Effect of selinexor (KPT-330), a novel oral selective inhibitor of nuclear export (SINE), on tumor suppressors and cell cycle proteins in prostate cancer cells and regression of castration-resistant patient-derived xenograft tumor growth
| العنوان: | Effect of selinexor (KPT-330), a novel oral selective inhibitor of nuclear export (SINE), on tumor suppressors and cell cycle proteins in prostate cancer cells and regression of castration-resistant patient-derived xenograft tumor growth |
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| المؤلفون: | Sharon Shacham, Ana Aparicio, Jing-Fang Lu, Christopher J. Logothetis, Tami Rashal, Yosef Landesman, Dilara McCauley, Guanglin Wu, Keith A. Baggerly, Sankar N. Maity, John C. Araujo, Eleni Efstathiou, Robert W. Carlson, Bradley M. Broom, Anh Hoang |
| المصدر: | Journal of Clinical Oncology. 33:277-277 |
| بيانات النشر: | American Society of Clinical Oncology (ASCO), 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Cancer Research, medicine.medical_specialty, medicine.drug_class, Biology, urologic and male genital diseases, medicine.disease, Androgen, law.invention, XPO1, Prostate cancer, Endocrinology, Oncology, Cell culture, Exportin-1, law, Internal medicine, medicine, Cancer research, Suppressor, Cell Cycle Protein, Nuclear export signal |
| الوصف: | 277 Background: Androgen deprivation, anti-androgen and androgen biosynthesis inhibitor treatment can initially control the metastatic prostate cancer (PCa), but treatment-refractory progression frequently follows, with the loss of tumor suppressors (TSPs) and increased expression of cell cycle proteins. Inhibition of the nuclear export protein, Exportin 1 (XPO1) leads to nuclear accumulation of cargo proteins such as TSPs & cell-cycle regulators implicated in castration-resistant PCa (CRPC) progression. XPO1 and specific cargo genes are overexpressed in metastatic CRPC relative to benign & primary prostate tumors, implicating XPO1 activity as playing a role in disease progression. Selinexor (KPT-330), a novel, oral SINE currently in Phase 1/2 for both hematological and solid tumors, has potent activity against CRPC. We hypothesized this activity is due selinexor induced nuclear expression of TSPs. Methods: To test this hypothesis, we treated selected PCa cell lines and patient-derived xenografts (PDXs, two adenocarcinomas and one small cell carcinonoma) with selinexor to determine the effect on survival and cargo protein localization. Results: Treatment with selinexor markedly inhibited PCa cell proliferation in vitro, activated the tumor suppressor TP53 & inhibited cell-cycle regulators. Also, treatment of the PDXs with selinexor for at least 3 weeks significantly inhibited tumor growth & reduced the prostate-specific antigen level in the adenocarcinomas. Selinexor increased cell death in all three PDX tumors and reduced cell proliferation in the adenocarcinomas, but not in the small-cell tumor. Expression analyses demonstrated that selinexor induced nuclear accumulation of different cargo proteins unique to the PCa model, accounting for PDX-specific regression. Conclusions: These results point to an anti-tumorigenic effect of selinexor treatment across a spectrum of hormone-refractory PCa that may provide insight into the drivers of PCa treatment resistance and heterogeneity. |
| تدمد: | 1527-7755 0732-183X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::ece1a98b0fb508803463762b067492dcTest https://doi.org/10.1200/jco.2015.33.7_suppl.277Test |
| رقم الانضمام: | edsair.doi...........ece1a98b0fb508803463762b067492dc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15277755 0732183X |
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