Phosphodiesterase Type-5 Inhibitor Tadalafil Modulates Steroid Hormones Signaling in a Prostate Cancer Cell Line

Background: The androgen receptor (AR) plays a key role in normal prostate homeostasis and in prostate cancer (PCa) development, while the role of aromatase (Cyp19a1) is still unclear. We evaluated the effects of a treatment with Tadalafil (TAD) on both these proteins. Methods: Androgen-sensitive human PCa cell line (LnCAP) was incubated with/without TAD (10−6 M) and bicalutamide (BCT) (10−4 M) to evaluate a potential modulation on cell proliferation, protein and mRNA expression of Cyp19a, AR and estrogen receptor-β (ERβ), respectively. Results: TAD increased early AR nuclear translocation (p < 0.05, after 15 min of exposure), and increased AR transcriptional activity (p < 0.05) and protein expression (p < 0.05) after 24 h. Moreover, after 24 h this treatment upregulated Cyp19a1 and ERβ mRNA (p < 0.05 and p < 0.005 respectively) and led to an increase in protein expression of both after 48 h (p < 0.05). Interestingly, TAD counteracted Cyp19a1 stimulation induced by BCT (p < 0.05) but did not alter the effect induced by BCT on the AR protein expression. Conclusion: We demonstrate for the first time that TAD can significantly modulate AR expression and activity, Cyp19a1 and ERβ expression in PCa cells, suggesting a specific effect of these proteins. In addition, TAD potentiates the antiproliferative activity of BCT, opening a new clinical scenario in the treatment of PCa

Phosphodiesterase Type-5 Inhibitor Tadalafil Modulates Steroid Hormones Signaling in a Prostate Cancer Cell Line

Background: The androgen receptor (AR) plays a key role in normal prostate homeostasis and in prostate cancer (PCa) development, while the role of aromatase (Cyp19a1) is still unclear. We evaluated the effects of a treatment with Tadalafil (TAD) on both these proteins. Methods: Androgen-sensitive human PCa cell line (LnCAP) was incubated with/without TAD (10−6 M) and bicalutamide (BCT) (10−4 M) to evaluate a potential modulation on cell proliferation, protein and mRNA expression of Cyp19a, AR and estrogen receptor-β (ERβ), respectively. Results: TAD increased early AR nuclear translocation (p p p p p p p < 0.05) but did not alter the effect induced by BCT on the AR protein expression. Conclusion: We demonstrate for the first time that TAD can significantly modulate AR expression and activity, Cyp19a1 and ERβ expression in PCa cells, suggesting a specific effect of these proteins. In addition, TAD potentiates the antiproliferative activity of BCT, opening a new clinical scenario in the treatment of PCa

Reduction in Oxytocin levels predict body weight loss in patients with obesity after a very low carbohydrate ketogenic diet (VLCKD).

Background: Oxytocin (OXT) enhances glucose uptake and lipid utilization in adipose tissue and skeletal muscle.Dysfunction of the OXT system could underlie the pathogenesis of weight gain. Men and women with obesity were reported to have higher OXT blood levels compared to normal weight subjects. In contrast, metabolic syndrome has been associated with reduced fasting serum oxytocin in larger scale mixed gender studies. Aim: Data regarding the oxytocin system in rodent obesity models and human subjects with obesity appear divided. This study aimed to investigate the concentrations of OXT in a population affected by obesity before and after a very low carbohydrate ketogenic diet (VLCKD) induced weight loss. Materials and methods: Subjects with obesity were enrolled at the Center of High Specialization for the treatment of Obesity (CASCO), Umberto I Polyclinic, Sapienza University of Rome. At baseline (t0) and after eight weeks of VLCKD (t1), all patients underwent clinical evaluation, biochemical routine assessment, DXA examination for body composition (Hologic Inc., Bedford, MA, USA, QDR 4500W) and venous blood sampling in EDTA plus 500 KIU/ml of aprotinin (Abcam ab146286) for plasma OXT determination (Abcam, Ab133050, ELISA kit). Achievement of ketosis was monitored by measuring urinary β-OH-butyrate. Results: 40 patients (26 females and 14 males) suffering from obesity were enrolled, (age = 55.5 ±7 years and BMI = 35.7± 4.3 Kg/m2). OXT level at baseline (t0) was 1166 ±403 pg/ml, with no differences between males and females. At t0 OXT positively correlated with BMI and hip circumference. After VLCKD, a significant weight reduction was seen (mean BMI = 32.7 kg/m2, mean weight loss = -8.8 kg) and OXT (t1) significantly decreased (728.2± 201.7 pg/ml, P &lt; 0.001). Baseline OXT positively correlated with t1urinary β-OH-butyrate, after adjustment for age (r = 0.335, P = 0.046). A strong inverse age adjusted correlation between weight loss and baseline OXT was also reported (r = - 0.458, P &lt; 0.005). A regression analysis showed that the reduction in OXT between t1 and t0, the grade of ketosis during VLCKD and baselineút mass were all predictors of weight loss (R20.422; P = 0.025). Conclusion: Our study demonstrated that higher OXT levels associates with BMI and with ketosis induction. A lower OXT reduction during a VLCKD seems to be unfavorable for achieving weight loss. Differences in assay method used for measuring OXT, as well as expression patterns of oxytocin receptors, could explain the partial discrepancy of our results with the literature. Peripheral actions of oxytocin deserve further investigation