Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer.

Chih-Pin Chuu,Richard A Hiipakka,Junichi Fukuchi,Liang-Cheng Su,Chiech Huo,Ching-Yu Lin,John M Kokontis,Hui-Ping Lin

doi:10.1186/1423-0127-18-63

Abstract

Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR)-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR) suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.

Highlights

In 1941, Huggins and Hodges reported that androgen ablation therapy causes regression of primary and metastatic prostate cancer [1]
Conclusions our observations suggested that androgen suppress growth of androgen receptor (AR)-positive advanced prostate tumors while Vancouver group use Intermittent Androgen Deprivation (IAD) to show that cessation of anti-androgen therapy allowed tumor cells to recover their androgen-sensitivity and be sensitive to subsequent rounds of anti-ablation treatment
We believe that our LNCaP progression model may provide the molecular explanation for IAD treatment

Summary

Introduction

In 1941, Huggins and Hodges reported that androgen ablation therapy causes regression of primary and metastatic prostate cancer [1]. Recent studies revealed that androgen deprivation therapy significantly reduced serum testosterone concentrations, levels of testosterone and dihydrotestosterone occur in recurrent prostate cancer tissue are sufficient to stimulate AR transcription, PSA secretion, and tumor growth. Androgenic Suppression of Advanced Prostate Cancer Cells in Vivo Castration causes regression of 104-S xenografts, but tumors begin to regrow after 8 weeks as androgen ablation-resistant relapsed tumors called 104-Rrel with elevated AR mRNA and protein expression [18]. Androgen Treatment of Prostate Cancer Reduced serum testosterone levels by androgen ablation therapy causes regression of prostate tumors, but elevation of the testosterone level does not result in stimulation of tumor growth or secretion of PSA [71]. As patients on average did not achieve sustained supraphysiological serum testosterone levels, future studies maximizing testosterone serum levels in selected patients with AR overexpression may improve the treatment outcome

Conclusions

48. Mathew P

Findings

78. Chuu CP