Nevirapine restores androgen signaling in hormone-refractory human prostate carcinoma cells both in vitro and in vivo.
BACKGROUND
Prostate carcinomas are androgen-dependent neoplasms which progress toward a hormone-independent phenotype during hormone-deprivation therapy. We evaluated nevirapine, a reverse transcriptase inhibitor, as a new treatment in hormone-refractory prostate carcinoma cells with the aim of restoring the androgen-dependency of tumor cells, the rationale being that endogenous reverse transcriptase is up-regulated in transformed cells and reverse transcriptase inhibitors exert a differentiating activity in human tumors.


RESULTS
Nevirapine induced extensive reprogramming of gene expression in vitro with up-regulation of genes that might be silenced during prostate tumor progression (i.e., K18, PSA and androgen receptor) and down-regulation of genes involved in the progression toward an androgen-independent phenotype (i.e., K5, EGFR1, EGF and VEGF-A). Furthermore, nevirapine down-regulated the growth of prostate carcinoma xenografts in athymic mice and induced a differentiated phenotype in vivo with increased K18 expression. Interestingly, the drug restored androgen signaling by enhancing the ability of tumor cells to respond to dihydrotestosterone stimulation and to the antiproliferative activity of the androgen receptor blocker bicalutamide. Finally, nevirapine pretreatment increased the susceptibility of tumor cells to docetaxel, by enhancing their ability to undergo apoptosis.


CONCLUSIONS
These data suggest that nevirapine may be clinically tested in human hormone-refractory prostate carcinoma to restore the susceptibility to androgen deprivation therapy or to docetaxel.
Landriscina
Matteo
M
Clinical Oncology Unit, Department of Medical Sciences, University of Foggia, Viale Pinto, Foggia, Italy.
Bagalà
Cinzia
C
Piscazzi
Annamaria
A
Schinzari
Giovanni
G
Quirino
Michela
M
Fabiano
Annarita
A
Bianchetti
Sara
S
Cassano
Alessandra
A
Sica
Gigliola
G
Barone
Carlo
C
D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D000077143:Docetaxel; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D019829:Nevirapine / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
C410798:AR protein, human; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D009570:Nitriles; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; D018894:Reverse Transcriptase Inhibitors; D043823:Taxoids; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; D000077143:Docetaxel; D019829:Nevirapine; C053541:bicalutamide