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PIK3CA kinase mutations were highly clonal, more frequent in AR + vs. AR- TNBC (40% vs. 4%), and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR + TNBC cells. We also analyzed the combination of bicalutamide +/- the pan-PI3K inhibitor GDC-0941 or the dual PI3K/mTOR inhibitor GDC-0980 in xenograft tumor studies and observed additive effects.
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CWR22Rv1 and PC-3 were subjected to flow cytometry, electrophoretic mobility shift assays, and Western blot studies to measure DMAPT's ability to generate reactive oxygen species (ROS), inhibit NFkappaB DNA binding, and cause changes in anti-apoptotic proteins. N-acetyl cysteine (NAC) and short hairpin RNA (shRNA) were used to determine the contribution of ROS and JNK2 activation, respectively. The BrdU incorporation assay was used to measure proliferation and trypan blue studies assessed cell viability after DMAPT treatment. The in vivo activity of DMAPT as a single agent and in combination with bicalutamide or docetaxel was assessed in a subcutaneous xenograft model with athymic nude female mice.
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This is a comparative, prospective study. A total of 44 patients with biochemical progression after RRP were included in a clinical protocol for IAD once prostate-specific antigen (PSA) levels progressed over 0.4 ng/mL. The 44 cases were randomly assigned to receive two different treatment strategies: group A received IAD therapy using bicalutamide 150 mg once daily in the on-phases and no therapy in the off-phases; group B received IAD therapy using bicalutamide 150 mg once daily in the on-phases and etoricoxib 60 mg once daily in the off-phases.
Finasteride is known to inhibit Type 2 5α-reductase and thus block the conversion of testosterone to dihydrotestosterone (DHT). The structural similarity of finasteride to DHT raises the possibility that finasteride may also interfere with the function of the androgen receptor (AR). Experiments were carried out to evaluate the antiandrogenic effect of finasteride in LNCaP, C4-2 and VCaP human prostate cancer cells. Finasteride decreased DHT binding to AR, and DHT-stimulated AR activity and cell growth in LNCaP and C4-2 cells, but not in VCaP cells. LNCaP and C4-2 (derived from castration-resistant LNCaP) cells express the T877A mutant AR, while VCaP cells express the wild type AR. When PC-3 cells, which are AR-null, were transfected with either the wild type or the T877A mutant AR, only the mutant AR-expressing cells were sensitive to finasteride inhibition of DHT binding. Peroxiredoxin-1 (Prx1) is a novel endogenous facilitator of AR binding to DHT. In Prx1-rich LNCaP cells, the combination of Prx1 knockdown and finasteride was found to produce a greater inhibitory effect on AR activity and cell growth than either treatment alone. The observation suggests that cells with a low expression of Prx1 are likely to be more responsive to the antiandrogenic effect of finasteride. Additional studies showed that the efficacy of finasteride was comparable to that of bicalutamide (a widely used non-steroidal antiandrogen). The implication of the above findings is discussed in the context of developing strategies to improve the outcome of androgen deprivation therapy.
The nonsteroidal antiandrogen, bicalutamide (Casodex), has been evaluated as a component in combined androgen blockade and as monotherapy. We review the arguments that indicate why a 50-mg once-daily dose of bicalutamide is appropriate in combined androgen blockade, while ongoing clinical trials evaluate 150-mg once-daily as monotherapy in the treatment of prostate cancer.
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Enzalutamide is an androgen receptor (AR) inhibitor approved for therapy of metastatic castration resistant prostate cancer. However, clinical application revealed that 30 to 40% of patients acquire resistance after a short period of treatment. Currently, the molecular mechanisms underlying such resistances are not completely understood, partly due to a lack of model systems. In the present study we established three different cellular models of enzalutamide resistance including a cell line with wild type AR (LAPC4), DuCaP cells which overexpress wild-type AR, as well as a cell which has been adapted to long term androgen ablation (LNCaP Abl) and harbors the AR T878A mutation. After 10 months of cultivation, sustained growth in the presence of enzalutamide was achieved. When compared to controls, resistant cells exhibit significantly decreased sensitivity to enzalutamide as measured with 3[H]thymidine incorporation and WST assay. Moreover, these cell models exhibit partly re-activated AR signaling despite presence of enzalutamide. In addition, we show that enzalutamide resistant cells are insensitive to bicalutamide but retain considerable sensitivity to abiraterone. Mechanistically, enzalutamide resistance was accompanied by increased AR and AR-V7 mRNA and protein expression as well as AR gene amplification, while no additional AR mutations have been identified.
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Previously untreated patients with histologically proven stage C or D (American Urological Association Staging System) disease were randomly allocated to either bicalutamide (B) or goserelin plus flutamide (G+F). After disease progression, patients treated with B were assigned to castration. The primary endpoint for this trial was overall survival. Prostate cancer-specific survival and progression were included among secondary endpoints.
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The effect of an EGF-R selective tyrosine kinase (EGF-RTK) quinazoline inhibitor ZM252868 was determined on the androgen-sensitive human prostatic tumour cell line LNCaP, which can also respond via the EGF-R-regulated growth pathway for cell proliferation. Potential interaction or 'cross-talk' between steroid and the growth factor mitogen-activated protein kinase (MAPK) signalling pathway was also investigated.
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OSM receptor-beta expression was higher in DU-145 and PC-3 than in LNCaP cells. OSM caused ligand-independent activation of the AR in DU-145 cells, and the maximal activation was 62% of that induced by the synthetic androgen methyltrienolone. In the presence of OSM, hydroxyflutamide behaved as an AR agonist. Bicalutamide down-regulated AR activation caused by OSM only at a concentration of 1 microM. The inhibitor of the protein kinase A signaling pathway PKI and dn signal transducers and activators of transcription (STAT) 3 showed no effect on AR activation by OSM. The inhibitor of the MAPK pathway, PD 98059, caused only a minor down-regulation of OSM-induced reporter gene activity. OSM did not change AR expression in DU-145 cells transfected with AR cDNA.
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The majority of available antiandrogens have been reported to possess agonist activity to induce prostate-specific antigen, which might result in antiandrogen withdrawal syndrome. Here we report the identification of 3 beta-acetoxyandrost-1,5-diene-17-ethylene ketal (ADEK) from dehydroepiandrosterone metabolites and derivatives as a potent antiandrogen. We found ADEK could interrupt androgen binding to the androgen receptor (AR) and suppress androgen-induced transactivations of WT AR and a mutant AR in prostate cancer cells. ADEK inhibited prostate-specific antigen expression as well as growth in LNCaP prostate cancer cells stimulated by androgen. Importantly, ADEK had only marginal agonist effects, as compared with commonly used antiandrogens such as hydroxyflutamide and bicalutamide, leading to a lower possibility of inducing withdrawal response. Moreover, ADEK could block an adrenal androgen androstenediol-induced AR transactivation that hydroxyflutamide and bicalutamide failed to block. These unique antiandrogenic activities make ADEK a potential therapeutic compound that might be able to inhibit AR-mediated prostate cancer progression. Further in vivo studies might facilitate the development of a better antiandrogen for the treatment of prostate cancer.
Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation.
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The median duration of therapy was 39 weeks for bicalutamide-treated patients and 42 weeks for castrated patients; treatment failure occurred in 53% and 42% and disease progression in 43% and 33%, respectively. Treatment effects favored castration for both endpoints (P < or = 0.002), with hazard ratios (bicalutamide:castration) of 1.54 (95% confidence interval [CI], 1.18 to 2.00) for time to treatment failure and 1.6 (95% CI, 1.19 to 2.15) for time to disease progression. From the 1-year survival analysis, the hazard ratio for probability of death was 1.29 (95% CI, 0.96 to 1.72). Thus far, with a median follow-up of 86 weeks, median survival has not been reached in either group. Changes from baseline in several quality of life variables were significantly different (P < or = 0.01) between treatment groups periodically from months 1 to 6, and all favored bicalutamide. Overall, the antiandrogen was well tolerated compared with castration; with bicalutamide, hot flushes occurred less often and breast tenderness and gynecomastia more often.
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Androgenic hormones regulate many aspects of animal social behavior, including the elaborate display routines on which many species rely for advertisement and competition. One way that this might occur is through peripheral effects of androgens, particularly on skeletal muscles that control complex movements and postures of the body and its limbs. However, the specific contribution of peripheral androgen-muscle interactions to the performance of elaborate behavioral displays in the natural world has never been examined. We study this issue in one of the only natural physiological models of animal acrobatics: the golden-collared manakin (Manacus vitellinus). In this tropical bird, males compete with each other and court females by producing firecracker-like wing- snaps and by rapidly dancing among saplings over the forest floor. To test how activation of peripheral androgen receptors (AR) influences this display, we treat reproductively active adult male birds with the peripherally selective antiandrogen bicalutamide (BICAL) and observe the effects of this manipulation on male display performance. We not only validate the peripheral specificity of BICAL in this species, but we also show that BICAL treatment reduces the frequency with which adult male birds perform their acrobatic display maneuvers and disrupts the overall structure and fine-scale patterning of these birds' main complex wing-snap sonation. In addition, this manipulation has no effect on the behavioral metrics associated with male motivation to display. Together, our findings help differentiate the various effects of peripheral and central AR on the performance of a complex sociosexual behavioral phenotype by indicating that peripheral AR can optimize the motor skills necessary for the production of an elaborate animal display.
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The study population consisted of 379 untreated patients with histologically diagnosed prostate cancer: 197 with T2N0M0, 93 with T3N0M0, 19 with TxN1Mx, and 70 with TxNxM1. Serum HER2 levels were assessed in the prostate cancer patients prior to treatment as well as in a control group of 100 patients with histologically confirmed non-cancer. Biochemical recurrence-free curves for the patients were investigated separately using the Kaplan-Meier method.