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Biomedical subjects

Ralph Buttyan

Publications and source records attributed to Ralph Buttyan.

At least 19 recordsLinked to original sources
PubMed2006

Multifaceted interaction between the androgen and Wnt signaling pathways and the implication for prostate cancer.

Androgen action in prostate and prostate cancer cells is dependent upon the androgen receptor (AR) protein that transcriptionally regulates the expression of androgen-dependent genes in the presence of a steroid ligand. Whereas the overall schema of androgen action mediated by this receptor protein appears to be relatively simple, androgen signaling is now known to be influenced by several other cell signal transduction pathways and here we review the evidence that the canonical Wnt signaling pathway also modulates androgen signaling at multiple levels. Wnt is a complex signaling pathway whose endpoint involves activation of transcription from LEF-1/TCF transcription factors and it is known to be involved in the development and progression of numerous human epithelial tumors including prostate cancer. beta-catenin protein, a particularly critical molecular component of canonical Wnt signaling is now known to promote androgen signaling through its ability to bind to the AR protein in a ligand-dependent fashion and to enhance the ability of liganded AR to activate transcription of androgen-regulated genes. Under certain conditions, glycogen synthase kinase-3beta (GSK-3beta), a protein serine/threonine kinase that regulates beta-catenin degradation within the Wnt signaling pathway, can also phosphorylate AR and suppress its ability to activate transcription. Finally, it was recently found that the human AR gene itself is a target of LEF-1/TCF-mediated transcription and that AR mRNA is highly upregulated by activation of Wnt signaling in prostate cancer cells. Paradoxically, Wnt activation also appears to stimulate Akt activity promoting an MDM-2-mediated degradation process that reduces AR protein levels in Wnt-stimulated prostate cancer cells. Collectively, this information indicates that the multifaceted nature of the interaction between the Wnt and the androgen signaling pathways likely has numerous consequences for the development, growth, and progression of prostate cancer.

Androgens↗
PubMed2006

Protocadherin-PC promotes androgen-independent prostate cancer cell growth.

BACKGROUND: Protocadherin-PC (PCDH-PC) expression is upregulated in apoptosis-resistant sublines of the LNCaP human prostate cancer (CaP) cell line. Here, we assess the role of PCDH-PC in CaP cells and its mRNA expression in human prostate tissues. METHODS: LNCaP cells transfected with PCDH-PC were tested for their ability to grow in vitro and in vivo in androgen-deprived conditions. PCDH-PC mRNA expression was evaluated by semi-quantitative RT-PCR and by in situ hybridization. RESULTS: PCDH-PC expression induced Wnt signaling in CaP cells and permitted androgen-independent growth of hormone-sensitive CaP cells. Expression of PCDH-PC-homologous transcripts was low and restricted to some epithelial cells in normal tissue and to CaP cells in tumors. However, hormone-resistant CaP cells expressed significantly higher levels of PCDH-PC-related mRNA. CONCLUSIONS: Our findings suggest a novel mechanism for the progression of CaP involving expression of PCDH-PC. This novel protocadherin induces Wnt signaling, promotes malignant behavior and hormone-resistance of CaP cells.

Androgens↗
PubMed2006

The use of herbal and over-the-counter dietary supplements for the prevention of prostate cancer.

Having a high probability of experiencing prostate cancer during their lifetime, men are increasingly seeking protection against this disease with the use of over-the-counter dietary supplements containing herbs, vitamins, or plant-derived biochemical agents. The use of these agents for prostate cancer prevention is driven by epidemiology supporting the idea that regional diets and consumption of specific dietary components (certain herbs, vitamins, isoflavones, and polyphenols) are associated with a lower risk for prostate cancer, in conjunction with basic research that is defining molecules within food substances that kill or suppress growth of cultured human prostate cancer cells. Moreover, there is a sense that these dietary agents lack side effects, although this assumption often is faulty. Unfortunately, at this time, there is insufficient clinical evidence to support the widespread use of these dietary supplements for chemoprevention of prostate cancer, although ongoing clinical trials of the most promising vitamins and minerals are approaching conclusion.

Chemoprevention↗
PubMed2006

The use of herbal and over-the-counter dietary supplements for the prevention of prostate cancer.

Having a high probability of experiencing prostate cancer during their lifetime, men are increasingly seeking protection against this disease with the use of over-the-counter dietary supplements containing herbs, vitamins, or plant-derived biochemical agents. The use of these agents for prostate cancer prevention is driven by epidemiology supporting the idea that regional diets and consumption of specific dietary components (certain herbs, vitamins, isoflavones, and polyphenols) are associated with a lower risk for prostate cancer, in conjunction with basic research that is defining molecules within food substances that kill or suppress growth of cultured human prostate cancer cells. Moreover, there is a sense that these dietary agents lack side effects, although this assumption often is faulty. Unfortunately, at this time, there is insufficient clinical evidence to support the widespread use of these dietary supplements for chemoprevention of prostate cancer, although ongoing clinical trials of the most promising vitamins and minerals are approaching conclusion.

Anticarcinogenic Agents↗
PubMed2006

Detection of carbonic anhydrase-9 gene expression in peripheral blood cells predicts risk of disease recurrence in patients with renal cortical tumors.

OBJECTIVES: To present extended follow-up on a cohort of patients with renal cortical tumors treated with partial or radical nephrectomy and preoperatively assess for carbonic anhydrase 9 tumor marker expression in the peripheral blood. METHODS: All patients were originally enrolled in an institutional review board-approved study assessing the role of a reverse-transcriptase polymerase chain reaction peripheral blood assay designed to detect the tumor-specific gene carbonic anhydrase-9 (CA9). A total of 41 patients with renal cortical tumors confined to the kidney were enrolled at a single institution and assessed preoperatively with peripheral blood test for CA9 expression before undergoing partial or radical nephrectomy. A Kaplan-Meier estimated survival analysis and log-rank test were performed to determine whether detection of peripheral blood cells expressing the CA9 gene influences disease-free and disease-specific survival. RESULTS: The median follow-up was 4.3 years. The median age was 71 years. Of the 41 patients, 26 were men and 15 were women. The estimated 5-year disease-free survival for patients with detectible expression of the CA9 gene in the peripheral blood was 39.5% compared with 88.1% for patients without detection of the CA9 gene (P = 0.048). On bivariate analysis, disease-free survival correlated with histologic type, tumor diameter, and tumor grade. CONCLUSIONS: The expression of the tumor-specific marker CA9 in the peripheral blood is associated with decreased disease-free survival in patients with renal cortical tumors. This is the first study reporting on the prognostic value of this peripheral blood-based tumor marker for kidney tumors.

Adenoma, Oxyphilic↗
PubMed2006

Clinical trials of natural products as chemopreventive agents for prostate cancer.

Epidemiological research on prostate cancer risk in men throughout the world has identified significant correlations between dietary habits and prostate cancer occurrence. These studies served as a catalyst for exploration into the potential of dietary substances to act as chemopreventive agents against this disease, and include green tea catechins, lycopene, soy isoflavones, pomegranate phenolics, selenium, vitamins E and D, curcumin and resveratrol. Before these agents (in the dietary or purified forms) can be recommended as useful chemopreventive strategies for patients, their activity must be confirmed in rigorously designed clinical trials. This review discusses the preclinical and clinical data available for these dietary agents and describes relevant clinical trials currently being conducted.

Animals↗
PubMed2005

Complementary and alternative medicine for chronic prostatitis/chronic pelvic pain syndrome.

To discuss challenges concerning treatment for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and review complementary and alternative medical (CAM) therapies being evaluated for this condition, we performed a comprehensive search of articles published from 1990-2005 using the PubMed, Medline databases. Data from the articles were abstracted and pooled by subject. Keywords cross-searched with CP/CPPS included: complementary, alternative, integrative, therapies, interventions, nutrition, antioxidants, herbs, supplements, biofeedback and acupuncture. Listed articles with no abstracts were not included. Various CAM therapies for CP/CPPS exist including biofeedback, acupuncture, hyperthermia and electrostimulation. Additionally, a variety of in vitro and in vivo studies testing herbal and nutritional supplements were found. Saw palmetto, cernilton and quercetin were the most frequently tested supplements for CP/CPPS. Although many CAM therapies demonstrate positive preliminary observations as prospective treatments for CP/CPPS, further exploratory studies including more randomized, controlled trials are necessary for significant validation as treatment options for this complex disorder.

Journal Article↗
PubMed2005

A human- and male-specific protocadherin that acts through the wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells.

Protocadherin-PC (PCDH-PC) is a gene on the human Y chromosome that is selectively expressed in apoptosis- and hormone-resistant human prostate cancer cells. The protein encoded by PCDH-PC is cytoplasmically localized and has a small serine-rich domain in its COOH terminus that is homologous to the beta-catenin binding site of classical cadherins. Variants of prostate cancer cells that express PCDH-PC have high levels of nuclear beta-catenin protein and increased wnt-signaling. In this study, we show that transfection of human prostate cancer cells (LNCaP) with PCDH-PC or culture of these cells in androgen-free medium (a condition that up-regulates PCDH-PC expression) activates wnt signaling as assessed by nuclear accumulation of beta-catenin, increased expression of luciferase from a reporter vector promoted by Tcf binding elements and increased expression of wnt target genes. Moreover, LNCaP cells transfected with PCDH-PC or grown in androgen-free medium transdifferentiate to neuroendocrine-like cells marked by elevated expression of neuron-specific enolase and chromogranin-A. Neuroendocrine transdifferentiation was also observed when LNCaP cells were transfected by stabilized beta-catenin. Increased wnt signaling and neuroendocrine transdifferentiation of LNCaP cells induced by culture in androgen-free medium was suppressed by short interfering RNAs that target PCDH-PC as well as by dominant-negative Tcf or short interfering RNA against beta-catenin, supporting the hypothesis that increased expression of PCDH-PC is driving neuroendocrine transdifferentiation by activating wnt signaling. These findings have significant implications for the process through which prostate cancers progress to hormone resistance in humans.

Cadherins↗
PubMed2005

Application of angiogenic factors for therapy of erectile dysfunction: protein and DNA transfer of VEGF 165 into the rat penis.

OBJECTIVES: To establish a laboratory animal model for vascular endothelial growth factor (VEGF) transfer in the rat penis to invent a curative therapy for erectile dysfunction (ED). Vascular insufficiency is a common pathomechanism of ED. Previous investigations have shown neovascularization of ischemic organs after gene transfer of VEGF. METHODS: For VEGF-protein transfer, osmotic pumps were connected to the renal arteries of rats. The pumps were filled with human VEGF 165 protein (n = 20) or sterile saline (n = 20). After 28 days, a VEGF serum immunoassay was performed to document successful delivery. For VEGF-DNA transfer, liposome complexes containing VEGF 165 expression vectors were injected into rat corpora cavernosa. After immunostaining, computerized image analysis was performed to quantify the percentage of area (within the corpora cavernosa) covered by smooth muscle or endothelial cells. RESULTS: The immunoassay of the VEGF-protein transfer showed a 10-fold greater VEGF concentration in the serum of rats carrying VEGF pumps than in the control group. In the VEGF-DNA transfer, the penes transfected with VEGF 165 vectors showed a 283-bp polymerase chain reaction product according to specific primers for human VEGF. Although statistical trends were measured in the VEGF protein-treated group, no statistically significant difference in smooth muscle or endothelial cell content was found between the control and VEGF-treated rats. CONCLUSIONS: Our findings have established proof of principle for successful delivery of VEGF protein and VEGF-DNA transfer in the rat penis. This study was a prelude to attempt to manipulate genetically expression of angiogenic factors in insufficient erectile tissue as a curative therapy for ED.

Animals↗
PubMed2005

Zyflamend, a unique herbal preparation with nonselective COX inhibitory activity, induces apoptosis of prostate cancer cells that lack COX-2 expression.

Cyclooxygenase (COX) inhibitors have suppressive effects on several types of cancer cells including prostate cancer. In this study, we considered the potential COX-inhibitory activity of a unique anti-inflammatory herbal preparation (Zyflamend; New Chapter, Inc., Brattleboro, VT) and analyzed its effects on the human prostate cancer cell line LNCaP. COX inhibitory activity of Zyflamend was determined by a spectrophotometric-based assay using purified ovine COX-1 and COX-2 enzymes. Effects of Zyflamend on LNCaP cell growth and apoptosis in vitro were assessed by cell counting, Western blot detection of poly ADP-ribose polymerase (PARP) cleavage, and measurement of caspase-3 activity in treated and control cell extracts. Western blotting techniques were conducted to determine the effects of this herbal preparation on the expression of the cell signaling proteins, p21, androgen receptor (AR), phospho-protein kinase C (pPKC)(alpha/beta), and phospho (p)Stat3. The phospohorylation status of several signal transduction phosphoproteins was profiled using a high-throughput phosphoprotein screening assay in treated cells and compared to controls. Zyflamend dramatically decreased COX-1 and COX-2 enzymatic activity. Elevated p21 expression coincided with attenuated cell growth following treatment of LNCaP cells with Zyflamend. PARP cleavage fragments were evident, and caspase-3 activity was upregulated over the control indicating the ability of Zyflamend to induce apoptosis of these cells. Androgen receptor expression levels declined by 40%, and decreases were observed in the active forms of Stat3 and PKC(alpha/beta) in Zyflamend-treated LNCaP cells. Zyflamend inhibited both COX-1 and COX-2 enzymatic activities, suppressed cell growth, and induced apoptosis in LNCaP cells. However, our data suggests that the effects are likely due to COX-independent mechanisms potentially involving enhanced expression of p21 and reduced expression of AR, pStat3, and pPKC(alpha/beta).

Apoptosis↗
PubMed2004

A concentrated aglycone isoflavone preparation (GCP) that demonstrates potent anti-prostate cancer activity in vitro and in vivo.

PURPOSE: Isoflavones have anticancer activities, but naturally occurring isoflavones are predominantly glycosylated and poorly absorbed. Genistein combined polysaccharide (GCP; Amino Up Chemical Co., Sapporo, Japan), is a fermentation product of soy extract and basidiomycetes mycillae that is enriched in biologically active aglycone isoflavones. This study analyzes GCP in vitro and in vivo for potential utility as a prostate cancer chemopreventative agent. EXPERIMENTAL DESIGN: Androgen-sensitive LNCaP and androgen-independent PC-3 cells were grown with various concentrations of GCP. In vitro cell growth was analyzed by the WST-1 assay, and apoptosis was assessed by fluorescence-activated cell sorting and detection of poly(ADP-ribose) polymerase cleavage using Western blot techniques. Effects of GCP on expression of cell cycle-regulatory proteins p53 (LNCaP only), p21, and p27 and the protein kinase Akt were considered using Western blot techniques. An in vivo LNCaP xenograft model was used to study the effects of a 2% GCP-supplemented diet on tumor growth in comparison with a control diet. RESULTS: GCP significantly suppressed LNCaP and PC-3 cell growth over 72 h (89% and 78% in LNCaP and PC-3, respectively, at 10 microg/ml; P < 0.0001). This reduction was associated with apoptosis in LNCaP cells, but not in PC-3 cells. GCP induced p27 and p53 (LNCaP only) protein expression within 6 h and suppressed phosphorylated Akt in both cell lines. The 2% GCP-supplemented diet significantly slowed LNCaP tumor growth, increasing apoptosis (P < 0.001), and decreasing proliferation (P < 0.001) over 4 weeks. CONCLUSIONS: GCP has potent growth-inhibitory effects against prostate cancer cell lines in vitro and in vivo. These data suggest GCP has potential as an effective chemopreventive agent against prostate cancer cell growth.

Animals↗
PubMed2004

Role of angiogenesis in bladder response to partial outlet obstruction.

Benign prostatic hyperplasia (BPH) is a disease that has its etiology in the abnormal growth of the adult human prostate gland that accompanies the aging process in men. The symptomatic presentation of this disease, however, is related largely to degenerative changes in the bladder that occur as a result of the increasing urethral resistance and partial bladder outlet obstruction (PBOO) caused by the growing prostate gland. BPH is characterized by bladder hypertrophy, significant decreases in urinary flow and compliance, presence of residual urine after voiding, voiding urgency and incontinence (). Obstructed bladder dysfunction secondary to BPH is a slow, progressive disease that is so strongly associated with human aging that it is an expected occurrence of the male aging process. Although the symptoms of BPH are usually not life threatening, they effect an extremely negative quality of life for men who suffer from them. However, many men delay seeking medical treatment for early BPH since bladder function can remain relatively normal as the hypertrophying bladder initially compensates for the progressive increase in urethral resistance caused by prostatic obstruction. The limited changes in micturition pressure and flow characteristics that occur during compensated function are not usually disabling enough to motivate seeking medical attention, which, often, is not sought until the symptoms become typical of advanced disease. Recent advances in detection methods enable identification of patients with significant BPH during compensation before the bladder becomes dysfunctional (decompensated). A more complete understanding of the disease processes that underlie the loss of bladder function associated with BPH might enable the development of treatments that better protect these early-stage BPH patients from the more debilitating aspects of the disease. This review updates the understanding of obstructive bladder dysfunction via the use of animal models.

Animals↗
PubMed2003

Acute hypoxia increases the aggressive characteristics and survival properties of prostate cancer cells.

BACKGROUND: Androgen withdrawal, the standard therapeutic strategy for advanced prostate cancer, induces a rapid reduction of blood flow to prostate and prostate cancer tissues and the concomitant onset of a hypoxic environment in these tissues. To establish whether hypoxia-responsiveness (by means of the action of hypoxia inducible factor [HIF] -1alpha protein) might affect the tumorigenic or survival properties of prostate cancer cells, we studied how acute exposure of cultured human prostate cancer cells (LNCaP cell line) to hypoxia might alter their pattern of gene expression and their in vitro behavior. METHODS: LNCaP cultures were placed in a hypoxia chamber for up to 24 hr and were compared with control (normoxic) cells for the expression of gene products by Western blotting and semiquantitative reverse transcription-polymerase chain reaction techniques. RESULTS: Exposure of LNCaP cells to acute hypoxia activated a typical cellular hypoxia response characterized by up-regulation of HIF-1alpha and vascular endothelial growth factor protein expression. In contrast, expression of differentiation-specific proteins (prostate specific antigen and androgen receptor) or proliferative-regulatory proteins (c-myc, cyclin D1, p27) were down-regulated by hypoxia. Some of these latter changes (reduction of c-myc and cyclin D expression) were not accompanied by corresponding reduction of mRNAs and were abrogated by a proteosome inhibitor (MG132), suggesting that their loss was associated with their increased degradation rather than through transcriptional controls. The phosphorylation of Akt/protein kinase B and its downstream target, forkhead protein, was highly up-regulated by hypoxia, and cells exposed to transient periods of hypoxia became significantly less sensitive to an apoptotic stimulus (exposure to phorbol ester) when compared with normoxic cells. CONCLUSION: This study demonstrates that even acute hypoxia has the potential to drastically alter the growth, differentiation characteristics, and apoptotic sensitivity of a prostate cancer cell.

Apoptosis↗
PubMed2003

Acute intravesical infusion of a cobalt solution stimulates a hypoxia response, growth and angiogenesis in the rat bladder.

PURPOSE: Experimental partial bladder outlet obstruction of rats induces a bladder growth and remodeling process similar to that in humans with benign prostatic hyperplasia. Previously we have proposed that bladder hypoxia associated with partial bladder outlet obstruction is a stimulus of this bladder growth process. We report our results of testing the acute effects of a simple chemical agent (cobaltous ion) known to mimic hypoxia in the rat bladder. We measured its ability to effect bladder gene expression, angiogenesis and growth processes. MATERIALS AND METHODS: Adult rats were divided into 2 groups. One group (controls) received intravesical saline 3 times for 30 minutes in 6 days and the other received intravesical saline with 100 microM. CoCl(2) at the same times. All animals also received continuous infusion of BrdU for the 6-day period through an implanted osmotic pump. Portions of the bladders from these rats were fixed, sectioned, stained for microscopic analysis and immunohistochemically stained to identify BrdU positive cells and vascular elements via factor VIII staining. Other portions were frozen, extracted for proteins and the proteins were comparatively analyzed for the expression of hypoxia inducible factor-1alpha and vascular endothelial growth factor on Western blots. RESULTS: Bladders infused with CoCl(2) showed extensive expansion of the submucosal region, which was significant compared with that in saline infused bladders. Cells in this expanded region as well as cells within the urothelium were found to be extensively labeled with BrdU, in contrast to control bladders, which had rare BrdU labeled cells in any region. Immunohistochemical analysis for factor VIII showed that the submucosal region of cobalt treated rats contained numerous small vessels and microvessels that were not apparent in controls. These cellular changes were consistent with our finding of increased hypoxia inducible factor-1alpha and vascular endothelial growth factor protein expression in cobalt treated bladders compared with controls. CONCLUSIONS: Acute intravesical instillation of cobalt ion solution into the rat bladder initiated a hypoxia response accompanied by increased bladder angiogenesis and growth. This finding supports the idea that hypoxia is a stimulus for bladder growth subsequent to partial bladder outlet obstruction.

Administration, Intravesical↗
PubMed2003

Tumor cell hypoxia and the hypoxia-response signaling system as a target for prostate cancer therapy.

The accumulation of cancerous cells within a growing prostate tumor can deprive them of adequate vascular support. Without this support, the affected tumor cells become hypoxic, a condition that is usually unfavorable for the further growth and survival of eukaryotic cells. Mammalian cells, however, have the ability of responding to a hypoxic environment by activating a "hypoxia-response" signaling system. Ultimately, this signaling system upregulates the expression of a network of gene products that increase the propensity of the cell to survive even in this adverse environment. With increasing evidence that hypoxia and an activated hypoxia-response signaling system can influence progression (via increased angiogenic propensity and apoptotic resistance) and the therapeutic responsiveness of prostate cancer cells, this review will examine the concept of targeting hypoxia or the hypoxia-response system of prostate tumor cells as a means to suppress prostate tumor progression and metastasis or perhaps even as a means for eliminating prostate tumors in advanced prostate cancer patients.

Angiogenesis Inhibitors↗