Next-generation steroidogenesis inhibitors, dutasteride and abiraterone, attenuate but still do not eliminate androgen biosynthesis in 22RV1 cells in vitro

Pham, Steven; Deb, Subrata; Ming, Dong Sheng; Adomat, Hans; Hosseini‐Beheshti, Elham; Zoubeidi, Amina; Gleave, Martin; Guns, Emma S. Tomlinson

doi:10.1016/j.jsbmb.2014.09.004

Cited by 15 publications

(20 citation statements)

References 37 publications

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“…This result is consistent with reports that Rv1 cells can synthesize androgen (41,42) and with our profiling array data revealing regulation of steroidogenic enzymes by Siah2 (19). Restoring the expression of AKR1C3 in the Siah2 KD Rv1 cells partly rescued the AR activity and cell proliferation defects, demonstrating that AKR1C3 is a key downstream effector of Siah2.…”

Section: Discussionsupporting

confidence: 93%

The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

Fan

Peng

Hussain

et al. 2015

Journal of Biological Chemistry

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Background: Ubiquitin ligase Siah2 promotes activity of androgen receptor (AR) in prostate cancer cells. Results:The steroidogenic enzyme AKR1C3 binds and stabilizes Siah2 by blocking Siah2 self-ubiquitination and degradation. Conclusion: We identified a catalytic independent role for AKR1C3 on AR activity via Siah2. Significance: The findings may provide new targets for development of AKR1C3 inhibitors as prostate cancer therapy.

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Section: Discussionsupporting

confidence: 93%

The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

Fan

Peng

Hussain

et al. 2015

Journal of Biological Chemistry

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“…More complete androgen synthesis blockade through this multipronged approach could provide greater clinical benefit than solitary pathway inhibition. Preclinical studies have demonstrated that the combination of abiraterone and dutasteride decreased intratumoral testosterone and DHT (13). Additionally, we previously conducted a phase II trial of ketoconazole, a less potent CYP17A1 inhibitor, with dutasteride and hydrocortisone in patients with CRPC (14).…”

Section: Introductionmentioning

confidence: 99%

A Phase II Trial of Abiraterone Combined with Dutasteride for Men with Metastatic Castration-Resistant Prostate Cancer

McKay

Werner

Mostaghel

et al. 2017

Clinical Cancer Research

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Purpose Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride. Experimental Design Eligible metastatic CRPC patients underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles. After this time, high-dose dutasteride (3.5mg daily) was added. Patients continued therapy until study withdrawal or radiographic progression. Repeat metastasis biopsy was obtained at progression. The primary endpoint was to assess mechanisms of resistance. Serum hormone and abiraterone levels were assessed. Tissue was assessed for androgen receptor (AR) and AR splice variant-7 (ARV7) expression. Results Forty patients were enrolled. 60% (n=24) achieved a ≥50% reduction in PSA. The median time to radiographic progression was 11 months. Nearly all baseline (n=29/30) and post-treatment (n=16/16) tumors tested for AR nuclear expression were positive. Of those tested, ARV7 expression was present in 48% (n=10/21) of baseline and 42% (n=5/12) of treatment discontinuation specimens. Compared to patients with higher serum abiraterone levels at treatment discontinuation, patients with lower levels had higher circulating androgens. Conclusions Despite increased androgen synthesis inhibition, we demonstrate that tumor AR axis remains important in disease progression. We highlight that abiraterone metabolism and pharmacokinetics may play a role in resistance. The non-comparative design limits conclusions on the efficacy of dual therapy with abiraterone and dutasteride, but the results support development of further multifaceted approaches towards AR inhibition.

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“…It has been demonstrated that although LNCaP cells show varying levels of steroidogenic enzymes depending on their passage number and growth environment, they express the full complement of enzymes necessary for the conversion of cholesterol to testosterone [ 10 , 21 , 22 , 23 , 27 ]. 22Rv1 cells have demonstrated high levels of steroidogenic enzymes and the ability to form testosterone and DHT using upstream precursors [ 10 , 28 ]. The precursors can affect various enzyme levels, adaptations between the classical and backdoor pathway, and androgen metabolism.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Precursor-Dependent Steroidogenesis in Human Prostate Cancer Models

Deb

Pham

Ming

et al. 2018

Cancers

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Castration-resistant prostate tumors acquire the independent capacity to generate androgens by upregulating steroidogenic enzymes or using steroid precursors produced by the adrenal glands for continued growth and sustainability. The formation of steroids was measured by liquid chromatography-mass spectrometry in LNCaP and 22Rv1 prostate cancer cells, and in human prostate tissues, following incubation with steroid precursors (22-OH-cholesterol, pregnenolone, 17-OH-pregnenolone, progesterone, 17-OH-progesterone). Pregnenolone, progesterone, 17-OH-pregnenolone, and 17-OH-progesterone increased C21 steroid (5-pregnan-3,20-dione, 5-pregnan-3,17-diol-20-one, 5-pregnan-3-ol-20-one) formation in the backdoor pathway, and demonstrated a trend of stimulating dihydroepiandrosterone or its precursors in the backdoor pathway in LNCaP and 22Rv1 cells. The precursors differentially affected steroidogenic enzyme messenger RNA (mRNA) expressions in the cell lines. The steroidogenesis following incubation of human prostate tissue with 17-OH-pregnenolone and progesterone produced trends similar to those observed in cell lines. Interestingly, the formation of C21 steroids from classical pathway was not stimulated but backdoor pathway steroids (e.g., 5-pregnan-3,20-dione, 5-pregnan-3-ol-20-one) were elevated following incubations with prostate tissues. Overall, C21 steroids were predominantly formed in the classical as well as backdoor pathways, and steroid precursors induced a diversion of steroidogenesis to the backdoor pathway in both cell lines and human prostate tissue, and influenced adaptive steroidogenesis to form C21 steroids.

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Next-generation steroidogenesis inhibitors, dutasteride and abiraterone, attenuate but still do not eliminate androgen biosynthesis in 22RV1 cells in vitro

Cited by 15 publications

References 37 publications

The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

A Phase II Trial of Abiraterone Combined with Dutasteride for Men with Metastatic Castration-Resistant Prostate Cancer

Characterization of Precursor-Dependent Steroidogenesis in Human Prostate Cancer Models

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