Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR
| العنوان: | Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR |
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| المؤلفون: | Olga Goloubeva, Angela Brodie, G Sabnis, Vincent C. O. Njar, A Schayowitz |
| المصدر: | British Journal of Cancer |
| بيانات النشر: | Springer Science and Business Media LLC, 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Male, Cancer Research, anti-androgens, Mice, SCID, urologic and male genital diseases, signal transduction inhibitors, Tosyl Compounds, Mice, Prostate cancer, 0302 clinical medicine, androgen receptor, Anilides, Androgen Receptor Antagonists, 0303 health sciences, TOR Serine-Threonine Kinases, Intracellular Signaling Peptides and Proteins, 3. Good health, Oncology, 030220 oncology & carcinogenesis, mTOR, Disease Progression, Drug Therapy, Combination, cross-talk, Signal Transduction, medicine.drug, medicine.medical_specialty, Neoplasms, Hormone-Dependent, Bicalutamide, Protein Serine-Threonine Kinases, Biology, 03 medical and health sciences, Cell Line, Tumor, Internal medicine, Nitriles, LNCaP, medicine, Animals, Castration, Everolimus, PI3K/AKT/mTOR pathway, 030304 developmental biology, Sirolimus, Prostatic Neoplasms, Androgen Antagonists, Receptor Cross-Talk, Prostate-Specific Antigen, medicine.disease, Xenograft Model Antitumor Assays, Androstadienes, Androgen receptor, Endocrinology, Cancer research, Benzimidazoles, Translational Therapeutics |
| الوصف: | Background: To determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer (PCa), we investigated the relationship between the androgen receptor (AR) and mTOR pathways and the impact of inhibiting both pathways in androgen-dependent and castration-resistant PCa models. Experimental design: Androgen-dependent (LNCaP) and castration-resistant PCa (HP-LNCaP) cells were grown as tumours in SCID mice. Once tumours reached 500 mm3, animals were grouped and injected subcutaneous with vehicle, our novel anti-androgen/androgen synthesis inhibitor, VN/124-1, bicalutamide, and everolimus. Tumour volumes were measured biweekly. The PSA and protein analyses were performed after completion of the treatment. Results: The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes. Anti-androgen treatment also increased protein expression of multiple signal transduction pathways earlier than vehicle-treated control xenografts. VN/124-1 plus everolimus acted in concert to reduce tumour growth rates in our castration-resistant xenograft model. Conclusions: This study suggests that dual inhibition of AR and mTOR in castration-resistant xenograft models can restore sensitivity of tumours to anti-androgen therapy. Furthermore, after bicalutamide failure, dual inhibition with VN/124-1 and everolimus was the most effective treatment. |
| تدمد: | 1532-1827 0007-0920 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::214f82216f6fdd7fcb6b51dbb80c988aTest https://doi.org/10.1038/sj.bjc.6605882Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....214f82216f6fdd7fcb6b51dbb80c988a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15321827 00070920 |
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