Dataset Information

SIRNA-directed in vivo silencing of androgen receptor inhibits the growth of castration-resistant prostate carcinomas.

ABSTRACT:

Background

Prostate carcinomas are initially dependent on androgens, and castration or androgen antagonists inhibit their growth. After some time though, tumors become resistant and recur with a poor prognosis. The majority of resistant tumors still expresses a functional androgen receptor (AR), frequently amplified or mutated.

Methodology/principal findings

To test the hypothesis that AR is not only expressed, but is still a key therapeutic target in advanced carcinomas, we injected siRNA targeting AR into mice bearing exponentially growing castration-resistant tumors. Quantification of siRNA into tumors and mouse tissues demonstrated their efficient uptake. This uptake silenced AR in the prostate, testes and tumors. AR silencing in tumors strongly inhibited their growth, and importantly, also markedly repressed the VEGF production and angiogenesis.

Conclusions/significance

Our results demonstrate that carcinomas resistant to hormonal manipulations still depend on the expression of the androgen receptor for their development in vivo. The siRNA-directed silencing of AR, which allows targeting overexpressed as well as mutated isoforms, triggers a strong antitumoral and antiangiogenic effect. siRNA-directed silencing of this key gene in advanced and resistant prostate tumors opens promising new therapeutic perspectives and tools.

SUBMITTER: Compagno D

PROVIDER: S-EPMC1994591 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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Publications

SIRNA-directed in vivo silencing of androgen receptor inhibits the growth of castration-resistant prostate carcinomas.

Compagno Daniel D Merle Carole C Morin Aurélie A Gilbert Cristèle C Mathieu Jacques R R JR Bozec Aline A Mauduit Claire C Benahmed Mohammed M Cabon Florence F

PloS one 20071010 10

<h4>Background</h4>Prostate carcinomas are initially dependent on androgens, and castration or androgen antagonists inhibit their growth. After some time though, tumors become resistant and recur with a poor prognosis. The majority of resistant tumors still expresses a functional androgen receptor (AR), frequently amplified or mutated.<h4>Methodology/principal findings</h4>To test the hypothesis that AR is not only expressed, but is still a key therapeutic target in advanced carcinomas, we injec ...[more]

PMID: 17925854

Similar Datasets

Project description:BackgroundWith almost 30,000 deaths per year, prostate cancer is the second-leading cause of cancer-related death in men. Androgen Deprivation Therapy (ADT) has been the corner stone of prostate cancer treatment for decades. However, despite an initial response of prostate cancer to ADT, this eventually fails and the tumors recur, resulting in Castration Resistant Prostate Cancer (CRPC). Triptolide, a diterpene triepoxide, has been tested for its anti-tumor properties in a number of cancers for over a decade. Owing to its poor solubility in aqueous medium, its clinical application had been limited. To circumvent this problem, we have synthesized a water-soluble pro-drug of triptolide, Minnelide, that is currently being evaluated in a Phase 1 clinical trial against gastrointestinal tumors. In the current study, we assessed the therapeutic potential of Minnelide and its active compound triptolide against androgen dependent prostate cancer both in vitro as well as in vivo.MethodsCell viability was measured by a MTT based assay after treating prostate cancer cells with multiple doses of triptolide. Apoptotic cell death was measured using a caspase 3/7 activity. Androgen Receptor (AR) promoter-binding activity was evaluated by using luciferase reporter assay. For evaluating the effect in vivo, 22Rv1 cells were implanted subcutaneously in animals, following which, treatment was started with 0.21 mg/kg Minnelide.ResultsOur study showed that treatment with triptolide induced apoptotic cell death in CRPC cells. Triptolide treatment inhibited AR transcriptional activity and decreased the expression of AR and its splice variants both at the mRNA and the protein level. Our studies show that triptolide inhibits nuclear translocation of Sp1, resulting in its decreased transcriptional activity leading to downregulation of AR and its splice variants in prostate cancer cells. In vivo, Minnelide (0.21 mg/kg) regressed subcutaneous tumors derived from CRPC 22RV1 at our study endpoint. Our animal studies further confirmed that Minnelide was more efficacious than the standard of care therapies, Docetaxel and Enzalutamide.ConclusionOur study indicates that Minnelide is very effective as a therapeutic option against CRPC at a dose that is currently tolerated by patients in the ongoing clinical trials. Prostate 77: 584-596, 2017. © 2017 Wiley Periodicals, Inc.

Dataset Information

SIRNA-directed in vivo silencing of androgen receptor inhibits the growth of castration-resistant prostate carcinomas.

Background

Methodology/principal findings

Conclusions/significance

Publications

SIRNA-directed in vivo silencing of androgen receptor inhibits the growth of castration-resistant prostate carcinomas.

Similar Datasets

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