goodyear

Frontiers | Artesunate Suppresses the Proliferation and Development of Estrog... - 0 views

www.frontiersin.org/...full

ER alpha ER-alpha uterine cancer endometrial cancer cancer artesunate mTOR

shared by Nathan Goodyear on 02 Sep 22 - No Cached
  • Nathan Goodyear on 02 Sep 22
     
    artesunate down regulates ER-alpha expression
Nathan Goodyear

The premenstrual endometrial pattern of women with breast cancer. A study of progestati... - 0 views

onlinelibrary.wiley.com/...abstract

breast cancer androgens Testosterone women female hormone hormones

shared by Nathan Goodyear on 21 Mar 14 - No Cached
  • Nathan Goodyear on 21 Mar 14
     
    Women with elevated ovarian androgens have an associated increased risk of pre menopause breast cancer.
Nathan Goodyear

Low Ascorbate Levels Are Associated with Increased Hypoxia-Inducible Factor-1 Activity ... - 0 views

cancerres.aacrjournals.org/...5749.long

HIF-1 HIF-1alpha vitamin C cancer Hypoxia-inducible Factor 1

shared by Nathan Goodyear on 01 Apr 21 - No Cached
  • Nathan Goodyear on 01 Apr 21
     
    "That ascorbate deficiency compromises HIF hydroxylase activity and upregulates HIF-1 has been shown in vitro in both primary and cancer cells."
Nathan Goodyear

High Progesterone Receptor Expression in Prostate Cancer Is Associated with Clinical Fa... - 0 views

www.ncbi.nlm.nih.gov/...PMC4344236

prostate cancer progesterone progesterone receptor hormones cancer prostate

shared by Nathan Goodyear on 03 Jun 18 - No Cached
  • Currently, there is a general agreement of PGR presence in the stromal cells of PCa
  • expressed in both stromal and tumor cells of the PCa tissue
  • In univariate analysis, a high density level of PGR in both TE and TS was associated with CF
  • ...17 more annotations...
  • High density level of PGR in the TE was an independent prognostic factor for CF.
  • Our large-sized study demonstrates a wide distribution of PGR in stromal and epithelial cells of both benign and malignant prostate tissue
  • there seems to be a general agreement of PGR presence in the stromal cells of PCa
  • In line with our findings, several have also reported a high PGR expression in TE of PCa [9,10,23,25]. In contrast, others have demonstrated a total lack of PGR expression in TE
  • the actions of progesterone are tissue specific
  • In our work univariate analysis demonstrated a high PGR expression in TS to be associated with clinical failure in PCa patients. So far we have not yet demonstrated the mechanism underlying this association
  • Several non-genomic proliferative actions of progesterone have been proposed in tumor cells of other organs, including breast [35–37], astrocytoma [38] and osteosarcoma [39] cell lines. However, such results are contradicted by suggestions of anti-proliferative actions of progesterone in endometrial cancer
  • Yu et al. found PGR to be negatively regulating stromal cell proliferation in vitro
  • high PGR density level in TE was associated with CF in patients with Gleason score ≥ 7
  • Bonkhoff et al. have suggested progressive emergence of PGR during PCa progression and metastasis
  • Latil and co-workers found a decreased PGR expression in clinically localized tumors and increased PGR expression in hormone-refractory tumors, when compared with normal prostate tissue
  • Our findings provide further support to these findings, indicating that PGR plays a role in the pathogenesis of PCa
  • Ki67 and PGR in TE were correlated with CF (S3 Text), indicating an association between PGR and proliferative activity
  • The mechanism behind the PGR up-regulation in PCa has not yet been elucidated
  • The PGR is, like the glucocorticoid receptor, similar to androgen receptor with 88% sequence homology in the ligand-binding domain
  • progesterone induced expression of androgen receptor-regulated genes could be a potential mechanism contributing to the development of castrate resistant PCa
  • A possibility of different roles by the two PGR isoforms in normal prostate tissue and PCa, as is suggested for the estrogen receptors [13], must also be taken into account
  • Nathan Goodyear on 03 Jun 18
     
    STudy finds that increased Progesterone receptor expression on epithelial and stromal cells is associated with increased clinical failure of therapy.  Several proposed mechanisms: 88% homologous with androgen receptor suggesting cross-stimulation and via progesterone induced increased androgen receptor gene stimulation i.e. epigenetics.
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