Multidrug resistant P-glycoprotein positive L1210/VCR cells are also cross-resistant to cisplatin via a mechanism distinct from P-glycoprotein-mediated drug efflux activity
| Autor: | Martina Labudova, Albert Breier, Miroslav Barancik, Lenka Gibalová, Jan Sedlak, Zdena Sulova, Alena Reháková |
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| Rok vydání: | 2009 |
| Předmět: |
Cytoplasm
Physiology Biophysics Apoptosis DNA Fragmentation Pharmacology Mice Necrosis chemistry.chemical_compound Annexin Cell Line Tumor medicine Animals ATP Binding Cassette Transporter Subfamily B Member 1 Propidium iodide bcl-2-Associated X Protein P-glycoprotein Cisplatin biology Apoptotic DNA fragmentation Cytochromes c General Medicine Cell cycle Molecular biology Drug Resistance Multiple Protein Transport Proto-Oncogene Proteins c-bcl-2 chemistry Drug Resistance Neoplasm Vincristine biology.protein L1210 cells medicine.drug |
| Zdroj: | General Physiology and Biophysics. 28:391-403 |
| ISSN: | 0231-5882 |
| DOI: | 10.4149/pb_2009_04_391 |
| Popis: | P-glycoprotein (P-gp, a drug transporter found in the plasma membrane)-mediated multidrug resistance of leukemia cells represents a real obstacle in the effective chemotherapeutic treatment of leukemia. While cisplatin (CisPt) is known to be a substance that is untransportable by P-gp, P-gp positive cells were often found to be resistant to CisPt. The aim of the current paper is to study this phenomenon using P-gp positive mouse leukemia cells L1210/VCR in which the overexpression of P-gp was induced by its ability to adapt to growth on vincristine (VCR). L1210/VCR cells are also resistant to CisPt. However, resistance to this substance could not be reversed by addition of the known P-gp inhibitor verapamil. CisPt induced more pronounced entry into apoptosis, as measured using the annexin V/propidium iodide kit, in sensitive L1210 cells than in resistant L1210/VCR cells. In addition, CisPt induced an increase in the proportion of L1210 cells that were in the g2 phase of the cell cycle when compared to L1210/VCR cells, as measured by staining with propidium iodide. Similarly, a higher release of cytochrome c from the mitochondria to the cytosol was induced by CisPt treatment in L1210 than in L1210/VCR cells. While similar levels of Bax and Bcl-2 proteins were observed in sensitive and resistant cells, CisPt induced a more pronounced decrease of the Bcl-2 levels in L1210 cells than in L1210/VCR cells. Consistent with this observation, CisPt induced a larger decrease of the Bcl-2 content in the Bcl-2:Bax heterooligomer in L1210 cells than in L1210/VCR cells. Moreover, CisPt induced a similar apoptotic DNA fragmentation pattern in both resistant and sensitive cells. All of the above observations indicated that L1210/VCR cells are also resistant to CisPt and that this resistance is related to the differences in the regulatory mechanisms responsible for CisPt-induced apoptosis in L1210/VCR cells without any contribution from the drug efflux activity of P-gp. |
| Databáze: | OpenAIRE |
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