Nevirapine restores androgen signaling in hormone-refractory human prostate carcinoma cells both in vitro and in vivo
| Autor: | Annamaria Piscazzi, Gigliola Sica, Cinzia Bagalà, Michela Quirino, Annarita Fabiano, Carlo Barone, Matteo Landriscina, Alessandra Cassano, Giovanni Schinzari, Sara Bianchetti |
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| Rok vydání: | 2009 |
| Předmět: |
Male
medicine.medical_specialty Neoplasms Hormone-Dependent Bicalutamide medicine.drug_class Urology Mice Nude Cell Growth Processes Docetaxel Biology Tosyl Compounds Androgen deprivation therapy Mice Random Allocation Prostate cancer Cell Movement Cell Line Tumor Internal medicine Nitriles Androgen Receptor Antagonists medicine Animals Humans Anilides Nevirapine RNA Neoplasm Prostatic Neoplasms Androgen Antagonists Cell Differentiation Dihydrotestosterone Drug Synergism medicine.disease Androgen Xenograft Model Antitumor Assays Androgen receptor Endocrinology Oncology Receptors Androgen Tumor progression Cancer research Reverse Transcriptase Inhibitors Taxoids Signal Transduction medicine.drug |
| Zdroj: | The Prostate. 69:744-754 |
| ISSN: | 1097-0045 0270-4137 |
| Popis: | 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. METHODS AND 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. Prostate 69: 744–754, 2009. © 2009 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
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