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In vitro glioblastoma model of multi-drug resistance as a tool for the development of new therapeutic strategies

Ana Podolski-Renić, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia; Jasna Banković, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia; Tijana Stanković, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia; Jelena Dinić, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia; María R. Durán, Universidad de Cadiz, Espana; Arturo Álvarez-Arenas, Universidad de Castilla-La Mancha, Espana; Juan Belmonte-Beitia, Universidad de Castilla-La Mancha, Espana; Alicia Martínez-González, Universidad de Castilla-La Mancha, Espana; Sonja Stojković, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia; Zorica Milošević, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia; Víctor M. Pérez García, Universidad de Castilla-La Mancha, Espana; Milica Pešić, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia;


Multi-drug resistance (MDR) is the main limitation for the accomplishment of successful cancer treatment. MDR phenotype often relates to the over-expression of P-glycoprotein (P-gp), a membrane transporter that effectively extrudes the cytotoxic drugs from cancer cells and changes their pharmacokinetics. In addition, P-gp is expressed in physiological CNS barrier where it prevents penetration of systemically delivered molecules and limits treatment of brain malignancies. Therefore, P-gp is considered as therapeutic target for overcoming MDR in glioblastomas.
The discovery of new lead compounds that could abrogate or overcome the MDR grew rapidly in the last two decades and still emerges. In vitro models such as resistant cancer cell lines are required and necessary for translational studies of cellular properties impaired after cytotoxic drug treatment. Their contribution to anti-cancer drug development is also very important. Therefore, we established new MDR glioblastoma cell line – U87-TxR. The induction of resistance led to the significant molecular and cytogenetic changes in U87-TxR cells: induction of P-gp expression and activity, inactivation of p53 and polyploidy reduction. Mathematical models based on global populations (ordinary differential equations), local competition of the populations (partial differential equations) and incorporating the diffusion of factors conferring resistances were used to assess changes in growth properties, induction and transfer of MDR characteristics among parental U87, MDR U87-TxR cells and their mixed culture.

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