Downregulation of MDR 1 gene contributes to tyrosine kinase inhibitor induce apoptosis and reduction in tumor metastasis: A gravity to space investigation
| Autor: | Harshavardhan Janga, Shashank Reddy Pinnapireddy, Uzma Ali, Imran Tariq, Sajid Ali, Muhammad Yasir Ali, Jens Schäfer, Ghazala Ambreen, Udo Bakowsky, Muhammad Umair Amin, Leon N. Schulte |
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| Rok vydání: | 2020 |
| Předmět: |
Small interfering RNA
medicine.drug_class Down-Regulation Pharmaceutical Science Apoptosis 02 engineering and technology 030226 pharmacology & pharmacy Tyrosine-kinase inhibitor 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Humans Gene silencing RNA Small Interfering Protein Kinase Inhibitors Gene knockdown Chemistry 021001 nanoscience & nanotechnology Multiple drug resistance Imatinib mesylate Drug Resistance Neoplasm Tumor progression Cancer research Caco-2 Cells Lipid modification 0210 nano-technology |
| Zdroj: | International Journal of Pharmaceutics. 591:119993 |
| ISSN: | 0378-5173 |
| DOI: | 10.1016/j.ijpharm.2020.119993 |
| Popis: | P-glycoprotein (P-gp) associated multidrug resistance (MDR) represents a major failure in cancer treatment. The overexpression of P-gp is responsible for ATP-dependent efflux of drugs that decrease their intracellular accumulation. An effective downregulation of MDR1 gene using small interfering RNA (siRNA) is one of the safe and effective tools to overcome the P-gp triggered MDR. Therefore, the development of an efficient and non-toxic carrier system for siRNA delivery is a fundamental challenge for effective cancer treatment. Polyamidoamine (PAMAM) dendrimer has been used for efficient delivery of siRNA (dendriplexes) to the tumor cells but the associated toxicity problems render its use in biological applications. A non-covalent lipid modification (lipodendriplexes) is supposed to offer a promising strategy to overcome the demerits linked to the naked dendriplexes system. In the current study, we deliver siRNA, designed against MDR1 gene (si-MDR1), in colorectal carcinoma cells (Caco-2), having overexpression of P-gp, to check the role of MDR1 gene in tumor progression and multidrug resistance using two dimensional (2D) and three dimensional (3D) environment. Imatinib mesylate (IM), a P-gp substrate, was used as model drug. Our results revealed that the effective knockdown by lipodendriplexes system can significantly reduce the tumor cell migration in 2D (p 0.001) and 3D (p 0.001) cell cultures as compared to unmodified dendriplexes and si-Control groups. It was also observed that lipodendriplexes aided downregulation of MDR1 gene effectively, re-sensitized the Caco-2 cells for IM uptake and showed a significantly (p 0.001) higher apoptosis. Our findings imply that our lipodendriplexes system has a great potential for siRNA delivery, however, further in vivo application using a suitable targeted system can play a major role for better cancer therapeutics. |
| Databáze: | OpenAIRE |
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