The steroidal enzyme cytochrome P45017alpha catalyzes the conversion of progesterone and pregnenolone into androgens, androstenedione and dehydroepiandrosterone, respectively, the direct precursors of estrogens and testosterone. Dihydrotestosterone is the principal active androgen in the prostate, testosterone is also an active stimulant of the growth of prostatic cancer tissue. Inhibition of this enzyme as a mechanism for inhibiting androgen biosynthesis could be a worthwhile therapeutic strategy for the treatment of PCA. In this paper, four categories of steroidal inhibitors of cytochrome P45017alpha will be reviewed, a diverse range of steroidal inhibitors had been synthesized and shown to be potent inhibitors of P45017alpha.
Androstenedione ; biosynthesis ; Androstenes ; Androstenols ; chemical synthesis ; chemistry ; pharmacology ; Animals ; Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Dehydroepiandrosterone ; biosynthesis ; Dihydrotestosterone ; metabolism ; Enzyme Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Humans ; Male ; Molecular Structure ; Pregnenolone ; metabolism ; Progesterone ; metabolism ; Prostatic Neoplasms ; pathology ; Steroid 17-alpha-Hydroxylase ; antagonists & inhibitors ; Testosterone ; biosynthesis

AIMTo modify the structure of dehydroepiandrosterone (DHEA).

METHODSUsing hairy root cultures of Anisodus tanguticus to perform biotransformation of DHEA, using chromatographic and spectral techniques to isolate and identify the products.

RESULTS(1) The MS medium without plant hormone was suitable for the growth of the hairy root. (2) DHEA was converted into five products: androst-4-ene-3, 17-dione (I); 6alpha-hydroxyandrost-4-ene-3, 17-dione (II); 6alpha, 17beta-dihydroxyandrost-4-ene-3-one (III); androst-4-ene-3, 6, 17-trione (IV) and 17beta-hydroxyandrost-4-ene-3-one (V).

CONCLUSIONIt is the first time to use hairy root cultures of Anisodus tanguticus for the biotransformation of DHEA and five DHEA-related compounds were obtained.

Androstenedione ; chemistry ; isolation & purification ; Androstenes ; chemistry ; isolation & purification ; Biotransformation ; Culture Media ; Dehydroepiandrosterone ; chemistry ; metabolism ; Molecular Structure ; Plant Roots ; metabolism ; Plants, Medicinal ; metabolism ; Solanaceae ; metabolism ; Tissue Culture Techniques

Abiraterone Acetate/therapeutic use* ; Androstenes/therapeutic use* ; Dexamethasone/therapeutic use* ; Humans ; Male ; Prostatic Neoplasms, Castration-Resistant/pathology*

Individualized treatment of prostate cancer depends on an accurate stratification of patients who are sensitive to various treatments. Interleukin-23 (IL-23) was reported to play a significant role in prostate cancer. Here, we aimed to explore the clinical value of IL-23-secreting (IL-23+) cells in prostate cancer patients. We evaluated interleukin-23A (IL-23A) expression in The Cancer Genome Atlas database and retrospectively enrolled 179 treatment-naïve metastatic prostate cancer patients diagnosed in our institute between June 2012 and December 2014. IL-23⁺ cells were stained and evaluated via immunohistochemistry. Further, survival and multivariate Cox regression analyses were conducted to explore the prognostic value of IL-23⁺ cells. We found that IL-23A expression correlated with disease progression, while IL-23⁺ cells were clearly stained within prostate cancer tissue. Patients with higher Gleason scores and multiple metastatic lesions tended to have more IL-23⁺ cell infiltration. Further analyses showed that patients with higher levels of IL-23⁺ cells had significantly worse overall survival (hazard ratio [HR] = 2.996, 95% confidence interval [95% CI]: 1.812-4.955; P = 0.001) and a higher risk of developing castration resistance (HR = 2.725, 95% CI: 1.865-3.981; P = 0.001). Moreover, subgroup analyses showed that when patients progressed to a castration-resistant status, the prognostic value of IL-23⁺ cells was observed only in patients treated with abiraterone instead of docetaxel. Therefore, we showed that high IL-23⁺ cell infiltration is an independent prognosticator in patients with metastatic prostate cancer. IL-23⁺ cell infiltration may correlate with abiraterone effectiveness in castration-resistant prostate cancer patients.
Abiraterone Acetate/therapeutic use* ; Androstenes ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Disease-Free Survival ; Humans ; Interleukin-23/metabolism* ; Male ; Prostatic Neoplasms, Castration-Resistant/pathology* ; Retrospective Studies ; Treatment Outcome

Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we investigated the potential biomarkers for predicting the efficacy of corticosteroid switching during treatment with abiraterone acetate (AA). We retrospectively analyzed 101 mCRPC patients receiving corticosteroid switching from West China Hospital and Sun Yat-Sen University Cancer Center between January 2016 and December 2018. All cases received AA plus prednisone as first-line therapy during mCRPC. Primary end points were biochemical progression-free survival (bPFS) and overall survival (OS). The risk groups were defined based on multivariate analysis. A total of 42 (41.6%) and 25 (24.8%) patients achieved 30% and 50% decline in prostate-specific antigen (PSA), respectively, after corticosteroid switching. The median bPFS and median OS on AA plus dexamethasone were 4.9 (95% confidence interval [CI]: 3.7-6.0) months and 18.8 (95% CI: 16.2-30.2) months, respectively. Aldo-keto reductase family 1 member C3 (AKR1C3) expression (hazard ratio [HR]: 2.15, 95% Cl: 1.22-3.80, P = 0.008) and baseline serum alkaline phosphatase (ALP; HR: 4.95, 95% Cl: 2.40-10.19, P < 0.001) were independent predictors of efficacy before corticosteroid switching in the multivariate analysis of bPFS. Only baseline serum ALP >160 IU l^-1 (HR: 3.41, 95% Cl: 1.57-7.38, P = 0.002) together with PSA level at switch ≥50 ng ml^-1 (HR: 2.59, 95% Cl: 1.22-5.47, P = 0.013) independently predicted poorer OS. Based on the predictive factors in multivariate analysis, we developed two risk stratification tools to select candidates for corticosteroid switching. Detection of serum ALP level, PSA level, and tissue AKR1C3 expression in mCRPC patients could help make clinical decisions for corticosteroid switching.
Abiraterone Acetate/therapeutic use* ; Adrenal Cortex Hormones/therapeutic use* ; Androstenes ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Dexamethasone/therapeutic use* ; Disease-Free Survival ; Humans ; Male ; Prednisone/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms, Castration-Resistant/pathology* ; Retrospective Studies ; Treatment Outcome

PURPOSE: To compare the effect of loteprednol etabonate (LE) with prednisolone acetate (PDA) drops on the proliferation of human Tenon's capsule fibroblasts (HTFBs). METHODS: Primarily cultured HTFBs were treated with serially diluted PDA and LE for 3 days. Cellular survival was determined by a rapid colorimetric assay using MTT. RT-PCR was performed to determine the relative expression of TGF-beta mRNA in response to LE and PDA. RESULTS: PDA inhibited proliferation of HTCF in a dose-dependent manner and LE inhibited significantly the proliferation of HTCF at the higher concentration of 50 microg/ml (p < 0.05). Compared to LE, PDA inhibited proliferation of HTCF significantly at each diluted concentration (p < 0.05). Expressions of TGF-beta were decreased as the concentration of both PDA and LE increased. PDA decreased expression of TGF-beta more significantly compared to LE at each concentration (p < 0.05). CONCLUSIONS: Although LE has offered promising anti-inflammatory efficacy with decreased impact on intraocular pressure, LE may be less effective than PDA in inhibiting fibroblast proliferation and may be not comparable to PDA in preventing excessive scarring after glaucoma filtering surgery.
Androstadienes ; Cicatrix ; Fibroblasts ; Filtering Surgery ; Glaucoma ; Humans ; Intraocular Pressure ; Ophthalmic Solutions ; Prednisolone ; RNA, Messenger ; Tenon Capsule ; Transforming Growth Factor beta ; Loteprednol Etabonate

In order to improve transformation efficiency of dehydroepiandrosterone (DHEA) into 3beta,7alpha,15alpha-trihydroxy-5-androsten-17-one (7alpha,15alpha-diOH-DHEA) by Gibberella intermedia CA3-1, we investigated the strains breeding and their conversion process optimization. G. intermedia CA3-1 strains were treated with 0.12 mg/mL 1-methyl-3-nitro-1-nitroso-guanidin (NTG) for 30 min and chosen by 350 micromol/L minimum inhibitory concentration ketoconazole resistance marker. The high production strain named M-10 with a good genetic stability was selected and the product molar yield achieved to 70.2%, which was 20% higher than that of original strain. Under the improved conversion process with the DHEA concentration of 5 g/L, the product molar yield of the mutant M-10 reached 75.6%, which was improved by 31.3% than that of original strain.
Androstenols ; metabolism ; Biotransformation ; Dehydroepiandrosterone ; metabolism ; Gibberella ; growth & development ; metabolism ; Industrial Microbiology

OBJECTIVES: To determine the baseline serum concentrations of estradiol and estrone in postmenopausal Korean women and the serum concentrations of estradiol and estrone after 4 and 16 weeks of treatment using 1 mg of estradiol and 2 mg of drospirenone. METHODS: This was a multicenter study. Thirty-six subjects were screened. Serum estradiol, estrone and drospirenone levels were determined by gas chromatography-mass spectrometry and radioimmunoassay. RESULTS: The mean estradiol concentration was 8.37 +/- 12.1 pg/mL at baseline and increased to 53.7 +/- 52.1 and 41.4 +/- 26.1 pg/mL after 4 and 16 weeks of treatment, respectively. The mean estrone concentrations were 28.7 +/- 26.8, 266.1 +/- 182.9, and 256.1 +/- 179.1 pg/mL at baseline, and after 4 and 16 weeks of treatment, respectively. When women were stratified according to the basal estradiol level, the level after 4 weeks of treatment was significantly higher in the women with a detectable level (> or = 5 pg/mL) than in women with an undetectable level (< 5 pg/mL; 65.2 +/- 21.5 vs. 37.4 +/- 25.8 pg/mL, P = 0.008). After 16 weeks of treatment, the estradiol level was still higher in the detectable group (51.6 +/- 28.6 vs. 38.7 +/- 21.7 pg/mL, P = 0.09). CONCLUSION: This study showed that 1 mg of estradiol and 2 mg of drospirenone is an appropriate regimen to achieve the desired serum estradiol level. The difference in serum hormonal levels after 4 weeks of treatment could be caused by different basal levels.
Administration, Oral ; Androstenes ; Estradiol ; Estrogen Replacement Therapy ; Estrone ; Female ; Gas Chromatography-Mass Spectrometry ; Humans ; Postmenopause

OBJECTIVE: To evaluate effects of Drospirenone 2 mg (DRSP) with 17-beta-Estradiol 1 mg (E2) on blood pressure (BP) and body weight in postmenopausal Korean women. METHODS: BP and body weight were measured at baseline and 3 months of the treatment. We compared the change in BP and body weight between normotensive (group 1, control) and high-normotensive (group 2) group during treatment. And we compared the change in BP and body weight between hypertensive group receiving anti-hypertensive with (group 3) and without (group 4, control) DRSP/E2 during treatment. RESULTS: The mean systolic BP/diastolic BP of group 1 was not significantly decreased from baseline (116.9/75.0 mmHg) after treatment with DRSP/E2 for 3 months (116.1/73.2 mmHg) (P<0.152/P=0.088), however that of group 2 was significantly decreased from baseline (128.8/81.8 mmHg) after treatment with DRSP/E2 for 3 months (126.2/79.3 mmHg) (P<0.001/P=0.002). The mean systolic BP/diastolic BP of group 3 was significantly decreased from baseline (133.5/82.5 mmHg) after treatment with DRSP/E2 for 3 months (129.3/77.9 mmHg) (P<0.001/P<0.001), and that of group 4 was also significantly decreased from baseline (133.2/80.7 mmHg) after treatment with DRSP/E2 for 3 months (131.0/78.3 mmHg) (P=0.002/P<0.001). However change in the mean systolic BP/diastolic BP of group 3 was greater than that of group 4 (P=0.041/P=0.024). There was no weight change in all four groups. CONCLUSION: The use of DRSP/E2 showed a tendency to decrease the BP of high-normotensive or above in postmenopausal Korean women, and hypertensive patients receiving anti-hypertensive showed greater decline in BP. However there was no statistical significance in body weight change.
Androstenes ; Blood Pressure ; Body Weight ; Body Weight Changes ; Female ; Humans ; Postmenopause

Androstenes ; Docetaxel ; Humans ; Male ; Prednisone ; Prostatic Neoplasms ; Prostatic Neoplasms, Castration-Resistant