کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
8456938 1548787 2017 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Trabectedin and Campthotecin Synergistically Eliminate Cancer Stem Cells in Cell-of-Origin Sarcoma Models
ترجمه فارسی عنوان
ترابکتین و کمپوتوتین سلول های بنیادی سرطانی را در سلول های سرکومای سلولی از بین می برد
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
چکیده انگلیسی
Trabectedin has been approved for second-line treatment of soft tissue sarcomas. However, its efficacy to target sarcoma initiating cells has not been addressed yet. Here, we used pioneer models of myxoid/round cell liposarcoma (MRCLS) and undifferentiated pleomorphic sarcoma (UPS) developed from transformed human mesenchymal stromal/stem cells (MSCs) to evaluate the effect of trabectedin in the cell type responsible for initiating sarcomagenesis and their derived cancer stem cells (CSC) subpopulations. We found that low nanomolar concentrations of trabectedin efficiently inhibited the growth of sarcoma-initiating cells, induced cell cycle arrest, DNA damage and apoptosis. Interestingly, trabectedin treatment repressed the expression of multiple genes responsible for the development of the CSC phenotype, including pluripotency factors, CSC markers and related signaling pathways. Accordingly, trabectedin induced apoptosis and reduced the survival of CSC-enriched tumorsphere cultures with the same efficiency that inhibits the growth of bulk tumor population. In vivo, trabectedin significantly reduced the mitotic index of MRCLS xenografts and inhibited tumor growth at a similar extent to that observed in doxorubicin-treated tumors. Combination of trabectedin with campthotecin (CPT), a chemotherapeutic drug that shows a robust anti-tumor activity when combined with alkylating agents, resulted in a very strong synergistic inhibition of tumor cell growth and highly increased DNA damage and apoptosis induction. Importantly, the enhanced anti-tumor activity of this combination was also observed in CSC subpopulations. These data suggest that trabectedin and CPT combination may constitute a novel strategy to effectively target both the cell-of-origin and CSC subpopulations in sarcoma.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neoplasia - Volume 19, Issue 6, June 2017, Pages 460-470
نویسندگان
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