Extracellular Matrix Composition Modulates the Responsiveness of Differentiated and Stem Pancreatic Cancer Cells to Lipophilic Derivate of Gemcitabine

Autor: 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
Jazyk: angličtina
Rok vydání: 2021
Předmět:
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
Zdroj: International Journal of Molecular Sciences, Vol 22, Iss 29, p 29 (2021)
International Journal of Molecular Sciences
Volume 22
Issue 1
ISSN: 1661-6596
1422-0067
Popis: 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.
Databáze: OpenAIRE
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