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Nathan Goodyear

Testosterone: a vascular hormone in health and disease - 0 views

joe.endocrinology-journals.org/...R47.full

testosterone hormone health disease hormones men male cardiovascular disease CVD

shared by Nathan Goodyear on 13 May 13 - No Cached
  • Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation
  • In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure.
  • testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells
  • ...54 more annotations...
  • Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis
  • there is no compelling evidence that testosterone replacement to levels within the normal healthy range contributes adversely to the pathogenesis of CVD (Carson & Rosano 2011) or prostate cancer (Morgentaler & Schulman 2009)
  • bidirectional effect between decreased testosterone concentrations and disease pathology exists as concomitant cardiovascular risk factors (including inflammation, obesity and insulin resistance) are known to reduce testosterone levels and that testosterone confers beneficial effects on these cardiovascular risk factors
  • Achieving a normal physiological testosterone concentration through the administration of testosterone replacement therapy (TRT) has been shown to improve risk factors for atherosclerosis including reducing central adiposity and insulin resistance and improving lipid profiles (in particular, lowering cholesterol), clotting and inflammatory profiles and vascular function
  • It is well known that impaired erectile function and CVD are closely related in that ED can be the first clinical manifestation of atherosclerosis often preceding a cardiovascular event by 3–5 years
  • no decrease in the response (i.e. no tachyphylaxis) of testosterone and that patient benefit persists in the long term.
  • free testosterone levels within the physiological range, has been shown to result in a marked increase in both flow- and nitroglycerin-mediated brachial artery vasodilation in men with CAD
  • Clinical studies, however, have revealed either small reductions of 2–3 mm in diastolic pressure or no significant effects when testosterone is replaced within normal physiological limits in humans
  • Endothelium-independent mechanisms of testosterone are considered to occur primarily via the inhibition of voltage-operated Ca2+ channels (VOCCs) and/or activation of K+ channels (KCs) on smooth muscle cells (SMCs)
  • Testosterone shares the same molecular binding site as nifedipine
  • Testosterone increases the expression of endothelial nitric oxide synthase (eNOS) and enhances nitric oxide (NO) production
  • Testosterone also inhibited the Ca2+ influx response to PGF2α
  • one of the major actions of testosterone is on NO and its signalling pathways
  • In addition to direct effects on NOS expression, testosterone may also affect phosphodiesterase type 5 (PDE5 (PDE5A)) gene expression, an enzyme controlling the degradation of cGMP, which acts as a vasodilatory second messenger
  • the significance of the action of testosterone on VSMC apoptosis and proliferation in atherosclerosis is difficult to delineate and may be dependent upon the stage of plaque development
  • Several human studies have shown that carotid IMT (CIMT) and aortic calcification negatively correlate with serum testosterone
  • t long-term testosterone treatment reduced CIMT in men with low testosterone levels and angina
  • neither intracellular nor membrane-associated ARs are required for the rapid vasodilator effect
  • acute responses appear to be AR independent, long-term AR-mediated effects on the vasculature have also been described, primarily in the context of vascular tone regulation via the modulation of gene transcription
  • Testosterone and DHT increased the expression of eNOS in HUVECs
  • oestrogens have been shown to activate eNOS and stimulate NO production in an ERα-dependent manner
  • Several studies, however, have demonstrated that the vasodilatory actions of testosterone are not reduced by aromatase inhibition
  • non-aromatisable DHT elicited similar vasodilation to testosterone treatment in arterial smooth muscle
  • increased endothelial NOS (eNOS) expression and phosphorylation were observed in testosterone- and DHT-treated human umbilical vein endothelial cells
  • Androgen deprivation leads to a reduction in neuronal NOS expression associated with a decrease of intracavernosal pressure in penile arteries during erection, an effect that is promptly reversed by androgen replacement therapy
  • Observational evidence suggests that several pro-inflammatory cytokines (including interleukin 1β (IL1β), IL6, tumour necrosis factor α (TNFα), and highly sensitive CRP) and serum testosterone levels are inversely associated in patients with CAD, T2DM and/or hypogonadism
  • patients with the highest IL1β concentrations had lower endogenous testosterone levels
  • TRT has been reported to significantly reduce TNFα and elevate the circulating anti-inflammatory IL10 in hypogonadal men with CVD
  • testosterone treatment to normalise levels in hypogonadal men with the MetS resulted in a significant reduction in the circulating CRP, IL1β and TNFα, with a trend towards lower IL6 compared with placebo
  • parenteral testosterone undecanoate, CRP decreased significantly in hypogonadal elderly men
  • Higher levels of serum adiponectin have been shown to lower cardiovascular risk
  • Research suggests that the expression of VCAM-1, as induced by pro-inflammatory cytokines such as TNFα or interferon γ (IFNγ (IFNG)) in endothelial cells, can be attenuated by treatment with testosterone
  • Testosterone also inhibits the production of pro-inflammatory cytokines such as IL6, IL1β and TNFα in a range of cell types including human endothelial cells
  • decreased inflammatory response to TNFα and lipopolysaccharide (LPS) in human endothelial cells when treated with DHT
  • The key to unravelling the link between testosterone and its role in atherosclerosis may lay in the understanding of testosterone signalling and the cross-talk between receptors and intracellular events that result in pro- and/or anti-inflammatory actions in athero-sensitive cells.
  • testosterone functions through the AR to modulate adhesion molecule expression
  • pre-treatment with DHT reduced the cytokine-stimulated inflammatory response
  • DHT inhibited NFκB activation
  • DHT could inhibit an LPS-induced upregulation of MCP1
  • Both NFκB and AR act at the transcriptional level and have been experimentally found to be antagonistic to each other
  • As the AR and NFκB are mutual antagonists, their interaction and influence on functions can be bidirectional, with inflammatory agents that activate NFκB interfering with normal androgen signalling as well as the AR interrupting NFκB inflammatory transcription
  • prolonged exposure of vascular cells to the inflammatory activation of NFκB associated with atherosclerosis may reduce or alter any potentially protective effects of testosterone
  • DHT and IFNγ also modulate each other's signalling through interaction at the transcriptional level, suggesting that androgens down-regulate IFN-induced genes
  • (Simoncini et al. 2000a,b). Norata et al. (2010) suggest that part of the testosterone-mediated atheroprotective effects could depend on ER activation mediated by the testosterone/DHT 3β-derivative, 3β-Adiol
  • TNFα-induced induction of ICAM-1, VCAM-1 and E-selectin as well as MCP1 and IL6 was significantly reduced by a pre-incubation with 3β-Adiol in HUVECs
  • 3β-Adiol also reduced LPS-induced gene expression of IL6, TNFα, cyclooxygenase 2 (COX2 (PTGS2)), CD40, CX3CR1, plasminogen activator inhibitor-1, MMP9, resistin, pentraxin-3 and MCP1 in the monocytic cell line U937 (Norata et al. 2010)
  • This study suggests that testosterone metabolites, other than those generated through aromatisation, could exert anti-inflammatory effects that are mediated by ER activation.
  • The authors suggest that DHT differentially effects COX2 levels under physiological and pathophysiological conditions in human coronary artery smooth muscle cells and via AR-dependent and -independent mechanisms influenced by the physiological state of the cell
  • There are, however, a number of systematic meta-analyses of clinical trials of TRT that have not demonstrated an increased risk of adverse cardiovascular events or mortality
  • The TOM trial, which was designed to investigate the effect of TRT on frailty in elderly men, was terminated prematurely as a result of an increased incidence of cardiovascular-related events after 6 months in the treatment arm
  • trials of TRT in men with either chronic stable angina or chronic cardiac failure have also found no increase in either cardiovascular events or mortality in studies up to 12 months
  • Evidence may therefore suggest that low testosterone levels and testosterone levels above the normal range have an adverse effect on CVD, whereas testosterone levels titrated to within the mid- to upper-normal range have at least a neutral effect or, taking into account the knowledge of the beneficial effects of testosterone on a series of cardiovascular risk factors, there may possibly be a cardioprotective action
  • The effect of testosterone on human vascular function is a complex issue and may be dependent upon the underlying androgen and/or disease status.
  • the majority of studies suggest that testosterone may display both acute and chronic vasodilatory effects upon various vascular beds at both physiological and supraphysiological concentrations and via endothelium-dependent and -independent mechanisms
  • Nathan Goodyear on 13 May 13
     
    Good deep look into the testosterone and CVD link.
Nathan Goodyear

Role of Oxidative Stress and the Microenvironment in Breast Cancer Development and Progression - 0 views

www.ncbi.nlm.nih.gov/...PMC3950899

cancer oxidative stress warburg effect reverse warburg effect ROS

shared by Nathan Goodyear on 11 Nov 14 - No Cached
  • oxidative stress leads to HIF-1α accumulation
  • Oxidative stress generated by breast cancer cells activates HIF-1α and NFκB in fibroblasts, leading to autophagy and lysosomal degradation of Cav-1
  • increased levels of hydrogen peroxide in exhaled breath condensate from patients with localized breast malignancy, associated with increased clinical severity
  • ...18 more annotations...
  • Comparing mitochondrial metabolic activity revealed a difference between stroma and epithelial cells
  • Overexpression of NOX4 in normal breast epithelial cells results in cellular senescence, resistance to apoptosis, and tumorigenic transformation, as well as increased aggressiveness of breast cancer cells
  • metalloproteinases (MMP) such as MMP-2, MMP-3, and MMP-9 increase extracellular matrix turnover and are themselves activated by oxidative stress
  • Lowered expression of Cav-1 not only leads to myofibroblast conversion and inflammation but also seems to impact aerobic glycolysis, leading to secretion of high energy metabolites such as pyruvate and lactate that drive mitochondrial oxidative phosphorylation in cancer cells
  • Reverse Warburg Effect
  • secreted transforming growth factor β (TGFβ), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), fibroblast growth factor 2, and stromal-derived factor 1 (SDF1) are able to activate fibroblasts and increase cancer cell proliferation
  • oxidative stress has an important role in the initiation and preservation of breast cancer progression
  • cancer preventive role of healthy mitochondria
  • the cancer cells produce hydrogen peroxide and by driving the “Reverse Warburg Effect” initiate oxidative stress in fibroblasts. As a result of this process, fibroblasts exhibited reduced mitochondrial activity, increased glucose uptake, ROS, and metabolite production.
  • Oxidative stress results from an imbalance between unstable reactive species lacking one or more unpaired electrons (superoxide anion, hydrogen peroxide, hydroxyl radical, reactive nitrogen species) and antioxidants
  • cancer cells are able to induce drivers of oxidative stress, autophagy and mitophagy: HIF-1α and NFκB in surrounding stroma fibro-blasts
  • Studies show that loss of Cav-1 in adjacent breast cancer stroma fibroblasts can be prevented by treatment with N-acetyl cysteine, quercetin, or metformin
  • However, diets rich in antioxidants have fallen short in sufficiently preventing cancer
  • hydrogen peroxide is one of the main factors that can push fibroblasts and cancer cells into senescence
  • It is widely held that HIF-1α function is dependent upon its location within the tumor microenvironment. It acts as a tumor promoter in CAFs and as a tumor suppressor in cancer cells
  • It was reported that overexpression of recombinant (SOD2) (Trimmer et al., 2011) or injection of SOD, catalase, or their pegylated counterparts can block recurrence and metastasis in mice
  • obstructing oxidative stress in the tumor microenvironment can lead to mitophagy and promote breast cancer shutdown is a promising discovery for the development of future therapeutic interventions.
  • Recent studies show that in the breast cancer microenvironment, oxidative stress causes mitochondrial dysfunction
  • Nathan Goodyear on 11 Nov 14
     
    Really fascinating article on tumor signaling. The article points to a complex signaling between cancer cells and stromal fibroblasts that results in myofibroblast transformation that increases the microenvironment favorability of cancer. This article points to oxidative stress as the primary driving force.  
Nathan Goodyear

Growth Inhibition of Ovarian Tumor-Initiating Cells by Niclosamide | Molecular Cancer Therapeutics - 0 views

mct.aacrjournals.org/...1703.long

Niclosamide Tumor-initiation cells TIC ovarian cancer cancer CSC cancer stem cells

shared by Nathan Goodyear on 16 Apr 18 - No Cached
  • Ovarian cancer is the most lethal gynecologic malignancy and the fifth-most cause of overall cancer death of women in developed countries
  • An increasingly accepted cancer stem cell hypothesis regards tumors as caricatures of normal organs, possessing a hierarchy of cell types, at various stages of aberrant differentiation, descended from precursor tumor-initiating cells (TIC) cells that are highly resistant to conventional cytotoxics
  • Significant changes of gene expression in 2,928 genes were identified after niclosamide treatment for different time periods
  • ...14 more annotations...
  • uncoupling of mitochondrial oxidative phosphorylation is believed to be its anti-helminthic mechanism of action
  • we hypothesized that niclosamides antagonistic effects on OTICs could, in part, be due to its disruption of metabolism
  • niclosamide represses metabolic enzymes responsible for bioenergetics, biosynthesis, and redox regulation specifically in OTICs, presumably leading to mitochondrial intrinsic apoptosis pathways, loss of tumor stemness, and growth inhibition
  • niclosamide treatment resulted in a more than 20% increase in reactive oxygen species (ROS) in cultured OTICs
  • niclosamide, which has proved to be safe and effective for the past 2 decades against numerous parasites, inhibited OTIC growth both in vitro and in vivo
  • Our results showed that genes participating in protein complexes of oxidative phosphorylation were downregulated
  • Niclosamide is believed to inhibit mitochondrial oxidative phosphorylation
  • Niclosamide was reported to inactivate NF-κB, causing mitochondrial damage and the generation of ROS, leading to apoptosis of leukemic stem cells
  • niclosamide were identified in a screen for mTOR-signaling inhibitors
  • mTOR was reported to maintain stemness properties of HSCs by inhibiting mitochondrial biogenesis and ROS levels (39), implying that mTOR inhibitors (such as niclosamide) may interfere with mitochondria and various metabolic pathways in TICs via disruption of antioxidant responses
  • We observed Wnt hyperactivity in OTICs, in agreement with previous hypotheses of Wnt inhibitor effectiveness as an ovarian cancer therapy
  • niclosamide has now been independently identified in screens for Wnt inhibitors
  • downregulation of the Wnt/β-catenin target oncogenes survivin and c-Myc
  • ovarian carcinogenesis, the cell-to-cell signaling pathway Notch (8), were also suppressed by niclosamide (data not shown). These results agree with another recent niclosamide study in leukemia (49), and it has been widely hypothesized that disruption of Notch signaling may represent a highly effective therapy for ovarian and other solid tumors, via its essentiality to maintaining TIC stemness
  • Nathan Goodyear on 16 Apr 18
     
    Niclosamide, common anti-parasitic medication, inhibits cellular metabolism and increases ROS; both of which provide powerful anti-proliferative, anti-cancer treatment mechanism in TICs. Powerful target therapy for cancer stem cells. Also shown to inhibit Wnt stimulated oncogenes survivin and c-Myc, disrupts Notch signaling, inactivates NF-kappaBeta, and inhibits mTOR-signaling.  This has been found in in vitro and in vivo studies.
Nathan Goodyear

Drug Screening Identifies Niclosamide as an Inhibitor of Breast Cancer Stem-Like Cells - 0 views

journals.plos.org/...article

Niclosamide cancer cancer stem cells breast cancer

shared by Nathan Goodyear on 21 Mar 18 - No Cached
  • cancer stem cells may also contribute to tumor formation, metastasis, and treatment resistance
  • Studies have shown that some agents (such as metformin) can selectively target cancer stem cells and that dietary polyphenols, curcumin, peperine, and sulforaphane, which are derived from broccoli/broccoli sprouts, are able to target breast cancer stem cells via inhibition of the Wnt signaling, which affects mammosphere size and colony formation
  • niclosamide inhibits tumor growth and reduces tumor weight
  • ...8 more annotations...
  • Niclosamide treatment inhibited the expression of cyclin D1, Hes1, and PTCH by 33%, 57%, and 79%, respectively
  • The mechanism via which niclosamide, a protonophoric anthelmintic drug, induces stem-like-cell-specific toxicity in breast cancer is interesting. It is an old drug that has been used to treat tapeworms in animals
  • Niclosamide is known to uncouple mitochondrial oxidative phosphorylation during tapeworm killing
  • A screening of autophagy modulators revealed that niclosamide is a novel inhibitor of mTORC1 signaling
  • A recent work also demonstrated that niclosamide induces the apoptosis of myelogenous leukemic cells via the inactivation of NF-kappaB and reactive oxygen species generation
  • Niclosamide was also reported to inhibit Wnt signaling [31]–[33] in colon cancer cells
  • Our recent work demonstrated that niclosamide disrupts multiple metabolic pathways in ovarian-cancer-initiating cells
  • The present study showed that niclosamide treatment resulted in the downregulation of target genes involved in the self-renewal of cancer stem-like cells and inhibited breast SPS
  • Nathan Goodyear on 21 Mar 18
     
    Old ant-parasitic, niclosamide, found to down-regulate cancer stem cell activity.
Nathan Goodyear

microRNA Expression in Ethnic Specific Early Stage Breast Cancer: an Integration and Comparative Analysis | Scientific Reports - 0 views

www.nature.com/...s41598-017-16978-y

genetics cancer epigenetics breast cancer

shared by Nathan Goodyear on 06 Feb 18 - No Cached
mamdouh_hfz liked it
  • dysregulated miRNA could be involved in tumor cell proliferation and growth as well as cell cycle progression
  • under-expression of miR-497, 376c and 1271 in Lebanese breast cancer tissues
  • The upregulated miR-183 in our samples was predicted to be responsible for the decrease in expression of the BTG1 mRNA whose protein is involved in cell cycle arrest and apoptosis in breast cancer cells18.
  • ...9 more annotations...
  • nother molecule related to cell proliferation that was over-expressed in our data and suggested as a target of downregulated miR-376c is AURKA
  • the over-expression of miR-183 and miR-21 in Lebanese breast cancer tissues is consistent with downregulation of two important tumor suppressor predicted targets: AKAP12 whose protein regulates cellular adhesion dynamics by controlling cytoskeletal architecture, cell migration, and mitogenic signaling20; and LATS2 whose protein causes cell cycle arrest
  • dysregulation in cancer particularly in breast cancer highlights their importance in tumor development
  • mRNA-miRNA integration analysis of early breast cancer revealed a potential role of miRNA in increasing cellular proliferation and progression, and decreasing invasion and migration
  • most of the miRNA dysregulated in Lebanese breast cancer patients are similar to those dysregulated in American patients, differences in miRNA expression exist and could be attributed either to the patients’ age at diagnosis or to ethnic variation in miRNA epigenetic regulation and sequence variation of pre-miRNA
  • the number one cancer killer of women worldwide
  • microRNA (miRNA) are small non-coding 18–25 nucleotide RNA molecules currently being studied as potential diagnostic, prognostic and therapeutic biomarkers for cancer and other diseases
  • Extensive research on these post-transcriptional modulators has proven that they are deregulated in breast cancerous tissues and even in biological fluids from breast cancer patients
  • five candidate miRNAs (miR-10b, miR-148b, miR-221, miR-21, and miR-155)
  • Nathan Goodyear on 06 Feb 18
     
    Epigenetics plays a role, via disregulated miRNA, in increased cell growth, progression, and invasion in Lebanese women with breast cancer.  It is not just genetics that play a role, but epigenetics.
Nathan Goodyear

Oncotarget | NADH autofluorescence, a new metabolic biomarker for cancer stem cells: Identification of Vitamin C and CAPE as natural products targeting "stemness" - 0 views

www.oncotarget.com/index.php

vitamin C IV vitamin C cancer cancer stem cells milk thistle silymarin ascorbic acid bee propolis CAPE glycolytic inhibitor natural

shared by Nathan Goodyear on 08 Dec 17 - No Cached
  • Vitamin C was ~10 times more potent than 2-DG for the targeting of CSCs
  • Cancer stem-like cells (CSCs) are thought to be the root cause of chemotherapy-resistance and radio-resistance
  • ultimately leading to treatment failure in patients with advanced disease [1-3]. They have been directly implicated mechanistically in tumor recurrence and metastasis, resulting in poor patient survival
  • ...26 more annotations...
  • mitochondrial biogenesis may be a key driver of the CSC phenotype
  • Our results indicate that increased mitochondrial oxidative stress and high NADH levels are both key characteristics of the CSC metabolic phenotype
  • high levels of NAD(P)H auto-fluorescence are known to be a surrogate marker for mitochondrial “power”, high OXPHOS capacity and increased ATP production
  • CSCs may be strictly dependent on NAD(P)H to maintain their enhanced mitochondrial function
  • an intact NAD+ salvage pathway is strictly required for mammosphere formation, supporting our results using NAD(P)H auto-fluorescence, which enriched CSC activity by more than 5-fold.
  • Since glycolysis is especially critical for maintaining the TCA cycle, OXPHOS and overall mitochondrial function, we next assessed the effects of known glycolytic inhibitors
  • we show that two other natural products that function as effective glycolysis inhibitors, also inhibited mammosphere formation. More specifically, vitamin C (ascorbic acid), which induces oxidative stress and inhibits the activity of GAPDH (a key glycolytic enzyme) [17], also inhibited mammosphere formation, with an IC-50 of 1 mM (Figure 7B). Therefore, vitamin C was ~10 times more potent than 2-DG at targeting CSC propagation
  • silibinin (the major active constituent of silymarin, an extract of milk thistle seeds) [18], which specifically functions as an inhibitor of glucose uptake, blocked mammosphere formation, with an IC-50 between 200 and 400 µM
  • caffeic acid phenyl ester (CAPE), a key component of honey-bee propolis, has potent anti-cancer properties
  • Propolis has a strong history of medicinal use, dating back more than 2,000 years
  • Because of it aromatic ring structure (Figure 8), we speculated that CAPE might function as a potent inhibitor of oxidative mitochondrial metabolism
  • CAPE quantitatively inhibits the mitochondrial oxygen consumption rate (OCR) and, in turn, induces the onset of aerobic glycolysis (ECAR)
  • CAPE shows a clear selectivity for targeting CSCs and adherent cancer cells, relative to normal fibroblasts.
  • CAPE functions as a “natural” mitochondrial OXPHOS inhibitor, that preferentially targets the CSC sub-population. This could explain CAPE’s known anti-cancer properties
  • Our data directly shows that a small fraction of the total cell population, characterized by increased PGC1α activity, high mitochondrial ROS/H2O2 and high NADH levels, has the ability to survive and grow under anchorage-independent conditions, driving mammosphere formation
  • We highlight the utility of certain natural products, such as Silibinin, Vitamin C and CAPE, that could be used to therapeutically target CSCs. Silibinin is the major active component of silymarin, which is an extract prepared from milk thistle seeds.
  • high NADH is a property that is conserved between normal and cancerous stem cells
  • Previous studies have also shown that when non-CSCs and CSCs are both fed mitochondrial fuels (such as L-lactate or ketone bodies), that CSCs quantitatively produce more NADH in response to this stimulus
  • CSCs may be strictly dependent on NADH to maintain their enhanced mitochondrial function
  • The Noble Prize winner, Linus Pauling, was among the first to describe and clinically test the efficacy of Vitamin C, as a relatively non-toxic anti-cancer agent
  • Vitamin C has two mechanisms of action. First, it is a potent pro-oxidant, that actively depletes the reduced glutathione pool, leading to cellular oxidative stress and apoptosis in cancer cells. Moreover, it also behaves as an inhibitor of glycolysis, by targeting the activity of GAPDH, a key glycolytic enzyme.
  • Here, we show that Vitamin C can also be used to target the CSC population, as it is an inhibitor of energy metabolism that feeds into the mitochondrial TCA cycle and OXPHOS
  • Vitamin C may prove to be promising agent for new clinical trials, aimed at testing its ability to reduce CSC activity in cancer patients, as an add-on to more conventional therapies, to prevent tumor recurrence, further disease progression and metastasis
  • Interestingly, a breast cancer based clinical study has already shown that the use of Vitamin C, concurrent with or within 6 months of chemotherapy, significantly reduces both tumor recurrence and patient mortality
  • CAPE quantitatively reduces mitochondrial oxygen consumption (OCR), while inducing a reactive increase in glycolysis (ECAR). As such, it potently inhibits mammosphere formation with an IC-50 of ~2.5 µM. Similarly, it also significantly inhibits cell migration
  • we also demonstrate that 7 different inhibitors of key energetic pathways can be used to effectively block CSC propagation, including three natural products (silibinin, ascorbic acid and CAPE). Future studies will be necessary to test their potential for clinical benefit in cancer patients.
  • Nathan Goodyear on 08 Dec 17
     
    The future of cancer therapy is cancer stem cells.  Study finds that Vitamin C, silymarin, and bee propolis blocks mitochondrial energy pathways in cancer stem cells.  Vitamin C is a known glycolytic inhbitor. Vitamin C was found to inhibit glycolysis via GAPDH targeting to inhibit the energy pathways of the mitochondria in CSCs.  The authors propse that Vitamin C can be used as add on therapies for conventional therapies to specifically attack the CSCs and their contribution to recrurence, treatment resistance, and metastasis potential all in addition to the ability of vitamin C to reduce the side effects of chemotherapy.
Nathan Goodyear

Evolution of the Cancer Stem Cell Model: Cell Stem Cell - 0 views

www.cell.com/...S1934-5909(14)00057-5

CSC cancer stem cells cancer

shared by Nathan Goodyear on 01 Feb 18 - No Cached
  • cancer is widely understood to be a heterogeneous disease and there is increasing awareness that intratumoral heterogeneity contributes to therapy failure and disease progression
  • Evidence from both experimental models and clinical studies indicate that CSCs survive many commonly employed cancer therapeutics
  • both CSCs and normal tissue stem cells possess self-renewal capacity; however, self-renewal is typically deregulated in CSCs
  • ...2 more annotations...
  • the properties and transcriptional signatures specific to CSC are highly predictive of overall patient survival pointing to their clinical relevance
  • CSCs represent a distinct population that can be prospectively isolated from the remainder of the tumor cells and can be shown to have clonal long-term repopulation and self-renewal capacity—the defining features of a CSC
  • Nathan Goodyear on 01 Feb 18
     
    Great review on Cancer Stem Cells
Nathan Goodyear

Ivermectin: enigmatic multifaceted 'wonder' drug continues to surprise and exceed expectations | The Journal of Antibiotics - 0 views

www.nature.com/ja201711

Ivermectin cancer

shared by Nathan Goodyear on 19 Mar 18 - No Cached
  • The avermectins are known to possess pronounced antitumor activity
  • Over the past few years, there have been steadily increasing reports that ivermectin may have varying uses as an anti-cancer agent, as it has been shown to exhibit both anti-cancer and anti-cancer stem cell properties
  • In human ovarian cancer and NF2 tumor cell lines, high-dose ivermectin inactivates protein kinase PAK1 and blocks PAK1-dependent growth
  • ...13 more annotations...
  • PAK1 is essential for the growth of more than 70% of all human cancers, including breast, prostate, pancreatic, colon, gastric, lung, cervical and thyroid cancers, as well as hepatoma, glioma, melanoma, multiple myeloma and for neurofibromatosis tumors
  • Ivermectin suppresses breast cancer by activating cytostatic autophagy, disrupting cellular signaling in the process, probably by reducing PAK1 expression
  • Cancer stem cells are a key factor in cancer cells developing resistance to chemotherapies and these results indicate that a combination of chemotherapy agents plus ivermectin could potentially target and kill cancer stem cells, a paramount goal in overcoming cancer
  • Triple-negative breast cancers, which lack estrogen, progesterone and HER2 receptors, account for 10–20% of breast cancers and are associated with poor prognosis
  • Ivermectin addition led to transcriptional modulation of genes associated with epithelial–mesenchymal transition and maintenance of a cancer stem cell phenotype in triple-negative breast cancers cells, resulting in impairment of clonogenic self-renewal in vitro and inhibition of tumor growth and metastasis in vivo
  • Ivermectin-induced cytostatic autophagy also leads to suppression of tumor growth in breast cancer xenografts, causing researchers to believe there is scope for using ivermectin to inhibit breast cancer cell proliferation and that the drug is a potential treatment for breast cancer
  • ivermectin synergizes with the chemotherapy agents cytarabine and daunorubicin to induce cell death in leukemia cells
  • Ivermectin inhibits proliferation and increases apoptosis of various human cancers
  • Activation of WNT-TCF signaling is implicated in multiple diseases, including cancers of the lungs and intestine,
  • A new screening system has found that ivermectin inhibits the expression of WNT-TCF targets
  • It represses the levels of C-terminal β-catenin phosphoforms and of cyclin D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases
  • In vivo, ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without side effects
  • ivermectin has an exemplary safety record, it could swiftly become a useful tool as a WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases, encompassing multiple cancers.117
  • Nathan Goodyear on 19 Mar 18
     
    Ivermectin shows promise and usefullness in several cancer types.  This is a review article.
Nathan Goodyear

Dutasteride affects progesterone metabolizing enzyme activity/expression in human breast cell lines resulting in suppression of cell proliferation and detachment - 0 views

www.sciencedirect.com/...S0960076006001397

hormones progesterone cancer breast cancer 5alpha-pregnane 4-pregnenes progesterone metabolites 5 alpha reductase 5 alpha reductase inhibitors

shared by Nathan Goodyear on 07 Oct 16 - No Cached
  • Nathan Goodyear on 07 Oct 16
     
    Cell culture study finds that 5alpha-reductase inhibition decreased 5alpha-pregnanes and thus inhibited cell proliferation and detachment; this is in contrast to the 4 pregnenes that occur through the enzymes 3alpha-hydroxysteroid oxidoreductase and the 20alpha-hydroxysteroid oxidoreductase, which show anti cell proliferation and cell detachment.
Nathan Goodyear

Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial | Blood Journal - 0 views

www.bloodjournal.org/...88

AML acute myeloid leukemia leukemia IL-2 histamine

shared by Nathan Goodyear on 12 May 18 - No Cached
  • several independent lines of evidence suggest that cytotoxic effector cells such as T cells and natural killer (NK) cells participate in protecting patients with AML against relapse
  • A plethora of mechanisms have been proposed to account for the dysfunctional antileukemic lymphocytes in AML, including the production of T-cell- and NK-cell-inhibitory factors by AML blasts,48 a deficient expression of NK-cell receptors on leukemic cells,49 inhibition of antileukemic lymphocytes by mononuclear phagocytes,4 and an impaired stimulatory interaction between the CD28 antigen expressed by T cells and contact antigens on AML blasts
  • This trial met the primary endpoint and thus showed a significantly improved LFS for patients receiving HDC/IL-2 as compared with the current standard of care
  • ...2 more annotations...
  • T cells and NK cells with antileukemic activity can be recovered from most patients with AML in remission not receiving a transplant,
  • The present study evaluated an approach to immunotherapy in AML in which IL-2 is supplemented with histamine dihydrochloride (HDC) to enhance the function of cytotoxic antileukemic lymphocytes
  • Nathan Goodyear on 12 May 18
     
    IL-2 plus histamine in patients with AML complete remission improves leukemia free survival.
Nathan Goodyear

The anti-malarial drug artesunate causes cell cycle arrest and apoptosis of triple-negative MDA-MB-468 and HER2-enriched SK-BR-3 breast cancer cells. - PubMed - 0 views

www.ncbi.nlm.nih.gov/...30660598

breast cancer cancer artesunate

shared by Nathan Goodyear on 01 Jul 19 - No Cached
  • Nathan Goodyear on 01 Jul 19
     
    ART inhibited breast cancer cell proliferation via a reactive oxygen species (ROS)-dependent G2/M arrest and ROS-independent G1 arrest. ART-treated MDA-MB-468 and SK-BR-3 cells also experienced apoptotic cell death, which was both ROS- and iron-dependent. ART-induced oxidative stress caused the loss of mitochondrial outer membrane integrity and damage to the cellular DNA of MDA-MB-468 and SK-BR-3 cells. Only abstract available...I will post full article once available.
Nathan Goodyear

A novel mechanism of lung cancer inhibition by methionine enkephalin through remodeling the immune status of the tumor microenvironment | Request PDF - 0 views

www.researchgate.net/..._of_the_tumor_microenvironment

M2 macrophages M1 macrophages cancer MET-enkephalins TME MET-5 tumor microenvironment

shared by Nathan Goodyear on 15 Aug 21 - No Cached
  • Nathan Goodyear on 15 Aug 21
     
    MENK increased the infiltration of M1-type macrophages, natural killer cells, CD8+ T cells, CD4+ T cells, and dendritic cells into the TME, and decreased the proportion of myeloid inhibitory cells and M2-type macrophages. Plays particular role in preventing immune escape and immune dysfunction paramount to cancer metastasis
Nathan Goodyear

Molecular Control of Immune/Inflammatory Responses: Interactions Between Nuclear Factor-κB and Steroid Receptor-Signaling Pathways - 0 views

edrv.endojournals.org/...435.long

progesterone NK macrophage T cell activity inflammation immune system

shared by Nathan Goodyear on 09 Nov 12 - No Cached
  • Nathan Goodyear on 09 Nov 12
     
    Benefits of progesterone, are in part, due to its function on the immune system.  Progesterone shown to decrease T cell activity, macrophage activity and NK cell activity.  Aside, NK cell activity has been found to be increased in those with recurrent first trimester miscarriages and progesterone defects.  So, low progesterone allows for a rise in NK cell activity and inflammation that is detrimental to a developing pregnancy.  If that is the case in pregnancy, what about the rest of the body?
Nathan Goodyear

Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling - 0 views

www.ncbi.nlm.nih.gov/...PMC3139478

vitamin d vitamin D autoimmune disease inflammation Th17 Treg cells Treg

shared by Nathan Goodyear on 31 Jul 13 - No Cached
  • Nathan Goodyear on 31 Jul 13
     
    Low vitamin D levels or the receptors for vitamin D appear to result in an increase in Th17 cells.  An increase in Th17 cells will lead to an imbalance with Treg cells and this imbalance is associated with Lupus and other autoimmune processes.  Vitamin D inhibits Th17 cell activation.
Nathan Goodyear

Thyroid Hormones (T3 and T4): Dual Effect on Human Cancer Cell Proliferation - 0 views

ar.iiarjournals.org/...89.long

triiodothyronine thyroid hormones hormone cancer

shared by Nathan Goodyear on 13 Aug 14 - No Cached
  • Nathan Goodyear on 13 Aug 14
     
    The effects of T3 on cancer cell lines varies.  All cell lines came from the same tissue. It doesn't appear that simply stating T3 promotes cellular metabolism and thus provides an increase in cancer progression risk.  Some cell lines studies actually had an inhibition of cell growth, whereas others saw an increase.  
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

Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry - 0 views

www.ncbi.nlm.nih.gov/...PMC3669503

ki-67 cancer breast cancer

shared by Nathan Goodyear on 06 Sep 18 - No Cached
  • A wide range of techniques is available to assess tumor cell proliferation such as calculating mitotic figures in stained tissue segments, flow cytometric analysis to determine the proportion of cells being in the S phase of the cell cycle, examination of thymidine-labeling index, proliferating cell nuclear antigen (PCNA), or cyclins E and D
  • Ki-67 is a nuclear protein being associated with cellular proliferation and was originally identified by Gerdes et al.
  • Ki-67 nuclear antigen is expressed in certain phases of the cell cycle namely S, G1, G2, and M phases, but is nonexisting in G0
  • ...11 more annotations...
  • Ki-67 is also expressed at low levels (<3 % of cells) in ER-negative cells, but not in ER-positive cells
  • A meta-analysis involving 12,155 patients demonstrated that the Ki-67 positivity confers a higher risk of recurrence and a worse survival rate in patients with early breast cancer.
  • high levels of Ki-67 are associated with worse prognoses
  • Ki-67 was associated with worse survival rates
  • associated with proliferation
  • higher tumor stages and higher nodal status were associated with higher Ki-67 quartiles indicating that the more aggressive the tumor is the higher is the percentage of cells positively stained for Ki-67
  • Previous studies were able to demonstrate that a prognostic model, the IHC 4 score, using ER, PR, HER2, and Ki-67 provides similar prognostic information to that in the 21-gene Genomic Health recurrence score
  • ER status has been largely identified as being inversely correlated with Ki-67, with the higher rates of ER positivity shown in the lowest proliferating tumors
  • high levels of Ki-67 are associated with HER2/-neu positivity according to former studies
  • higher values of Ki-67-labeling index were associated with adverse prognostic factors
  • Ki-67-labeling index was associated with larger tumors, higher tumor grade, peritumoral vascular invasion, and HER-2 positivity
  • Nathan Goodyear on 06 Sep 18
     
     Increased disease free survival and overall survival in people with breast cancer with ki-67 <15%
Nathan Goodyear

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer | Proceedings of the National Academy of Sciences - 0 views

www.pnas.org/E7301

Ivermectin cancer ovarian cancer oncogene oncogenes

shared by Nathan Goodyear on 20 Mar 18 - No Cached
  • we functionally validated a potent EOC oncogene, KPNB1, and showed its clinical relevance to human EOC
  • a well-established antiparasitic drug, ivermectin, has antitumor effects on EOC through its inhibition of KPNB1
  • EOC has high intertumor and intratumor heterogeneity at the molecular and epigenetic levels
  • ...22 more annotations...
  • the mortality rate of EOC has not been significantly changed for several decades
  • Sequencing revealed that almost all tumors (96%) had mutations in TP53, which serves as a major driver of this cancer
  • Low-prevalence but statistically significant mutations in nine other genes including NF1, BRCA1, BRCA2, RB1, and CDK12 were also identified, but the majority of genes were mutated at low frequency, making it difficult to distinguish between driver and passenger mutations
  • KPNB1 inhibition via any of three KPNB1 siRNAs or importazole treatment induced apoptosis in human EOC cell lines (Fig. 3 A–F and Fig. S4), and was accompanied by an increase in the expression levels of the proapoptotic proteins BAX and cleaved caspase-3
  • Stable overexpression of KPNB1 in SKOV3 and OVCAR3 (Fig. S6) significantly accelerated cell proliferation/survival (Fig. 5 A–C), confirming that KPNB1 functions as an oncogene in EOC
  • KPNB1 overexpression significantly decreased caspase-3/7 activity (Fig. 5D), in addition to the expression levels of cleaved caspase-3 and BAX proteins (Fig. 5E). KPNB1 overexpression also decreased p21 and p27 protein levels (Fig. 5E), as opposed to their increase by KPNB1 inhibition
  • KPNB1 functions as an antiapoptotic and proproliferative oncogene in EOC.
  • Patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1
  • KPNB1 acts as an oncogene in human EOC and represents a promising therapeutic target.
  • ivermectin treatment suppressed cell proliferation/viability in a dose-dependent manner (Fig. 7A), indicating that it exerts an antitumor effect on EOC
  • ivermectin also induced apoptosis
  • ivermectin increased the expression levels of BAX, and cleaved PARP, as well as p21 and p27
  • KPNB1 inhibition is responsible for the antitumor effect of ivermectin
  • we found that ivermectin synergistically reduced cell proliferation/viability in combination with paclitaxel in human EOC cells
  • Single treatment of ivermectin or paclitaxel reduced tumor growth in nude mice, but, notably, combination treatment of ivermectin and paclitaxel almost completely suppressed tumor growth
  • ERBB2, is amplified and overexpressed in many cancers, including breast (31), ovary (31), colon (32), bladder (33), non-small-cell lung (34), and gastric cancer (35), and is a poor prognostic factor in certain cancer types
  • KPNB1 was the second-highest-ranked gene identified in our screen
  • Increased KPNB1 protein levels have been reported in several cancers, including cervical cancer (42), hepatocellular carcinoma (43), and glioma (44), suggesting KPNB1’s oncogenic potential in these tumor types
  • our findings suggest that KPNB1 might serve as a master regulator of cell cycle by regulating several cell cycle-related proteins, including p21, p27, and APC/C family members
  • higher and/or more-frequent doses of ivermectin than currently approved for humans are well tolerated in humans
  • none of the mice in this study treated with the effective dosage of ivermectin for in vivo anticancer therapy showed severe adverse event
  • we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC cell lines than either drug alone
  • Nathan Goodyear on 20 Mar 18
     
    Ivermectin found to be pro-apoptotic for the epithelial ovarian cancer oncogene, KPNB1 in in Vivo study.  This effective anti-parasitic drug inhibits the KPNB1 oncogene.
Nathan Goodyear

Searching For an Old New Cure: Ivermectin Deficiency Syndrome? « The Healthy Planet - 0 views

thehealthyplanet.com/...ivermectin-deficiency-syndrome

Ivermectin cancer PAK1 oncogene oncogenes

shared by Nathan Goodyear on 21 Mar 18 - No Cached
  • Ivermectin can inactivate the protein kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines
  • PAK proteins encoded by the PAK1 gene are critical for cytoskeleton reorganization and nuclear signaling.
  • PAK-1 kinase is required for the growth of more than 70% of human cancers such as pancreatic, colon, breast and prostate cancers, and neurofibromatosis
  • ...5 more annotations...
  • The p21 activated Kinase PAK1 is implicated in tumor genesis.
  • Inhibiting PAK1 signals induce tumor cell apoptosis (cell death)
  • PAK1 has also been implicated for maintenance of glucose homeostasis in pancreatic beta cells and skeletal muscle
  • Ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells (Blood, November 4, 2010, vol.115). The paper states Ivermectin synergizes with chemo agents cytarabine and daunorubicin to induce cell death in leukemia cells.
  • Praziquantel , my other favorite parasite medication for liver flukes, synergistically enhances Paclitaxel (Taxol) efficacy to inhibit cancer cell growth
  • Nathan Goodyear on 21 Mar 18
     
    Just a commentary but with important information on ivermectin in its inhibitory activity against another oncogene PAK1.
Nathan Goodyear

High Progesterone Receptor Expression in Prostate Cancer Is Associated with Clinical Failure - 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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