Transgenic Mouse Model for Rapid Pharmacodynamic Evaluation of Antiandrogens

Ellwood-Yen, Katharine; Wongvipat, John; Sawyers, Charles L.

doi:10.1158/0008-5472.can-06-1397

Cited by 26 publications

(14 citation statements)

References 13 publications

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“…As shown in Fig. 2, the average serum T concentration in TP-treated castrated WT mice was approximately 7 ng/ml, similar to what has been reported (21,22). In contrast, the serum concentrations of T decreased significantly in TP-treated TG mice ( Fig.…”

Section: Activation Of Pxr In Mice Inhibited Androgendependent Prostasupporting

confidence: 89%

Pregnane X Receptor as a Therapeutic Target to Inhibit Androgen Activity

Zhang

Cheng

et al. 2010

Endocrinology

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The androgen-androgen receptor signaling pathway plays an important role in the pathogenesis of prostate cancer. Accordingly, androgen deprivation has been the most effective endocrine therapy for hormone-dependent prostate cancer. Here, we report a novel pregnane X receptor (PXR)-mediated and metabolism-based mechanism to reduce androgenic tone. PXR is a nuclear receptor previously known as a xenobiotic receptor regulating the expression of drug metabolizing enzymes and transporters. We showed that genetic (using a PXR transgene) or pharmacological (using a PXR agonist) activation of PXR lowered androgenic activity and inhibited androgen-dependent prostate regeneration in castrated male mice that received daily injections of testosterone propionate by inducing the expression of cytochrome P450 (CYP)3As and hydroxysteroid sulfotransferase (SULT)2A1, which are enzymes important for the metabolic deactivation of androgens. In human prostate cancer cells, treatment with the PXR agonist rifampicin (RIF) inhibited androgen-dependent proliferation of LAPC-4 cells but had little effect on the growth of the androgen-independent isogenic LA99 cells. Down-regulation of PXR or SULT2A1 in LAPC-4 cells by short hairpin RNA or small interfering RNA abolished the RIF effect, indicating that the inhibitory effect of RIF on androgens was PXR and SULT2A1 dependent. In summary, we have uncovered a novel function of PXR in androgen homeostasis. PXR may represent a novel therapeutic target to lower androgen activity and may aid in the treatment and prevention of hormone-dependent prostate cancer. (Endocrinology 151: 5721-5729, 2010) P rostate cancer is the most common malignancy diagnosed in American men and the second leading cause of male cancer mortality (1). In the 1940s, Charles Huggins found that metastatic prostate cancer responded to androgen deprivation therapy (ADT) (2), which has since become the mainstay of treatment for locally advanced and metastatic prostate cancer.The ADT strategies in prostate cancer patients include orchiectomy and the use of GnRH (also known as LHRH) agonists or antagonists, steroidal and nonsteroidal antiandrogens, and inhibitors for the 5␣-reductase (3). Orchiectomy is a simple surgical procedure, but it has fallen out of favor given its psychological impact and viable medical alternatives for androgen deprivation (4). GnRH agonist therapy is widely used as a medical and reversible castration. GnRH agonists induce a transient increase in plasma testosterone (T) levels during the first week of treatment, causing a "flare" reaction in prostate cancer patients (5). GnRH antagonists do not cause a T surge, but they could be associated with an enhanced risk of ana-

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Section: Activation Of Pxr In Mice Inhibited Androgendependent Prostasupporting

confidence: 89%

Pregnane X Receptor as a Therapeutic Target to Inhibit Androgen Activity

Zhang

Cheng

et al. 2010

Endocrinology

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“…We questioned whether AR-mediated transcription was active in each cell type by examining expression of known androgen regulated genes. Cells from each population were sorted from ARR2 Pb-Lux transgenic mice expressing luciferase under regulation of the androgen-regulated probasin promoter (19). Despite the roughly equal expression of AR in basal/stem and luminal cell fractions by qPCR and Western blot, luciferase activity was approximately 7-fold lower in basal/stem cells compared to luminal cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Basal epithelial stem cells are efficient targets for prostate cancer initiation

Lawson¹,

Zong

Memarzadeh³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

245

222

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Prevailing theories suggest that luminal cells are the origin of prostate cancer because it is histologically defined by basal cell loss and malignant luminal cell expansion. We introduced a series of genetic alterations into prospectively identified populations of murine basal/stem and luminal cells in an in vivo prostate regeneration assay. Stromal induction of FGF signaling, increased expression of the ETS family transcription factor ERG1, and constitutive activation of PI3K signaling were evaluated. Combination of activated PI3K signaling and heightened androgen receptor signaling, which is associated with disease progression to androgen independence, was also performed. Even though luminal cells fail to respond, basal/stem cells demonstrate efficient capacity for cancer initiation and can produce luminal-like disease characteristic of human prostate cancer in multiple models. This finding provides evidence in support of basal epithelial stem cells as one target cell for prostate cancer initiation and demonstrates the propensity of primitive cells for tumorigenesis.

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“…However, the programmability of polyamides might allow selective inhibition of a predetermined subset of AR target genes by one or a small mixture of tailored polyamide molecules. The utility of disrupting the AR-ARE interface with DNA-binding small molecules will depend on continued experimentation in small animal models of hormone refractory prostate cancer and AR-regulated gene expression (40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide

Nickols

Dervan

2007

Proc. Natl. Acad. Sci. U.S.A.

179

206

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Androgen receptor (AR) is essential for the growth and progression of prostate cancer in both hormone-sensitive and hormone-refractory disease. A DNA-binding polyamide that targets the consensus androgen response element binds the prostate-specific antigen (PSA) promoter androgen response element, inhibits androgeninduced expression of PSA and several other AR-regulated genes in cultured prostate cancer cells, and reduces AR occupancy at the PSA promoter and enhancer. Down-regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide (Casodex) at the same concentration. Genome-wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide. Direct inhibition of the AR-DNA interface by sequence-specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity.prostate cancer ͉ bicalutamide ͉ small molecule ͉ transcription

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Transgenic Mouse Model for Rapid Pharmacodynamic Evaluation of Antiandrogens

Cited by 26 publications

References 13 publications

Pregnane X Receptor as a Therapeutic Target to Inhibit Androgen Activity

Pregnane X Receptor as a Therapeutic Target to Inhibit Androgen Activity

Basal epithelial stem cells are efficient targets for prostate cancer initiation

Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide

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