- Hypogonadism as a Reversible Cause of Torsades de Pointes in Men. [Letter]
- CircCirculation 2018 Jul 03; 138(1):110-113
- Impact of prepubertal exposure to dietary protocatechuic acid on the hypothalamic-pituitary-testicular axis in rats. [Journal Article]
- CBChem Biol Interact 2018 Jun 25; 290:99-109
- Protocatechuic acid (PCA; 3, 4-dihydroxybenzoic acid) is a phenolic compound widely found in many edible fruits, vegetables, grape wine and plant-derived beverages. The present study investigated the...
Protocatechuic acid (PCA; 3, 4-dihydroxybenzoic acid) is a phenolic compound widely found in many edible fruits, vegetables, grape wine and plant-derived beverages. The present study investigated the impact of PCA on the hypothalamic-pituitary-testicular axis of rats orally treated with PCA during the period of prepubertal development to adulthood. Protocatechuic acid was administered to prepubertal male rats at doses of 0, 5, 10, 50 and 100 mg/kg body for 45 consecutive days. The results revealed no treatment-related changes in the body weight gain and organo-somatic indices of the hypothalamus, testes, epididymis, prostate gland and seminal vesicle in rats administered with PCA when compared with control. However, prepubertal exposure to PCA significantly enhanced antioxidant enzyme activities and glutathione level whereas it markedly decreased biomarkers of inflammation and oxidative stress in the hypothalamus, testes and epididymis of the treated rats. Protocatechuic acid significantly increased circulatory concentrations of luteinizing hormone and follicle-stimulating hormone with concomitant increase in serum and intra-testicular testosterone levels. Moreover, PCA-treated rats exhibited significant increase in marker enzymes of testicular function namely acid phosphatase, alkaline phosphatase, lactate dehydrogenase and glucose-6-phosphate dehydrogenase without statistically significant increase in spermatogenesis and sperm functional characteristics including sperm count, motility and viability. Light microscopic examination of the hypothalamus, testes and epididymis of rats treated with PCA showed histo-architectures similar to control. In conclusion, prepubertal exposure to PCA is safe and positively impacted reproductive function at sexual maturity in male rats. The observed beneficial effects of PCA is related to its anti-inflammatory and redox regulatory mechanisms.
- First-line use of novel hormonal agents in prostate cancer: a critical appraisal. [Journal Article]
- CAClin Adv Hematol Oncol 2018; 16(4):289-295
- Castration has been the hallmark of the treatment of advanced prostate cancer for nearly a century. Conventional surgical or medical castration for the management of metastatic prostate cancer has be...
Castration has been the hallmark of the treatment of advanced prostate cancer for nearly a century. Conventional surgical or medical castration for the management of metastatic prostate cancer has been associated with an initial response rate greater than 60% to 70%, depending on the criteria employed. The median duration of the initial response is usually less than 3 to 5 years, however, depending on the extent of disease. The failure of disease to respond to castration has been associated with an increase in the production of adrenal androgens and/or the evolution of upregulated or mutated androgen receptors. Second-line hormonal treatment with adrenal inhibitors is sometimes used, but remissions usually last for less than a year. Extensive translational research has produced a series of second-line, multitargeted, hormonally active agents that inhibit androgen receptor function and/or multiple sites within the hypothalamic/pituitary/end-organ axis. Abiraterone and enzalutamide have been shown to be active in second-line or subsequent hormonal therapy for castration-resistant prostate cancer, and recent data have shown a substantial anticancer effect in initial therapy. The potential use of abiraterone and enzalutamide as initial therapy for advanced prostate cancer is the focus of this brief review, which emphasizes that new approaches should not become the standard of care until they have been validated in randomized trials. In addition, it remains unclear whether first-line treatment with chemohormones or new-generation hormones should be the current standard for all patients with newly diagnosed metastatic prostate cancer.
- Androgen- and estrogen-receptor mediated activities of 4-hydroxytestosterone, 4-hydroxyandrostenedione and their human metabolites in yeast based assays. [Journal Article]
- TLToxicol Lett 2018; 292:39-45
- 4-Hydroxyandrost-4-ene-3,17-dione, also named formestane, is an irreversible aromatase inhibitor and therapeutically used as anti-breast cancer medication in post-menopausal women. Currently, no ther...
4-Hydroxyandrost-4-ene-3,17-dione, also named formestane, is an irreversible aromatase inhibitor and therapeutically used as anti-breast cancer medication in post-menopausal women. Currently, no therapeutical indication led to approval of its 17-hydroxylated analog 4-hydroxytestosterone, an anabolic steroid. However, it is currently investigated in a clinical trial for breast cancer. In context with sports doping, aromatase inhibitors are administered to reduce estrogenic side effects of misused anabolic substances or their metabolites. Therefore, both substances are prohibited in sports by the World Anti-Doping Agency (WADA). Analysis of urinary phase I and phase II metabolites showed similar results for both compounds. In the current investigation, 4-hydroxyandrost-4-ene-3,17-dione, 4-hydroxytestosterone and seven of their described urinary metabolites as well as 2α-hydroxyandrostenedione were tested in the yeast androgen screen and the yeast estrogen screen. Androgenic effects were observed for all tested substances, except for one, which showed anti-androgenic properties. With regard to the yeast estrogen screen, estrogenic effects were observed for only two metabolites at rather high concentrations, while six out of the ten substances tested showed anti-estrogenic properties. In terms of the strong androgenic effect observed for 4-hydroxytestosterone (10-8 M), 4-hydroxyandrost-4-ene-3,17-dione (10-8 M) and two more urinary metabolites, the yeast androgen assay may also be used to trace abuse in urine samples.
- Optimal dynamic control approach in a multi-objective therapeutic scenario: Application to drug delivery in the treatment of prostate cancer. [Journal Article]
- PCPLoS Comput Biol 2018; 14(4):e1006087
- Numerous problems encountered in computational biology can be formulated as optimization problems. In this context, optimization of drug release characteristics or dosing schedules for anticancer age...
Numerous problems encountered in computational biology can be formulated as optimization problems. In this context, optimization of drug release characteristics or dosing schedules for anticancer agents has become a prominent area not only for the development of new drugs, but also for established drugs. However, in complex systems, optimization of drug exposure is not a trivial task and cannot be efficiently addressed through trial-error simulation exercises. Finding a solution to those problems is a challenging task which requires more advanced strategies like optimal control theory. In this work, we perform an optimal control analysis on a previously developed computational model for the testosterone effects of triptorelin in prostate cancer patients with the goal of finding optimal drug-release characteristics. We demonstrate how numerical control optimization of non-linear models can be used to find better therapeutic approaches in order to improve the final outcome of the patients.
- Pharmacogenetics of androgen signaling in prostate cancer: Focus on castration resistance and predictive biomarkers of response to treatment. [Review]
- CRCrit Rev Oncol Hematol 2018; 125:51-59
- Tumor heterogeneity strongly affects the molecular mechanisms driving resistance to hormonal therapies in castration-resistant prostate cancer. Since the current use of available treatments can be op...
Tumor heterogeneity strongly affects the molecular mechanisms driving resistance to hormonal therapies in castration-resistant prostate cancer. Since the current use of available treatments can be optimized on the basis of the molecular profile of tumor, the present review focuses on genetic biomarkers in prostate cancer and their application to a personalized treatment.
- Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: A phase III study. [Randomized Controlled Trial]
- CSCancer Sci 2018; 109(6):1920-1929
- Non-inferiority in the cumulative castration rate of the 3-month formulation of degarelix compared with the 3-month formulation of goserelin was evaluated in subjects with prostate cancer. A phase II...
Non-inferiority in the cumulative castration rate of the 3-month formulation of degarelix compared with the 3-month formulation of goserelin was evaluated in subjects with prostate cancer. A phase III, open-label, parallel-arm study was carried out. An initial dose of 240 mg degarelix or 3.6 mg goserelin was given s.c.; after day 28, a maintenance dose of 480 mg degarelix or 10.8 mg goserelin was given once every 84 days. Non-inferiority in castration rate and safety of degarelix to goserelin were evaluated. The primary end-point was the cumulative castration rate from day 28 to day 364 and the non-inferiority margin was set to be 10%. A total of 234 subjects with prostate cancer were randomized to the degarelix group (n = 117) and the goserelin group (n = 117). The cumulative castration rate was 95.1% in the degarelix group and 100.0% in the goserelin group. As there were no events in the goserelin group, an additional analysis was carried out using 95% confidence intervals of the difference in the proportion of subjects with castration. Analyses indicated the non-inferiority of the 3-month formulation of degarelix to goserelin. Degarelix showed more rapid decreases in testosterone, luteinizing hormone, follicle stimulating hormone, and prostate-specific antigen levels compared with goserelin. The most common adverse events in the degarelix group were injection site reactions. Non-inferiority of the 3-month formulation of degarelix to goserelin was shown for testosterone suppression. The 3-month formulation of degarelix was also found to be tolerated as an androgen deprivation therapy for patients with prostate cancer. This trial was registered with ClinicalTrials.gov (identifier NCT01964170).
- Potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid. [Journal Article]
- EJEur J Med Chem 2018 Apr 25; 150:930-945
- The aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date ...
The aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data.
- In vitro mouse spermatogenesis with an organ culture method in chemically defined medium. [Journal Article]
- PlosPLoS One 2018; 13(2):e0192884
- We previously reported the successful induction and completion of mouse spermatogenesis by culturing neonatal testis tissues. The culture medium consisted of α-minimum essential medium (α-MEM), suppl...
We previously reported the successful induction and completion of mouse spermatogenesis by culturing neonatal testis tissues. The culture medium consisted of α-minimum essential medium (α-MEM), supplemented with Knockout serum replacement (KSR) or AlbuMAX, neither of which were defined chemically. In this study, we formulated a chemically defined medium (CDM) that can induce mouse spermatogenesis under organ culture conditions. It was found that bovine serum albumin (BSA) purified through three different procedures had different effects on spermatogenesis. We also confirmed that retinoic acid (RA) played crucial roles in the onset of spermatogonial differentiation and meiotic initiation. The added lipids exhibited weak promoting effects on spermatogenesis. Lastly, luteinizing hormone (LH), follicle stimulating hormone (FSH), triiodothyronine (T3), and testosterone (T) combined together promoted spermatogenesis until round spermatid production. The CDM, however, was not able to produce elongated spermatids. It was also unable to induce spermatogenesis from the very early neonatal period, before 2 days postpartum, leaving certain factors necessary for spermatogenic induction in mice unidentified. Nonetheless, the present study provided important basic information on testis organ culture and spermatogenesis in vitro.
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- Modulation of AKR1C2 by curcumin decreases testosterone production in prostate cancer. [Journal Article]
- CSCancer Sci 2018; 109(4):1230-1238
- Intratumoral androgen biosynthesis has been recognized as an essential factor of castration-resistant prostate cancer. The present study investigated the effects of curcumin on the inhibition of intr...
Intratumoral androgen biosynthesis has been recognized as an essential factor of castration-resistant prostate cancer. The present study investigated the effects of curcumin on the inhibition of intracrine androgen synthesis in prostate cancer. Human prostate cancer cell lines, LNCaP and 22Rv1 cells were incubated with or without curcumin after which cell proliferation was measured at 0, 24, 48 and 72 hours, respectively. Prostate tissues from the transgenic adenocarcinoma of the mouse prostate (TRAMP) model were obtained after 1-month oral administration of 200 mg/kg/d curcumin. Testosterone and dihydrotestosterone concentrations in LNCaP prostate cancer cells were determined through LC-MS/MS assay. Curcumin inhibited cell proliferation and induced apoptosis of prostate cancer cells in a dose-dependent manner. Curcumin decreased the expression of steroidogenic acute regulatory proteins, CYP11A1 and HSD3B2 in prostate cancer cell lines, supporting the decrease of testosterone production. After 1-month oral administration of curcumin, Aldo-Keto reductase 1C2 (AKR1C2) expression was elevated. Simultaneously, decreased testosterone levels in the prostate tissues were observed in the TRAMP mice. Meanwhile, curcumin treatments considerably increased the expression of AKR1C2 in prostate cancer cell lines, supporting the decrease of dihydrotestosterone. Taken together, these results suggest that curcumin's natural bioactive compounds could have potent anticancer properties due to suppression of androgen production, and this could have therapeutic effects on prostate cancer.