Effect of small inhibitors of nuclear export (SINE) on growth inhibition and apoptosis of human melanoma cells
| العنوان: | Effect of small inhibitors of nuclear export (SINE) on growth inhibition and apoptosis of human melanoma cells |
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| المؤلفون: | Jean-Richard Saint-Martin, Gregory B. Lesinski, Matthew A. Bill, William Senapedis, Jennifer Yang, Kari Kendra, Sharon Shacham, Yosef Landesman, Trinayan Kashyap, Michael Kauffman |
| المصدر: | Journal of Clinical Oncology. 30:e13549-e13549 |
| بيانات النشر: | American Society of Clinical Oncology (ASCO), 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Cancer Research, Biology, Molecular biology, law.invention, XPO1, chemistry.chemical_compound, Oncology, chemistry, law, Exportin-1, Apoptosis, Cancer research, Suppressor, Human melanoma, Growth inhibition, Nuclear export signal |
| الوصف: | e13549 Background: Inhibition of nuclear export can promote re-activation of tumor suppressor pathways. CRM1 (chromosomal regional maintenance 1) or XPO1 (exportin 1) is the major protein that mediates nuclear export. We hypothesized that CRM1 mediated nuclear export represents a novel therapeutic target that can be manipulated to inhibit melanoma cell survival. Methods: The growth inhibitory and pro-apoptotic effects of KPT-185, KPT-276 and KPT-330, small molecules selective inhibitor of nuclear export (SINE) were evaluated in human melanoma cell lines using an MTT assay and Annexin V/PI staining, respectively. Fluorescence microscopy and immunoblots were used to assess nuclear accumulation of tumor suppressor proteins. The trans-isomer of KPT-185 and DMSO (vehicle) were used as a negative controls in all assays. The pharmacokinetic (PK) profile of all compounds was evaluated in mice. Results: CRM1 protein was highly expressed in human melanoma cell lines with diverse molecular profiles (i.e., B-Raf, NRAS, p53). KPT-SINE inhibited melanoma cell growth in a concentration-dependent manner and induced apoptosis at nanomolar concentrations. Importantly, there was no evidence that B-Raf V600 mutational status influenced melanoma cell response to these agents. Nuclear accumulation and/or induction of p53, p21, FOXO3a, STAT1 and BAD, and reduction of MCL-1 occurred in melanoma cells at time points prior to apoptosis as shown by increase in cleaved PARP and caspase 3 levels. PK studies were conducted in mice following oral administration of 10 mg/kg, to guide drug selection for our ongoing efficacy studies in murine melanoma models. KPT-185 showed limited bioavailability and systemic exposure, while KPT-276 and KPT-330 showed >50% bioavailability reaching Cmax >5µM. Conclusions: This study represents the first report of CRM1 inhibition in melanoma. These data indicate that the novel SINE compounds can effectively inhibit CRM1-mediated nuclear export and induce apoptosis in melanoma cells. KPT-330 is currently under development as orally bioavailable, small molecule inhibitors for a human clinical trial. |
| تدمد: | 1527-7755 0732-183X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::ec23cc9a1e202c769bb554363ed8a39aTest https://doi.org/10.1200/jco.2012.30.15_suppl.e13549Test |
| رقم الانضمام: | edsair.doi...........ec23cc9a1e202c769bb554363ed8a39a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15277755 0732183X |
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