Extracellular Matrix Composition Modulates the Responsiveness of Differentiated and Stem Pancreatic Cancer Cells to Lipophilic Derivate of Gemcitabine
| العنوان: | Extracellular Matrix Composition Modulates the Responsiveness of Differentiated and Stem Pancreatic Cancer Cells to Lipophilic Derivate of Gemcitabine |
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| المؤلفون: | Elisa Dalla Pozza, Massimo Donadelli, Giulia Ambrosini, Cristian Andres Carmona-Carmona, Daria Di Molfetta, Ilaria Dando, Stefania Forciniti, Raffaella Pacchiana, Stephan J. Reshkin, Maria Raffaella Greco, Marta Palmieri, Rosa Angela Cardone, Tiago M.A. Carvalho, Barbara Rolando, Silvia Arpicco |
| المصدر: | International Journal of Molecular Sciences, Vol 22, Iss 29, p 29 (2021) International Journal of Molecular Sciences Volume 22 Issue 1 |
| بيانات النشر: | MDPI AG, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, cancer stem cells, endocrine system diseases, Apoptosis, Deoxycytidine, lcsh:Chemistry, 0302 clinical medicine, Cytotoxic T cell, Prodrugs, lcsh:QH301-705.5, Spectroscopy, Chemistry, gemcitabine, chemoresistance, Cell Differentiation, General Medicine, 3D organotypic cultures, extracellular matrix, pancreatic ductal adenocarcinoma, prodrug, 3. Good health, Computer Science Applications, Drug Combinations, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Proteoglycans, Collagen, Intracellular, Carcinoma, Pancreatic Ductal, Catalysis, Collagen Type I, Article, Inorganic Chemistry, 03 medical and health sciences, Organ Culture Techniques, Cancer stem cell, Pancreatic cancer, Cell Line, Tumor, medicine, Autophagy, Humans, Physical and Theoretical Chemistry, Molecular Biology, Matrigel, Organic Chemistry, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Cell culture, Drug Resistance, Neoplasm, Cancer research, Laminin |
| الوصف: | Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Gemcitabine (GEM) is used as the gold standard drug in PDAC treatment. However, due to its poor efficacy, it remains urgent to identify novel strategies to overcome resistance issues. In this context, an intense stroma reaction and the presence of cancer stem cells (CSCs) have been shown to influence PDAC aggressiveness, metastatic potential, and chemoresistance. Methods: We used three-dimensional (3D) organotypic cultures grown on an extracellular matrix composed of Matrigel or collagen I to test the effect of the new potential therapeutic prodrug 4-(N)-stearoyl-GEM, called C18GEM. We analyzed C18GEM cytotoxic activity, intracellular uptake, apoptosis, necrosis, and autophagy induction in both Panc1 cell line (P) and their derived CSCs. Results: PDAC CSCs show higher sensitivity to C18GEM treatment when cultured in both two-dimensional (2D) and 3D conditions, especially on collagen I, in comparison to GEM. The intracellular uptake mechanisms of C18GEM are mainly due to membrane nucleoside transporters&rsquo expression and fatty acid translocase CD36 in Panc1 P cells and to clathrin-mediated endocytosis and CD36 in Panc1 CSCs. Furthermore, C18GEM induces an increase in cell death compared to GEM in both cell lines grown on 2D and 3D cultures. Finally, C18GEM stimulated protective autophagy in Panc1 P and CSCs cultured on 3D conditions. Conclusion: We propose C18GEM together with autophagy inhibitors as a valid alternative therapeutic approach in PDAC treatment. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1661-6596 1422-0067 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::27e54dceefe65e08c338cfce1ebb8c8fTest https://www.mdpi.com/1422-0067/22/1/29Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....27e54dceefe65e08c338cfce1ebb8c8f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16616596 14220067 |
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