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Mol Cell Endocrinol ; 365(1): 95-107, 2013 Jan 05.
Article in English | MEDLINE | ID: mdl-23063623

ABSTRACT

Prostate cancer growth depends on androgens. Synthetic antiandrogens are used in the cancer treatment. However, antiandrogens, such as bicalutamide (BIC), have a mixed agonist/antagonist activity. Here we compare the antiandrogenic capacity of BIC to a new antiandrogen, MDV3100 (MDV) or Enzalutamide™. By reconstitution of a hormone-regulated enhancer in Xenopus oocytes we show that both antagonists trigger the androgen receptor (AR) translocation to the nucleus, albeit with a reduced efficiency for MDV. Once in the nucleus, both AR-antagonist complexes can bind sequence specifically to DNA in vivo. The forkhead box transcription factor A (FoxA1) is a negative prognostic indicator for prostate cancer disease. FoxA1 expression presets the enhancer chromatin and makes the DNA more accessible for AR binding. In this context the BIC-AR antiandrogenic effect is seriously compromised as demonstrated by a significant chromatin remodeling and induction of a robust MMTV transcription whereas the MDV-AR complex displays a more persistent antagonistic character.


Subject(s)
Anilides/pharmacology , Antineoplastic Agents, Hormonal/pharmacology , Hepatocyte Nuclear Factor 3-alpha/metabolism , Neoplasm Proteins/metabolism , Nitriles/pharmacology , Nonsteroidal Anti-Androgens/pharmacology , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms/drug therapy , Tosyl Compounds/pharmacology , Anilides/adverse effects , Anilides/metabolism , Animals , Antineoplastic Agents, Hormonal/adverse effects , Antineoplastic Agents, Hormonal/metabolism , Benzamides , Cell Line, Tumor , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Chromatin Assembly and Disassembly/drug effects , Female , HEK293 Cells , Hepatocyte Nuclear Factor 3-alpha/antagonists & inhibitors , Hepatocyte Nuclear Factor 3-alpha/genetics , Humans , Male , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Nitriles/adverse effects , Nitriles/metabolism , Nonsteroidal Anti-Androgens/adverse effects , Nonsteroidal Anti-Androgens/metabolism , Oocytes/cytology , Oocytes/drug effects , Oocytes/metabolism , Phenylthiohydantoin/metabolism , Phenylthiohydantoin/pharmacology , Prostate/drug effects , Prostate/metabolism , Prostate/pathology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Protein Transport/drug effects , RNA Interference , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Tosyl Compounds/adverse effects , Tosyl Compounds/metabolism , Xenopus laevis
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