ABSTRACT
Androgen deprivation therapy (ADT) is the standard treatment for patients with prostate-specific antigen progression after treatment for localized prostate cancer. An alternative to continuous ADT is intermittent ADT (IADT), which allows recovery of testosterone during off-cycles to stimulate regrowth and differentiation of the regressed prostate tumor. IADT offers patients a reduction in side effects associated with ADT, improved quality of life, and reduced cost with no difference in overall survival. Our previous studies showed that IADT coupled with 5α-reductase inhibitor (5ARI), which blocks testosterone conversion to DHT could prolong survival of animals bearing androgen-sensitive prostate tumors when off-cycle duration was fixed. To further investigate this clinically relevant observation, we measured the time course of testosterone-induced regrowth of regressed LuCaP35 and LNCaP xenograft tumors in the presence or absence of a 5ARI. 5α-Reductase inhibitors suppressed the initial regrowth of regressed prostate tumors. However, tumors resumed growth and were no longer responsive to 5α-reductase inhibition several days after testosterone replacement. This finding was substantiated by bromodeoxyuridine and Ki67 staining of LuCaP35 tumors, which showed inhibition of prostate tumor cell proliferation by 5ARI on day 2, but not day 14, after testosterone replacement. 5α-Reductase inhibitors also suppressed testosterone-stimulated proliferation of LNCaP cells precultured in androgen-free media, suggesting that blocking testosterone conversion to DHT can inhibit prostate tumor cell proliferation via an intracrine mechanism. These results suggest that short off-cycle coupled with 5α-reductase inhibition could maximize suppression of prostate tumor growth and, thus, improve potential survival benefit achieved in combination with IADT.
Subject(s)
5-alpha Reductase Inhibitors/therapeutic use , Prostatic Neoplasms/chemically induced , Prostatic Neoplasms/drug therapy , Testosterone/adverse effects , Animals , Azasteroids/pharmacology , Azasteroids/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Dutasteride , Finasteride/pharmacology , Finasteride/therapeutic use , Humans , Immunohistochemistry , Letrozole , Male , Mice , Mice, Nude , Mice, SCID , Nitriles/pharmacology , Nitriles/therapeutic use , Reverse Transcriptase Polymerase Chain Reaction , Triazoles/pharmacology , Triazoles/therapeutic useABSTRACT
BACKGROUND: Advanced prostate cancer is currently treated with androgen deprivation therapy (ADT). ADT initially results in tumor regression; however, all patients eventually relapse with castration-resistant prostate cancer. New approaches to delay the progression of prostate cancer to castration resistance are in desperate need. This study addresses whether targeting Heat shock protein 90 (HSP90) regulation of androgen receptor (AR) can inhibit prostate cancer progression to castration resistance. METHODS: The HSP90 inhibitor 17-AAG was injected intraperitoneally into nude mice bearing LuCaP35 xenograft tumors to determine the effect of HSP90 inhibition on prostate cancer progression to castration resistance and host survival. RESULTS: Administration of 17-AAG maintained androgen-sensitivity, delayed the progression of LuCaP35 xenograft tumors to castration resistance, and prolonged the survival of host. In addition, 17-AAG prevented nuclear localization of endogenous AR in LuCaP35 xenograft tumors in castrated nude mice. CONCLUSIONS: Targeting Hsp90 or the mechanism by which HSP90 regulates androgen-independent AR nuclear localization and activation may lead to new approaches to prevent and/or treat castration-resistant prostate cancer.
Subject(s)
Benzoquinones/pharmacology , Benzoquinones/therapeutic use , Disease Progression , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Lactams, Macrocyclic/pharmacology , Lactams, Macrocyclic/therapeutic use , Prostatic Neoplasms/drug therapy , Xenograft Model Antitumor Assays , Animals , Cell Line, Tumor , HSP90 Heat-Shock Proteins/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Orchiectomy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Random AllocationABSTRACT
Determining the source of regenerated luminal epithelial cells in the adult prostate during androgen deprivation and replacement will provide insights into the origin of prostate cancer cells and their fate during androgen deprivation therapy. Prostate stem cells in the epithelial layer have been suggested to give rise to luminal epithelium. However, the extent of stem cell participation to prostate regrowth is not clear. In this report, using prostate-specific antigen-CreER(T2)-based genetic lineage marking/tracing in mice, preexisting luminal epithelial cells were shown to be a source of regenerated luminal epithelial cells in the adult prostate. Prostatic luminal epithelial cells could survive androgen deprivation and were capable of proliferating upon androgen replacement. Prostate cancer cells, typically exhibiting a luminal epithelial phenotype, may retain this intrinsic capability to survive and regenerate in response to changes in androgen signaling, providing part of the mechanism for the ultimate failure of androgen deprivation therapy in prostate cancer.
Subject(s)
Epithelial Cells/cytology , Prostate/cytology , Animals , Cell Proliferation/drug effects , Epithelial Cells/metabolism , Male , Mice , Microscopy, Confocal , Microscopy, Fluorescence , Prostate/metabolism , Prostate-Specific Antigen/genetics , Prostate-Specific Antigen/metabolism , Testosterone/pharmacologyABSTRACT
BACKGROUND: Intermittent androgen deprivation therapy (IADT) was developed to improve the quality of life and retard prostate cancer progression to castration resistance. IADT involves regrowth of the tumor during the off cycle upon testosterone recovery. Our previous studies showed that testosterone is more potent than dihydrotestosterone (DHT) in the induction of a subset of androgen-responsive genes during rat prostate regrowth. However, it is not clear if the same phenomenon would occur during androgen-induced regrowth of prostate tumors. Understanding the differences between testosterone and DHT in inducing androgen-responsive genes during prostate tumor regrowth may provide new insight for improving IADT. METHODS: Nude mice bearing androgen-sensitive LNCaP xenograft were castrated and followed up for 7-10 days before being randomized into various androgen manipulations, consisting of continuous castration (C) or testosterone replacement (T) in the absence or presence of dutasteride (D), a 5alpha-reductase inhibitor that blocks the conversion of testosterone to DHT. Testes-intact animals in the absence or presence of D were used as controls. The expression of five androgen-responsive genes, including the tumor suppressor U19/Eaf2, was determined using real-time RT-PCR, 3 days after randomization. RESULTS: In LNCaP tumors, the expression of U19/Eaf2 was higher in the T+D group as compared with T alone (2.87-fold, P < 0.05). In contrast, dutasteride treatment in testes-intact animals inhibited the expression of U19/Eaf2. CONCLUSIONS: Inhibition of 5alpha-reductase during LNCaP tumor regrowth enhanced the expression of U19/Eaf2, an androgen-regulated tumor suppressor. This finding suggests that off cycle 5alpha-reductase inhibition may enhance the efficacy of IADT.
Subject(s)
Cholestenone 5 alpha-Reductase/antagonists & inhibitors , Nuclear Proteins/genetics , Prostatic Neoplasms/enzymology , Testosterone/pharmacology , Trans-Activators/genetics , Tumor Suppressor Proteins/genetics , Androgens/deficiency , Animals , Azasteroids/pharmacology , Cell Division/drug effects , Dihydrotestosterone/metabolism , Dutasteride , Enzyme Inhibitors/pharmacology , Finasteride/pharmacology , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Mice, Nude , Neoplasm Transplantation , Orchiectomy , Prostate-Specific Antigen/blood , Prostate-Specific Antigen/genetics , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Reverse Transcriptase Polymerase Chain Reaction , Testosterone/metabolism , Transplantation, HeterologousABSTRACT
BACKGROUND: We have previously reported that finasteride administration in intermittent androgen deprivation therapy (IADT) can improve survival of nude mice bearing LNCaP xenograft tumors when the duration of off-cycle in IADT was fixed. A recent retrospective study showed that addition of finasteride doubled the duration of the off-cycle, without changing progression to castration resistance. In view of the above difference, we attempted to investigate the relationship of 5alpha-reductase inhibition with the off-cycle interval and overall survival in a murine model. METHODS: Subcutaneous LNCaP tumors were established in nude mice (Balb/C-Nu). After the tumors reached a size of 0.5 cm in diameter, the mice were castrated and followed up for 2 weeks after which they were randomized to continuous androgen deprivation (CAD), CAD plus finasteride, IADT, and IADT plus finasteride. The off-cycle was discontinued when the tumor volume was doubled. Subsequent cycles were carried out similarly. RESULTS: Use of finasteride during the off-cycle of IADT doubled the first off-cycle duration. However, prolongation of the off-cycle by finasteride did not translate into an increase in overall survival. CONCLUSIONS: The survival advantage of IADT + finasteride over IADT that we previously reported was lost when the off-cycle prolongation by finasteride was allowed. Maximum possible lengthening of the off-cycle by 5alpha-reductase inhibition is not associated with survival improvement in this animal model.