Antiapoptotic signaling in LNCaP prostate cancer cells: a survival signaling pathway independent of phosphatidylinositol 3'-kinase and Akt/protein kinase B. (1/189)
Constitutive activation of the phosphatidylinositol 3'-kinase (PI3 kinase)-Akt/protein kinase B (PKB) "survival signaling" pathway is a likely mechanism by which many cancers become refractory to cytotoxic therapy. In LNCaP prostate cancer cells, the PTEN phosphoinositide phosphatase is inactivated, leading to constitutive activation of Akt/PKB and resistance to apoptosis. However, apoptosis and inactivation of Akt/PKB can be induced in these cells by treatment with PI3 kinase inhibitors. Surprisingly, androgen, epidermal growth factor, or serum can protect these cells from apoptosis, even in the presence of PI3 kinase inhibitors and without activation of Akt/PKB, indicating the activity of a novel, Akt/PKB-independent survival pathway. This pathway blocks apoptosis at a level prior to caspase 3 activation and release of cytochrome c from mitochondria. (+info)Effect of antioxidants on androgen-induced AP-1 and NF-kappaB DNA-binding activity in prostate carcinoma cells. (2/189)
BACKGROUND: Previous studies have suggested that male hormones (androgens) and certain forms of oxygen (reactive oxygen species) are linked to the development of prostate cancer. We hypothesized that androgens contribute to prostate carcinogenesis by increasing oxidative stress. We further hypothesized that antioxidants reduce prostate cancer risk by modulating androgen effects on cellular processes. METHODS: To test these hypotheses, we looked for 1) a change in the level of reactive oxygen species in the presence of androgens, 2) androgen-induced binding activity of transcriptional activators AP-1 and NF-kappaB, whose activities are known to be altered during cell proliferation, and 3) the effect of antioxidants on androgen-induced transcription factor binding. RESULTS: Physiologic concentrations (1 nM) of 5alpha-dihydrotestosterone or 1-10 nM R1881, a synthetic androgen, produced sustained elevation of AP-1 and NF-kappaB DNA-binding activity in LNCaP cells, an androgen-responsive human prostate carcinoma cell line. Androgen-independent DU145 cells (another human prostate carcinoma cell line) were unaffected by R1881 treatment. AP-1-binding activity increased 5 hours after 1 nM R1881 treatment; NF-kappaB DNA-binding activity increased after 36 hours. Both activities remained elevated for at least 120 hours. Nuclear AP-1 and NF-kappaB protein levels were not elevated. Antioxidant vitamins C plus E blocked both androgen-induced DNA-binding activity and production of reactive oxygen species. CONCLUSION: Physiologic concentrations of androgens induce production of reactive oxygen species and cause prolonged AP-1 and NF-kappaB DNA-binding activities, which are diminished by vitamins C and E. (+info)Androgen and epidermal growth factor down-regulate cyclin-dependent kinase inhibitor p27Kip1 and costimulate proliferation of MDA PCa 2a and MDA PCa 2b prostate cancer cells. (3/189)
Low levels of p27Kip1 in primary prostate cancer specimens have been shown to be associated with higher rates of disease recurrence and poor rates of disease-free survival in patients with localized disease. In this study, we provide the first direct evidence showing that dihydrotestosterone (DHT), a major proliferation regulator of prostate cancer, can down-regulate p27Kip1 and stimulate cyclin-dependent kinase-2 (CDK2) activity in established prostate cancer cell lines. We investigated the cooperative effects of DHT and epidermal growth factor (EGF) on the proliferation of androgen-responsive MDA PCa 2a and MDA PCa 2b prostate cancer cells. DHT and EGF each stimulated proliferation of these cells, but exposure of the cells to DHT and EGF together stimulated greater proliferation. Stimulation of cell proliferation by DHT and/or EGF was associated with increased CDK2 activity and a decreased level of p27Kip1. There seems to be a positive feedback stimulation loop between androgen-induced gene transcription and EGF-stimulated signal transduction, as one could stimulate the synthesis of the receptors for the other. Dual blockade of androgen receptor function with the antiandrogen hydroxyflutamide and EGF receptor superfamily-mediated signal transduction with the anti-EGF receptor monoclonal antibody C225 and the anti-HER2 receptor monoclonal antibody Herceptin significantly enhanced growth inhibition of the MDA PCa 2a cells. Our results demonstrate the importance of counteracting both androgen receptors and EGF receptors in the development of novel therapies for prostate cancer. (+info)Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer. (4/189)
The beta 1-subunit of Na+,K+-ATPase was isolated and identified as an androgen down-regulated gene. Expression was observed at high levels in androgen-independent as compared to androgen-dependent (responsive) human prostate cancer cell lines and xenografts when grown in the presence of androgens. Down-regulation of the beta 1-subunit was initiated at concentrations between 0.01 nM and 0.03 nM of the synthetic androgen R1881 after relatively long incubation times (> 24 h). Using polyclonal antibodies, the concentration of beta 1-subunit protein, but not of the alpha 1-subunit protein, was markedly reduced in androgen-dependent human prostate cancer cells (LNCaP-FGC) cultured in the presence of androgens. In line with these observations it was found that the protein expression of total Na+,K+-ATPase in the membrane (measured by 3H-ouabain binding) was also markedly decreased. The main function of Na+,K+-ATPase is to maintain sodium and potassium homeostasis in animal cells. The resulting electrochemical gradient is facilitative for transport of several compounds over the cell membrane (for example cisplatin, a chemotherapeutic agent experimentally used in the treatment of hormone-refractory prostate cancer). Here we observed that a ouabain-induced decrease of Na+,K+-ATPase activity in LNCaP-FGC cells results in reduced sensitivity of these cells to cisplatin-treatment. Surprisingly, androgen-induced decrease of Na+,K+-ATPase expression, did not result in significant protection against the chemotherapeutic agent. (+info)Domain requirements of DnaJ-like (Hsp40) molecular chaperones in the activation of a steroid hormone receptor. (5/189)
DnaJ-like proteins function in association with Hsp70 molecular chaperones to facilitate protein folding. We previously demonstrated that a yeast DnaJ-like protein, Ydj1p, was important for activation of heterologously expressed steroid hormone receptors (Caplan, A. J., Langley, E., Wilson, E. M., and Vidal, J. (1995) J. Biol. Chem. 270, 5251-5257). In the present study, we analyzed Ydj1p function by assaying hormone binding to the human androgen receptor (AR) heterologously expressed in yeast. We analyzed hormone binding in strains that were wild type or deleted for the YDJ1 gene. In the deletion mutant, the AR did not bind hormone to the same extent as the wild type. Introduction of mutant forms of Ydj1p to the deletion strain revealed that the J-domain is necessary but not sufficient for Ydj1p action, and that other domains of the protein are also functionally important. Of three human DnaJ-like proteins introduced into the deletion mutant, only Hdj2, which displays full domain conservation with Ydj1p, suppressed the hormone binding defect of the deletion mutant. By comparison of the domains shared by these three human proteins, and with mutants of Ydj1p that were functional, it was deduced that the cysteine-rich zinc binding domain is important for Hdj2/Ydj1p action in hormone receptor function. A model for the mechanism of DnaJ-like protein action is discussed. (+info)Effects of new 17alpha-hydroxylase/C(17,20)-lyase inhibitors on LNCaP prostate cancer cell growth in vitro and in vivo. (6/189)
Our laboratory has been developing new inhibitors of a key regulatory enzyme of testicular and adrenal androgen synthesis 17alpha-hydroxylase/C(17,20)-lyase (P450c17), with the aim of improving prostate cancer treatment. We designed and evaluated two groups of azolyl steroids: delta5-non-competitive inhibitors (delta5NCIs), VN/63-1, VN/85-1, VN/87-1 and their corresponding delta4 derivatives (delta4NCIs), VN/107-1, VN/108-1 and VN/109-1. The human P450c17 gene was transfected into LNCaP human prostate cancer cells, and the resultant LNCaP-CYP17 cells were utilized to evaluate the inhibitory potency of the new azolyl steroids. VN/85-1 and VN/108-1 had the lowest IC50 values of 1.25 +/- 0.44 nM and 2.96 +/- 0.78 nM respectively, which are much lower than that of the known P450 inhibitor ketoconazole (80.7 +/- 1.8 nM). To determine whether the compounds had direct actions on proliferation of wild-type LNCaP cells, cell growth studies were performed. All of the delta5NCIs and VN/108-1 blocked the growth-stimulating effects of androgens. In steroid-free media, the delta5NCIs decreased the proliferation of LNCaP cells by 35-40%, while all of the delta4NCIs stimulated LNCaP cells growth 1.5- to 2-fold. In androgen receptor (AR) binding studies, carried out to determine the mechanism of this effect, all of the delta4NCIs (5 microM) displaced 77-82% of synthetic androgen R1881 (5 nM) from the LNCaP AR. The anti-androgen flutamide and the delta5NCIs displaced 53% and 32-51% of R1881 bound to AR respectively. These results suggested that the delta5NCIs may also be acting as anti-androgens. We further evaluated our inhibitors in male severe combined immunodeficient mice bearing LNCaP tumour xenografts. In this model VN/85-1 was as effective as finasteride at inhibiting tumor growth (26% and 28% inhibition, respectively) and the inhibitory effect of VN/87-1 was similar to that of castration (33% and 36% inhibition respectively). These results suggest that VN/85-1 and VN/87-1 may be potential candidates for treatment of prostate cancer. (+info)Interleukin 6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells. (7/189)
Interleukin 6 (IL-6) is a cytokine that regulates not only immune and inflammatory responses but also the growth of some tumors, including prostate carcinomas. IL-6 signals through Janus kinase, signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinase and is also able to induce androgen receptor (AR)-mediated gene activation in prostate cancer, which is an important process in prostate cancer androgen-independent progression. We now show that IL-6-induced AR-mediated gene activation requires the activation of STAT3 by IL-6 in LNCaP prostate cancer cells. In particular, STAT3 associates with AR in an androgen-independent but IL-6-dependent manner. Inhibition of STAT3 rather than mitogen-activated protein kinase results in inhibition of AR-mediated gene activation in response to IL-6. These findings not only identify STAT3 as an important signaling molecule required for IL-6-signaling to induce AR-mediated gene activation in prostate carcinoma cells but also reveal the importance of activated STAT3 in human tumor development and progression. (+info)Specific recognition of androgens by their nuclear receptor. A structure-function study. (8/189)
Androgens, like progestins, are 3-ketosteroids with structural differences restricted to the 17beta substituent in the steroid D-ring. To better understand the specific recognition of ligands by the human androgen receptor (hAR), a homology model of the ligand-binding domain (LBD) was constructed based on the progesterone receptor LBD crystal structure. Several mutants of residues potentially involved in the specific recognition of ligands in the hAR were constructed and tested for their ability to bind agonists. Their transactivation capacity in response to agonist (R1881) and antagonists (cyproterone acetate, hydroxyflutamide, and ICI 176344) was also measured. Substitution of His(874) by alanine, only marginally impairs the ligand-binding and transactivation capacity of the hAR receptor. In contrast, mutations of Thr(877) and, to a greater extent, Asn(705) perturb ligand recognition, alter transactivation efficiency, and broaden receptor specificity. Interestingly, the N705A mutant acquires progesterone receptor (PR) properties for agonist ligands but, unlike wild type AR and PR, loses the capacity to repress transactivation with nonsteroidal antagonists. Models of the hAR.LBD complexes with several ligands are presented, which suggests new directions for drug design. (+info)Metribolone is a synthetic anabolic-androgenic steroid (AAS) drug, which is not widely used in clinical medicine. Its chemical structure and pharmacological properties are similar to the natural male hormone testosterone. It has been used in research settings to study its effects on muscle growth, bone density, and sexual development. However, due to its potential for abuse and serious side effects, it is not approved for use in many countries.
It's important to note that the possession, distribution, and use of anabolic steroids without a valid prescription is illegal and can be dangerous to one's health. It can cause a range of adverse effects such as liver damage, cardiovascular disease, hormonal imbalances, and psychological issues among others.
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Methyltrienolone6
- Metribolone (developmental code R1881, also known as methyltrienolone) is a synthetic and orally active anabolic-androgenic steroid (AAS) and a 17α-alkylated nandrolone (19-nortestosterone) derivative which was never marketed for medical use but has been widely used in scientific research as a hot ligand in androgen receptor (AR) ligand binding assays (LBAs) and as a photoaffinity label for the AR. (wikipedia.org)
- It is also known by the name methyltrienolone and its developmental code names R1881, R-1881, RU-1881, and RU1881, and is very commonly referred to by these other names rather than as metribolone in the scientific literature. (wikipedia.org)
- There's no difference between Metribolone and Methyltrienolone (only their names). (clickandbuild.com)
- Metribolone or Methyltrienolone is a synthetic steroid that has been derived from a 17 alpha alkylated nandrolone (19-nortestosterone). (clickandbuild.com)
- Methyltrienolone or Metribolone does have any medical uses and it never had any. (clickandbuild.com)
- Metribolone (methyltrienolone aka R1881) is a potent, non-aromatizable androgen that is structurally similar to trenbolone and has been referred to as "oral tren. (steroid-raw.com)
Oral Tren3
- Oral Tren (Metribolone) is the steroid that is considered one of the most potent and powerful oral anabolic and androgenic steroid. (clickandbuild.com)
- What is Oral Tren (Metribolone)? (clickandbuild.com)
- Where to Buy Metribolone Known as Oral Tren on Sale? (clickandbuild.com)
Trenbolone2
- More precisely, metribolone is the 17α-methylated derivative of trenbolone. (wikipedia.org)
- Our factory produces high-quality Injectable Metribolone and Trenbolone Raw Steroid Powders CAS 965-93-5. (taiguisteroids.com)
Steroid3
- Metribolone, also known as 17α-methyltrenbolone, as well as 17α-methyl-δ9,11-19-nortestosterone or 17α-methylestra-4,9,11-trien-17β-ol-3-one, is a synthetic estrane steroid and a 17α-alkylated derivative of nandrolone (19-nortestosterone). (wikipedia.org)
- Metribolone has been developed many years ago in 1960s as a steroid to help treating breast cancer, but it then got discontinued as scientists said that this steroid is too harsh on the liver. (clickandbuild.com)
- Metribolone or Methyltrienone is an extremely potent and powerful steroid which should be used with very big care in case you do make the decision of using it. (clickandbuild.com)
Oxandrolone1
- Que venden en farmacias oxandrolone, onde comprar testosterona trt. (wesleyfootballfoundation.org)
Potent1
- In addition, metribolone was identified in 2010 as a potent inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD) 1 and 2 (IC50 = 0.02 and 0.16 μM, respectively). (wikipedia.org)
Athletes2
- Prior to the 2008 Beijing Olympic Games, 11 members of the Greek national weightlifting team and 4 Greek track and field athletes tested positive for metribolone. (wikipedia.org)
- Bodybuilders and various other athletes have given a try to Metribolone and while it may be pretty harsh for liver and offering quite harsh side effects, they also found it to be very effective as a physique and performance enhancer. (clickandbuild.com)
Side effects3
- Side effects of metribolone include virilization and hepatotoxicity among others. (wikipedia.org)
- Metribolone is not very famous in bodybuilding due to the same reasons - quite nasty in side effects. (clickandbuild.com)
- The difference is that the side effects are much more likely to occur and they would be very pronounced with Metribolone. (clickandbuild.com)
Avoid2
- On the basis of this finding, it has been said that metribolone should be used very cautiously in scientific research, taking into account 3β-HSD inhibition to avoid erroneous interpretation. (wikipedia.org)
- Women should avoid Metribolone at all costs. (clickandbuild.com)
Muscle1
- Metribolone was created to help treat muscle wasting diseases like osteoporosis. (peru-info.net)
Results1
- This means that some people who use them, have amazing results in their very short cutting cycles with Metribolone. (clickandbuild.com)
Medical2
- Metribolone was never approved for medical use, a situation unlikely to change given its liver toxicity even at low doses. (wikipedia.org)
- Aside from scientific research, metribolone has also been encountered as an AAS in non-medical contexts, for instance in doping in sports and bodybuilding. (wikipedia.org)
Human1
- Metribolone has very low affinity for human serum sex hormone-binding globulin (SHBG), less than 5% of that of testosterone and less than 1% of that of dihydrotestosterone (DHT). (wikipedia.org)