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Theodore R Johnson - One of the best experts on this subject based on the ideXlab platform.

Catherine R. Kostlan - One of the best experts on this subject based on the ideXlab platform.

Matthew Carroll - One of the best experts on this subject based on the ideXlab platform.

P. E. Juniewicz - One of the best experts on this subject based on the ideXlab platform.

  • Effect of combination treatment with zanoterone (WIN 49596), a steroidal Androgen Receptor Antagonist, and finasteride (MK-906), a steroidal 5 alpha-reductase inhibitor, on the prostate and testes of beagle dogs.
    Endocrinology, 1993
    Co-Authors: P. E. Juniewicz, B. M. Lemp, T. A. Barbolt, S J Hoekstra, J A Devin, E Gauthier, G Frenette, J Y Dube, R R Tremblay
    Abstract:

    The effects of the steroidal Androgen Receptor Antagonist zanoterone (WIN 49596) and the steroidal 5 alpha-reductase inhibitor finasteride (MK-906) either alone or in combination on prostatic size, histomorphology, and biochemistry were determined in the intact male dog. Additionally, the effects of treatment with zanoterone and/or finasteride on testicular size, serum testosterone and LH levels, and spermatogenesis were determined in the same dogs. Daily oral treatment for 16 weeks with either zanoterone alone at 10 mg/kg.day or finasteride alone at 1.0 mg/kg.day reduced (P < 0.05) the size of the prostate, resulted in mild to moderate diffuse glandular atrophy of the prostate, and decreased prostatic DNA and prostatic arginine esterase (the primary canine prostatic protein) levels compared to those in intact controls. These changes occurred with no effect on testicular weight, testicular histomorphology, daily sperm production, or serum LH levels. Serum testosterone concentrations were increased (P < 0....

  • Evaluation of Win 49,596, a novel steroidal Androgen Receptor Antagonist, in animal models of prostate cancer.
    The Prostate, 1991
    Co-Authors: P. E. Juniewicz, N. Fetrow, J. Marinelli, M. Wolf, E. Young, J. Lamb, John T. Isaacs
    Abstract:

    A series of experiments were conducted to evaluate the effects of Win 49,596, a novel steroidal Androgen Receptor Antagonist, in animal models of prostate cancer. In the first experiment, oral administration of Win 49,596 at doses of 30, 100, or 300 mg/kg/day for 28 days inhibited (P less than 0.05) the growth of the Androgen-sensitive PAP variant of the Dunning R-3327 prostatic carcinoma in intact male rats relative to intact controls. The degree of inhibition at 100 and 300 mg/kg/day Win 49,596 was similar (P greater than 0.10) to that observed in castrate controls as well as in intact rats administered the nonsteroidal Androgen Receptor Antagonist flutamide orally at 15 mg/kg/day. Castration as well as treatment with either Win 49,596 or flutamide also decreased (P less than 0.05) the weight of the prostate in tumor-bearing animals. Additional studies were conducted to determine the effect of Win 49,596 on the growth of the Androgen-dependent PC-82 human prostatic carcinoma xenografted into athymic nude male mice. Oral administration of Win 49,596 at 30, 100, or 300 mg/kg/day for 35 days inhibited (P less than 0.05) tumor growth relative to intact controls. The degree of tumor inhibition was similar to that observed in intact male mice administered the nonsteroidal Androgen Receptor Antagonist flutamide orally at 30 mg/kg/day but was less than that observed following castration. Ventral prostate weights were also reduced (P less than 0.05) in castrate mice as well as in intact mice administered either Win 49,596 or flutamide. In the last experiment, at equivalent total daily dosages of either 150 or 300 mg/kg/day Win 49,596, twice a day (BID) dosing was more effective than once a day (SID) dosing in inhibiting tumor growth. The inhibitory effects of Win 49,596 at 150 mg/kg BID on tumor growth were similar to those observed following castration. Although Win 49,596 treatment reduced (P less than 0.05) ventral prostate weights relative to intact controls, there was no difference (P greater than 0.10) between SID vs. BID dosing. Based on the results of these studies and subject to further testing, Win 49,596 may have utility in the treatment of hormonally dependent metastatic prostate cancer in humans.

Yingying Gao - One of the best experts on this subject based on the ideXlab platform.

  • simvastatin delays castration resistant prostate cancer metastasis and Androgen Receptor Antagonist resistance by regulating the expression of caveolin 1
    International Journal of Oncology, 2019
    Co-Authors: Yingying Gao, Mengjuan Yuan, Wei Sun, Hong Lin Cheng, Lingfang Niu, Zhen Quan, Yanru Fan, Jiaxin Fan, Chunli Luo
    Abstract:

    The failure of Androgen deprivation therapy in prostate cancer treatment mainly results from drug resistance to Androgen Receptor Antagonists. Although an aberrant caveolin‑1 (Cav‑1) expression has been reported in multiple tumor cell lines, it is unknown whether it is responsible for the progression of castration‑resistant prostate cancer (CRPC). Thus, the aim of the present study was to determine whether Cav‑1 can be used as a key molecule for the prevention and treatment of CRPC, and to explore its mechanism of action in CRPC. For this purpose, tissue and serum samples from patients with primary prostate cancer and CRPC were analyzed using immunohistochemistry and enzyme‑linked immunosorbent assay, which revealed that Cav‑1 was overexpressed in CRPC. Furthermore, Kaplan‑Meier survival analysis and univariate Cox proportional hazards regression analysis demonstrated that Cav‑1 expression in tumors was an independent risk factor for the occurrence of CRPC and was associated with a shorter recurrence‑free survival time in patients with CRPC. Receiver operating characteristic curves suggested that serum Cav‑1 could be used as a diagnostic biomarker for CRPC (area under the curve, 0.876) using a cut‑off value of 0.68 ng/ml (with a sensitivity of 82.1% and specificity of 80%). In addition, it was determined that Cav‑1 induced the invasion and migration of CRPC cells by the activation of the H‑Ras/phosphoinositide‑specific phospholipase Ce signaling cascade in the cell membrane caveolae. Importantly, simvastatin was able to augment the anticancer effects of Androgen Receptor Antagonists by downregulating the expression of Cav‑1. Collectively, the findings of this study provide evidence that Cav‑1 is a promising predictive biomarker for CRPC and that lowering cholesterol levels with simvastatin or interfering with the expression of Cav‑1 may prove to be a useful strategy with which to prevent and/or treat CRPC.

  • Simvastatin delays castration‑resistant prostate cancer metastasis and Androgen Receptor Antagonist resistance by regulating the expression of caveolin‑1.
    International journal of oncology, 2019
    Co-Authors: Yingying Gao, Mengjuan Yuan, Wei Sun, Hong Lin Cheng, Lingfang Niu, Zhen Quan
    Abstract:

    The failure of Androgen deprivation therapy in prostate cancer treatment mainly results from drug resistance to Androgen Receptor Antagonists. Although an aberrant caveolin‑1 (Cav‑1) expression has been reported in multiple tumor cell lines, it is unknown whether it is responsible for the progression of castration‑resistant prostate cancer (CRPC). Thus, the aim of the present study was to determine whether Cav‑1 can be used as a key molecule for the prevention and treatment of CRPC, and to explore its mechanism of action in CRPC. For this purpose, tissue and serum samples from patients with primary prostate cancer and CRPC were analyzed using immunohistochemistry and enzyme‑linked immunosorbent assay, which revealed that Cav‑1 was overexpressed in CRPC. Furthermore, Kaplan‑Meier survival analysis and univariate Cox proportional hazards regression analysis demonstrated that Cav‑1 expression in tumors was an independent risk factor for the occurrence of CRPC and was associated with a shorter recurrence‑free survival time in patients with CRPC. Receiver operating characteristic curves suggested that serum Cav‑1 could be used as a diagnostic biomarker for CRPC (area under the curve, 0.876) using a cut‑off value of 0.68 ng/ml (with a sensitivity of 82.1% and specificity of 80%). In addition, it was determined that Cav‑1 induced the invasion and migration of CRPC cells by the activation of the H‑Ras/phosphoinositide‑specific phospholipase Ce signaling cascade in the cell membrane caveolae. Importantly, simvastatin was able to augment the anticancer effects of Androgen Receptor Antagonists by downregulating the expression of Cav‑1. Collectively, the findings of this study provide evidence that Cav‑1 is a promising predictive biomarker for CRPC and that lowering cholesterol levels with simvastatin or interfering with the expression of Cav‑1 may prove to be a useful strategy with which to prevent and/or treat CRPC.

  • plce knockdown overcomes drug resistance to Androgen Receptor Antagonist in castration resistant prostate cancer by suppressing the wnt3a β catenin pathway
    Journal of Cellular Physiology, 2019
    Co-Authors: Yingying Gao, Mengjuan Yuan, Wei Sun, Lingfang Niu, Yanru Fan, Jiaxin Fan, Yu Tang, Nanjing Liu, Jinxiao Yan, Limei Duan
    Abstract:

    Most prostate cancers (Pcas) develop into castration-resistant prostate cancer (CRPC) after receiving Androgen deprivation therapy (ADT). The expression levels of PLCe and wnt3a are increased in Pca and regulate Androgen Receptor (AR) activity. However, the biological function and mechanisms of PLCe and wnt3a in CRPC remain unknown. In this study, we found that the expression levels of PLCe, wnt3a, and AR were significantly increased in CRPC tissues as well as bicalutamide-resistant-LNCaP and enzalutamide-resistant-LNCaP cells. In addition, PLCe knockdown partly restored the sensitivity of drug-resistant cells to bicalutamide and enzalutamide by inhibiting the activity of the wnt3a/β-catenin/AR signaling axis. Interestingly, the resistance of LNCaP cells docetaxel is related to PLCe but not the wnt3a/β-catenin pathway. We also found that the combination of PLCe knockdown and enzalutamide treatment synergistically suppressed cell proliferation, tumor growth, and bone metastasis using in vitro and in vivo experiments. Our study revealed that PLCe is involved in the progression of drug-resistance in CRPC and could be a new target for the treatment of CRPC.