728 AZD5363, A NOVEL AKT INHIBITOR, DELAYS PROSTATE CANCER PROGRESSION
Bibliographic record
Abstract
You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 2011728 AZD5363, A NOVEL AKT INHIBITOR, DELAYS PROSTATE CANCER PROGRESSION Christian Thomas, Francois Lamoureux, Claire Crafter, Barry Davies, Amina Zoubeidi, and Martin E. Gleave Christian ThomasChristian Thomas Vancouver, Canada , Francois LamoureuxFrancois Lamoureux Vancouver, Canada , Claire CrafterClaire Crafter Macclesfield, United Kingdom , Barry DaviesBarry Davies Macclesfield, United Kingdom , Amina ZoubeidiAmina Zoubeidi Vancouver, Canada , and Martin E. GleaveMartin E. Gleave Vancouver, Canada View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1697AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Despite initial response to androgen deprivation therapy, prostate cancer (PCa) inevitably progresses after 3 to 4 years its castration-resistant state (CRPC). Consequently, there is an urgent need for novel therapeutic agents that can prevent or at least prolong the time to CRPC progression. The phosphoinositide 3-kinase (PI3K)/Akt pathway plays a key role in tumor progression and therefore is an attractive pharmacological target. In this study, we assessed the anti-cancer effects of the novel and selective Akt inhibitor, AZD5363, in vitro and in vivo in PCa. METHODS LNCaP and C4-2 cells were treated with AZD5363 and submitted to western blot, qRT-PCR and immunofluorescence analysis. AZD5363 was tested for its ability to modulate PSA transactivation by luciferase assay. Cell viability was assessed by crystal violet and cell cycle population by flow cytometry. For in vivo xenograft studies, LNCaP cells were inoculated s.c. in the flank region of athymic nude mice. Mice were castrated and randomly treated with AZD5363 or control by oral gavage. Tumor volume and serum prostate-specific antigen (PSA) were evaluated twice per week. RESULTS Here we report that AZD-5363 inhibits cell growth in a dose-dependent manner (IC50 ∼200nM) in both LNCaP and C4-2, induces cell apoptosis as measured with PARP cleavage expression, Caspase 3 activity, and increases sub-G1 population (20.2% and 22.2% at 500nM for LNCaP and C4-2 cells, respectively). Interestingly, AZD5363 significantly abrogates androgen-induced PSA transactivation at concentrations > ∼100nM and down-regulates AR expression at concentrations > ∼1uM. These biologic events were accompanied by inhibition of downstream PI3K/Akt signaling. Most important, targeting the Akt-pathway in vivo significantly reduces tumor volume and serum PSA-levels and thereby delays progression to CRPC. CONCLUSIONS This study reports as a preclinical proof-of-principle that targeting PI3K/Akt pathway with AZD-5363 inhibits androgen-dependent PCa progression in vitro and in vivo, using the AR-axis as a pharmacodynamic tool. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e292-e293 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christian Thomas Vancouver, Canada More articles by this author Francois Lamoureux Vancouver, Canada More articles by this author Claire Crafter Macclesfield, United Kingdom More articles by this author Barry Davies Macclesfield, United Kingdom More articles by this author Amina Zoubeidi Vancouver, Canada More articles by this author Martin E. Gleave Vancouver, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.009 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".