An in vitro model for preclinical testing of endocrine therapy combinations for prostate cancer.
BACKGROUND
Even though patients with prostate cancer commonly respond to endocrine treatment, in most cases the disease progresses to castration resistant prostate cancer (CRPC). Our objective was to generate a novel cell line model representing the endocrine treatment naive prostate cancer for testing treatments that target the androgen receptor (AR) and androgen metabolism.


METHODS
After culturing DuCaP cells 20 passages with additional 1 nM R1881, DuCaP-N(aive) cell line was developed and validated for testing endocrine therapy combinations. Cell viability, apoptosis and cell cycle distribution were assessed in DuCaP and DuCaP-N when interfering with the hormonal content.


RESULTS
Addition of 1 nM R1881 to DuCaP reduces cell viability and induces cell cycle inhibition and apoptosis. Eventually, an androgen accustomed DuCaP-N cell line developed. An antiandrogen (bicalutamide), a histone deacetylase (HDAC) inhibitor (trichostatin A) and a 5alpha-reductase (SRD5A) inhibitor (finasteride) reduce cell viability, and their combinations give a synergistic response in inducing apoptosis.


CONCLUSIONS
The TMPRSS2-ERG expressing DuCaP-N cell line represents human prostate cancer prior to endocrine treatment, and its parental DuCaP cell line is a model for CRPC. These cell lines can be used for preclinical evaluation of compounds that target the androgenic pathway.
Pfeiffer
Minja J
MJ
Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Mulders
Peter F
PF
Schalken
Jack A
JA
D000726:Androgen Antagonists / Q000627:therapeutic use*; D000728:Androgens / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D017931:DNA Primers; D018450:Disease Progression; D018120:Finasteride / Q000627:therapeutic use*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016133:Polymerase Chain Reaction / Q000379:methods; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D013256:Steroids / Q000627:therapeutic use
D000726:Androgen Antagonists; D000728:Androgens; D017931:DNA Primers; D012333:RNA, Messenger; D013256:Steroids; D018120:Finasteride; D002786:Cholesterol Side-Chain Cleavage Enzyme; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human