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Selective androgen receptor mediators

Zachery R Reichert, Maha Hussain
The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen deprivation therapy. This foundation of treatment has a high rate of biochemical and clinical response and meaningful clinical benefit but is finite in duration as most cancers will progress to castration resistance. Historically, treatment for mCRPC entailed androgen receptor (AR) inhibitors (nilutamide, flutamide, bicalutamide), nonspecific steroidal biosynthesis inhibitors (ketoconazole, itraconazole), steroids (prednisone, diethylstilbesterol, dexamethasone), or palliative chemotherapy (mitoxantrone, estramustine), but none of these strategies impacted survival...
September 2016: Cancer Journal
Nagarajarao Shamaladevi, Shinako Araki, Dominic A Lyn, Rajnikanth Ayyathurai, Jie Gao, Vinata B Lokeshwar, Hugo Navarrete, Bal L Lokeshwar
BIRM is an anticancer herbal formulation from Ecuador. Previous study established its antitumor and antimetastatic activity against prostate cancer models. The activity of BIRM against human prostate cancer (PCa) cells was investigated to uncover its mechanism of antitumor activity. In androgen receptor (AR)-expressing PCa cells BIRM was 2.5-fold (250%) more cytotoxic in presence of androgen (DHT) compared to cells grown in the absence of DHT. In AR-positive cells (LAPC-4 and LNCaP) BIRM caused a dose and time-dependent down-regulation of AR and increased apoptosis...
October 1, 2016: Oncotarget
Katia Jedeon, Sophia Loiodice, Khaled Salhi, Manon Le Normand, Sophia Houari, Jessica Chaloyard, Ariane Berdal, Sylvie Babajko
Endocrine-disrupting chemicals (EDCs) that interfere with the steroid axis can affect amelogenesis, leading to enamel hypomineralization similar to that of molar incisor hypomineralization, a recently described enamel disease. We investigated the sex steroid receptors that may mediate the effects of EDCs during rat amelogenesis. The expression of androgen receptor (AR), estrogen receptor (ER)-α, and progesterone receptor was dependent on the stage of ameloblast differentiation, whereas ERβ remained undetectable...
September 29, 2016: Endocrinology
Jie Shi, Shengjun Fu, Li Wang, Yan Tao, Ronald Rodriguez, Zhiping Wang
Our previous work confirmed that the bladder cancer-specific oncolytic adenovirus Ad/PSCAE/UPII/E1A could selectively replicate in bladder cancer cells, thus causing specific tumor cell lysis. The replicative potential is a crucial factor in determining the therapeutic efficacy of oncolytic adenoviruses. However, viral replication is attenuated by the low-activity promoter that we used, thus compromising viral cytotoxicity. In this study, we investigated the effect of the cell cycle-dependent kinase inhibitor p21/Waf-1 on an adenovirus...
September 12, 2016: Anti-cancer Drugs
Yi Cai, Cory Chew, Fernando Muñoz, Dale R Sengelaub
Partial depletion of spinal motoneuron populations induces dendritic atrophy in neighboring motoneurons, and treatment with testosterone is neuroprotective, attenuating induced dendritic atrophy. In this study we examined whether the protective effects of testosterone could be mediated via its androgenic or estrogenic metabolites. Furthermore, to assess whether these neuroprotective effects were mediated through steroid hormone receptors, we used receptor antagonists to attempt to prevent the neuroprotective effects of hormones after partial motoneuron depletion...
August 29, 2016: Developmental Neurobiology
Nooshin Mirkheshti, Sulgi Park, Shoulei Jiang, Jodie Cropper, Sherry L Werner, Chung S Song, Bandana Chatterjee
Androgen receptor (AR) and PI3K/AKT/mTORC1 are major survival signals that drive prostate cancer to a lethal disease. Reciprocal activation of these oncogenic pathways from negative cross talks contributes to low/limited success of pathway-selective inhibitors in curbing prostate cancer progression. We report that the antibiotic salinomycin, a cancer stem cell blocker, is a dual-acting AR and mTORC1 inhibitor, inhibiting PTEN-deficient castration-sensitive and castration-resistant prostate cancer in culture and xenograft tumors...
August 19, 2016: Oncotarget
K Miller, P Albers, R Eichenauer, G Geiges, M-O Grimm, F König, G Mickisch, D Pfister, C Schwentner, H Suttmann, S Zastrow
Therapies currently available in Germany for metastatic castration-resistant prostate cancer (mCRPC) include docetaxel, cabazitaxel, abiraterone acetate, enzalutamide and radium-223, all of which offer a potential survival benefit that adds up in their sequential application to a significant overall survival benefit. However, the optimal sequencing of these agents is still unclear. In the absence of evidence, treatment selection is based on the particular situation and on comorbid conditions of each individual patient...
September 2016: Der Urologe. Ausg. A
Małgorzata Kłósek, Anna Mertas, Wojciech Król, Dagmara Jaworska, Jan Szymszal, Ewelina Szliszka
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is an endogenous ligand, which plays role in immune surveillance and anti-tumor immunity. It has ability to selectively kill tumor cells showing no toxicity to normal cells. We tested the apoptotic and cytotoxic activities of xanthohumol, a prenylated chalcone found in Humulus lupulus on androgen-sensitive human prostate adenocarcinoma cells (LNCaP) in combination with TRAIL. Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium reduction assay (MTT) and lactate dehydrogenase assay (LDH)...
2016: International Journal of Molecular Sciences
Lei Wang, Ji Wang, Hua Xiong, Fengxia Wu, Tian Lan, Yingjie Zhang, Xiaolan Guo, Huanan Wang, Mohammad Saleem, Cheng Jiang, Junxuan Lu, Yibin Deng
Currently, no therapeutic options exist for castration-resistant prostate cancer (CRPC) patients who have developed resistance to the second generation anti-androgen receptor (AR) axis therapy. Here we report that co-deletion of Pten and p53 in murine prostate epithelium, often observed in human CRPC, leads to AR-independent CRPC and thus confers de novo resistance to second generation androgen deprivation therapy (ADT) in multiple independent yet complementary preclinical mouse models. In contrast, mechanism-driven co-targeting hexokinase 2 (HK2)-mediated Warburg effect with 2-deoxyglucose (2-DG) and ULK1-dependent autophagy with chloroquine (CQ) selectively kills cancer cells through intrinsic apoptosis to cause tumor regression in xenograft, leads to a near-complete tumor suppression and remarkably extends survival in Pten-/p53-deficiency-driven CRPC mouse model...
May 2016: EBioMedicine
Giovanni Luca Gravina, Francesco Marampon, Patrizia Sanità, Andrea Mancini, Alessandro Colapietro, Luca Scarsella, Ana Jitariuc, Leda Biordi, Corrado Ficorella, Claudio Festuccia
The high affinity nerve growth factor (NGF) NGF receptor, p75NTR, is a member of the tumor necrosis factor (TNF) receptor superfamily that shares a conserved intracellular death domain capable of inducing apoptosis and suppressing growth in prostate epithelial cells. Expression of this receptor is lost as prostate cancer progresses and is minimal in established prostate cancer cell lines. We aimed to verify the role of p75NTR in the azacitidine-mediated antitumor effects on 22Rv1 and PC3 androgen-independent prostate cancer cells...
July 2016: Oncology Reports
Jun Luo
Prostate cancer cells demonstrate a remarkable "addiction" to androgen receptor (AR) signaling in all stages of disease progression. As such, suppression of AR signaling remains the therapeutic goal in systemic treatment of prostate cancer. A number of molecular alterations arise in patients treated with AR-directed therapies. These molecular alterations may indicate the emergence of treatment resistance and may be targeted for the development of novel agents for prostate cancer. The presence of functional androgen receptor splice variants may represent a potential explanation for resistance to abiraterone and enzalutamide, newer AR-directed agents developed to treat metastatic castration-resistant prostate cancer (mCRPC)...
July 2016: Asian Journal of Andrology
Ana Paola G Lombardi, Raisa Pisolato, Carolina M Vicente, Maria Fatima M Lazari, Thaís F G Lucas, Catarina S Porto
The aim of the present study was to characterize the mechanism underlying estrogen effects on the androgen-independent prostate cancer cell line PC-3. 17β-estradiol and the ERβ-selective agonist DPN, but not the ERα-selective agonist PPT, increased the incorporation of [methyl-(3)H]thymidine and the expression of Cyclin D2, suggesting that ERβ mediates the proliferative effect of estrogen on PC-3 cells. In addition, upregulation of Cyclin D2 and incorporation of [methyl-(3)H]thymidine induced by 17β-estradiol and DPN were blocked by the ERβ-selective antagonist PHTPP in PC-3 cells...
July 15, 2016: Molecular and Cellular Endocrinology
Sudeshna Tripathy, Killivalavan Asaithambi, P Jayaram, R Medhamurthy
BACKGROUND: In several species, considerably higher levels of estradiol-17 (E2) are synthesized in the CL. E2 has been suggested to participate in the regulation of luteal steroidogenesis and luteal cell morphology. In pregnant rats, several experiments have been carried out to examine the effects of inhibition of luteal E2 synthesis on CL structure and function. METHODS: During days 12-15 of pregnancy in rats, luteal E2 was inhibited by way of daily oral administration of anastrozole (AI), a selective non-steroidal aromatase inhibitor, and experiments were also performed with E2 replacement i...
2016: Reproductive Biology and Endocrinology: RB&E
Anna R Kwilas, Andressa Ardiani, Sofia R Gameiro, Jacob Richards, Ashley B Hall, James W Hodge
Among breast cancer types, triple-negative breast cancer (TNBC) has the fewest treatment options and the lowest 5-year survival rate. Androgen receptor (AR) inhibition has displayed efficacy against breast cancer preclinically and is currently being examined clinically in AR positive TNBC patients. Androgen deprivation has been shown to induce immunogenic modulation; the alteration of tumor cell phenotype resulting in increased sensitivity to immune-mediated killing. We evaluated the ability of AR inhibition to reduce the growth and improve the immune-mediated killing of breast cancer cells with differing expression of the estrogen receptor and AR...
April 26, 2016: Oncotarget
Marie Picot, Jean-Marie Billard, Carlos Dombret, Christelle Albac, Nida Karameh, Stéphanie Daumas, Hélène Hardin-Pouzet, Sakina Mhaouty-Kodja
We studied the role of testosterone, mediated by the androgen receptor (AR), in modulating temporal order memory for visual objects. For this purpose, we used male mice lacking AR specifically in the nervous system. Control and mutant males were gonadectomized at adulthood and supplemented with equivalent amounts of testosterone in order to normalize their hormonal levels. We found that neural AR deletion selectively impaired the processing of temporal information for visual objects, without affecting classical object recognition or anxiety-like behavior and circulating corticosterone levels, which remained similar to those in control males...
2016: PloS One
Ahmed Mahfouz, Boudewijn P F Lelieveldt, Aldo Grefhorst, Lisa T C M van Weert, Isabel M Mol, Hetty C M Sips, José K van den Heuvel, Nicole A Datson, Jenny A Visser, Marcel J T Reinders, Onno C Meijer
Steroid receptors are pleiotropic transcription factors that coordinate adaptation to different physiological states. An important target organ is the brain, but even though their effects are well studied in specific regions, brain-wide steroid receptor targets and mediators remain largely unknown due to the complexity of the brain. Here, we tested the idea that novel aspects of steroid action can be identified through spatial correlation of steroid receptors with genome-wide mRNA expression across different regions in the mouse brain...
March 8, 2016: Proceedings of the National Academy of Sciences of the United States of America
Kideok Jin, Saraswati Sukumar
Long term treatment with therapies aimed at blocking the estrogen- (ER) or androgen receptor (AR) action often leads to the development of resistance to selective modulators of the estrogen receptor (SERMs) in ERα-positive breast cancer, or of the androgen receptor (SARMs) in AR-positive prostate cancer. Many underlying molecular events that confer resistance are known, but a unifying theme is yet to be revealed. Receptor tyrosine kinases (RTKs) such EGFR, ERBB2 and IGF1R are major mediators that can directly alter cellular response to the SERM, tamoxifen, but the mechanisms underlying increased expression of RTKs are not clear...
April 2016: Biochimica et Biophysica Acta
Lee B Smith
No abstract text is available yet for this article.
February 2016: Biology of Reproduction
Peter Paximadis, Abdo J Najy, Michael Snyder, Hyeong-Reh Kim
PURPOSE: To determine the functional relationship between androgen receptor (AR) and PDGF D as it relates to the radiation response of PTEN-null prostate cancer (PCa) cells and the effect of enzalutamide on these interactions. METHODS AND MATERIALS: Using murine PTEN-null prostate epithelial cell line and human prostate carcinoma LNCaP (PTEN-mutant) models, nuclear and cytosolic AR levels were determined by immunoblot analysis and the transcriptional activity of nuclear AR was assessed by RT-PCR analysis of its target genes with or without irradiation...
May 2016: Prostate
Ashraf Saeed, Grant M Vaught, Kostas Gavardinas, Donald Matthews, Jonathan E Green, Pablo Garcia Losada, Heather A Bullock, Nathan A Calvert, Nita J Patel, Stephanie A Sweetana, Venkatesh Krishnan, Judith W Henck, John G Luz, Yong Wang, Prabhakar Jadhav
A transdermal SARM has a potential to have therapeutic benefit through anabolic activity in muscle while sparing undesired effects of benign prostate hyperplasia (BPH) and liver-mediated decrease in HDL-C. 2-Chloro-4-[(2-hydroxy-2-methyl-cyclopentyl)amino]-3-methyl-benzonitrile 6 showed the desired muscle and prostate effects in a preclinical ORX rat model. Compound 6 had minimal effect on HDL-C levels in cynomolgus monkeys and showed human cadaver skin permeability, thus making it an effective tool for proof-of-concept studies in a clinical setting...
January 28, 2016: Journal of Medicinal Chemistry
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