scholarly journals Pharmacogenetic analysis of human steroid 5α reductase type II: comparison of finasteride and dutasteride

2005 ◽  
Vol 34 (3) ◽  
pp. 617-623 ◽  
Author(s):  
Nick Makridakis ◽  
Juergen K V Reichardt
Keyword(s):  
Prostate Cancer ◽  
Enzyme Inhibitor ◽  
Prostate Gland ◽  
Cancer Chemoprevention ◽  
Time Dependent ◽  
Type Ii ◽  
Reductase Inhibitors ◽  
Dependent Inhibition ◽  
Prostatic Diseases

Human steroid 5α-reductase type II is a prostate-specific, membrane-associated enzyme that catalyzes the conversion of testosterone to dihydrotestosterone, the most potent androgen in the prostate gland. Genetic variants of this enzyme have been associated with both the development and the progression of prostate cancer. Both finasteride and dutasteride are competitive inhibitors of the type II steroid 5α-reductase that have been effectively used for the treatment of benign prostatic hyperplasia. Finasteride has also been successfully utilized for prostate cancer chemoprevention. We here investigate 5α-reductase inhibition assays in vitro to measure the effect of incubation time on the apparent inhibition constant (Ki) for both constitutional and somatic (prostate cancer) enzyme variants. Our systematic pharmacogenetic analysis shows that both finasteride and dutasteride are slow, time-dependent inhibitors of steroid 5α-reductase type II, and that the inhibition kinetics depend on the 5α-reductase genotype. We also show that, overall, dutasteride is a more efficient steroid 5α-reductase inhibitor than finasteride. Based on our data, we are able to map areas of the enzyme that are responsible for this time-dependent inhibition for either (or both) enzyme inhibitor(s). This comprehensive pharmacogenetic analysis of steroid 5α-reductase variants unveiled significant pharmacogenetic variation for both finasteride and dutasteride and thus should be taken into account when designing protocols for treatment and/or chemoprevention of prostatic diseases with either one of these 5α-reductase inhibitors since there is considerable pharmacogenetic variation for both drugs.

scholarly journals In Vitro Assessment of Efficacy and Cytotoxicity of Prunus africana Extracts on Prostate Cancer C4-2 Cells

2021 ◽  
Author(s):  
Peace C. Asuzu ◽  
Alberta N.A. Aryee ◽  
Nicholas Trompeter ◽  
Yasmin Mann ◽  
Samuel A. Besong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lncap Cells ◽  
Leaf Extracts ◽  
Cytotoxic Effects ◽  
Prunus Africana ◽  
Plant Parts ◽  
Dependent Inhibition ◽  
Hormone Sensitive ◽  
In Vitro Assessment

AbstractPhenolic compounds are products of secondary plant metabolism known for their biological activity including their antimicrobial, antioxidant, analgesic, stimulant, anti- carcinogenic, and aphrodisiac properties. The main objective of this study was to assess the potency/cytotoxic effects of Prunus africana extracts on prostate cancer cells in vitro. Using different concentrations of P. africana extracts, prostate cancer C4-2 cells, a hormonally insensitive subline of LNCaP cells, were treated in a proliferation assay. A concentration dependent inhibition of cell growth in cells treated with P. africana bark and root extracts was present from days 1 through 3 of incubation, with the methanol extract of the bark showing the strongest effect. Compared to other plant parts, leaf extracts were significantly less cytotoxic at the same concentrations. As C4-2 cells are hormonally insensitive and designed to mimic advanced prostate cancer, crude extracts of P. africana are a possible treatment option, not only for hormone sensitive prostate cancer, but also advanced, hormonally insensitive prostate cancer.

scholarly journals LINC01006 facilitates cell proliferation, migration and invasion in prostate cancer through targeting miR-34a-5p to up-regulate DAAM1

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Enhui Ma ◽  
Qianqian Wang ◽  
Jinhua Li ◽  
Xinqi Zhang ◽  
Zhenjia Guo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Gland ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Protein Coding ◽  
Novel Target

Abstract Background Prostate cancer (PCa) is a kind of malignancy occurring in the prostate gland. Substantial researches have proved the major role of long noncoding RNAs (lncRNAs) in PCa. However, the role of long intergenic non-protein coding RNA 1006 (LINC01006) in PCa has not been investigated yet. Methods RT-qPCR was used to examine the expression levels of LINC01006 and its downstream targets. The function of LINC01006 in PCa was tested by in vitro and in vivo assays. With application of RNA pull down, RNA immunoprecipitation (RIP) and luciferase reporter assays, the interaction among LINC01006, miR-34a-5p and disheveled associated activator of morphogenesis 1 (DAAM1) were verified. Results LINC01006 expression presented high in PCa cell lines. LINC01006 silencing suppressed cell proliferative, migratory, invasive capacities while accelerated apoptotic rate. Besides, LINC01006 knockdown also suppressed tumor growth and metastasis in vivo. Furthermore, miR-34a-5p, a tumor suppressor in PCa, was sponged by LINC01006. Moreover, DAAM1 was targeted by miR-34a-5p and promoted PCa progression. More intriguingly, rescue assays suggested that the inhibitory effect of LINC01006 knockdown on PCa development was offset by DAAM1 overexpression. Conclusions LINC01006 promoted PCa progression by sponging miR-34a-5p to up-regulate DAAM1, providing a novel target for PCa therapy.

scholarly journals Valproic acid causes dose- and time-dependent changes in nuclear structure in prostate cancer cells in vitro and in vivo

2009 ◽  
Vol 8 (4) ◽  
pp. 802-808 ◽  
Author(s):  
Madeleine S.Q. Kortenhorst ◽  
Sumit Isharwal ◽  
Paul J. van Diest ◽  
Wasim H. Chowdhury ◽  
Cameron Marlow ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Valproic Acid ◽  
Cancer Cells ◽  
Nuclear Structure ◽  
Time Dependent ◽  
Prostate Cancer Cells

scholarly journals Dual Inhibition of Human Rhinovirus 2A and 3C Proteases by Homophthalimides

1998 ◽  
Vol 42 (4) ◽  
pp. 916-920 ◽  
Author(s):  
Q. May Wang ◽  
Robert B. Johnson ◽  
Louis N. Jungheim ◽  
Jeffrey D. Cohen ◽  
Elcira C. Villarreal
Keyword(s):  
Antiviral Activity ◽  
Viral Replication ◽  
Enzyme Inhibitor ◽  
Antiviral Drug ◽  
3C Protease ◽  
Dependent Inhibition ◽  
Dual Inhibition ◽  
2A Protease

ABSTRACT The 2A and 3C proteases encoded by human rhinoviruses (HRVs) are attractive targets for antiviral drug development due to their important roles in viral replication. Homophthalimides were originally identified as inhibitors of rhinovirus 3C protease through our screening effort. Previous studies have indicated that the antiviral activity of certain homophthalimides exceeded their in vitro inhibitory activity against the viral 3C protease, suggesting that an additional mechanism might be involved. Reported here is the identification of homophthalimides as potent inhibitors for another rhinovirus protease, designated 2A. Several homophthalimides exhibit time-dependent inhibition of the 2A protease in the low-micromolar range, and enzyme-inhibitor complexes were identified by mass spectrometry. Compound LY343814, one of the most potent inhibitors against HRV14 2A protease, had an antiviral 50% inhibitory concentration of 4.2 μM in the cell-based assay. Our data reveal that homophthalimides are not only 3C but also 2A protease inhibitors in vitro, implying that the antiviral activity associated with these compounds might result from inactivation of both 2A and 3C proteases in vivo. Since the processing of the viral polyprotein is hierarchical, dual inhibition of the two enzymes may result in cooperative inhibition of viral replication. On the basis of the current understanding of their enzyme inhibitory mechanism, homophthalimides, as a group of novel nonpeptidic antirhinovirus agents, merit further structure-action relationship studies.

Integrated in Silico−in Vitro Strategy for Addressing Cytochrome P450 3A4 Time-Dependent Inhibition

2010 ◽  
Vol 23 (3) ◽  
pp. 664-676 ◽  
Author(s):  
Michael Zientek ◽  
Chad Stoner ◽  
Robyn Ayscue ◽  
Jacquelyn Klug-McLeod ◽  
Ying Jiang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
In Silico ◽  
Time Dependent ◽  
Cytochrome P450 3A4 ◽  
Dependent Inhibition ◽  
Time Dependent Inhibition

scholarly journals Use of 5-α-Reductase Inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline

2009 ◽  
Vol 27 (9) ◽  
pp. 1502-1516 ◽  
Author(s):  
Barnett S. Kramer ◽  
Karen L. Hagerty ◽  
Stewart Justman ◽  
Mark R. Somerfield ◽  
Peter C. Albertsen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Clinical Oncology ◽  
Cancer Chemoprevention ◽  
Evidence Based ◽  
High Grade ◽  
Reductase Inhibitors ◽  
Potential Risks ◽  
American Society ◽  
American Urological Association

Purpose To develop an evidence-based guideline on the use of 5-α-reductase inhibitors (5-ARIs) for prostate cancer chemoprevention. Methods The American Society of Clinical Oncology (ASCO) Health Services Committee (HSC), ASCO Cancer Prevention Committee, and the American Urological Association Practice Guidelines Committee jointly convened a Panel of experts, who used the results from a systematic review of the literature to develop evidence-based recommendations on the use of 5-ARIs for prostate cancer chemoprevention. Results The systematic review completed for this guideline identified 15 randomized clinical trials that met the inclusion criteria, nine of which reported prostate cancer period prevalence. Conclusion Asymptomatic men with a prostate-specific antigen (PSA) ≤ 3.0 ng/mL who are regularly screened with PSA or are anticipating undergoing annual PSA screening for early detection of prostate cancer may benefit from a discussion of both the benefits of 5-ARIs for 7 years for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer). Men who are taking 5-ARIs for benign conditions such as lower urinary tract [obstructive] symptoms (LUTS) may benefit from a similar discussion, understanding that the improvement of LUTS relief should be weighed with the potential risks of high-grade prostate cancer from 5-ARIs (although the majority of the Panel members judged the latter risk to be unlikely). A reduction of approximately 50% in PSA by 12 months is expected in men taking a 5-ARI; however, because these changes in PSA may vary across men, and within individual men over time, the Panel cannot recommend a specific cut point to trigger a biopsy for men taking a 5-ARI. No specific cut point or change in PSA has been prospectively validated in men taking a 5-ARI.

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