Modulation of cisplatin cytotoxicity by permeabilization of the plasma membrane by digitonin in vitro
| Autor: | D. R. Shalinsky, Antti P. Jekunen, Dennis D. Heath, Stephen B. Howell, Kathy D. Albright, Doreen K. Hom |
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| Rok vydání: | 1993 |
| Předmět: |
Cell Membrane Permeability
Organoplatinum Compounds endocrine system diseases Detergents Cell Antineoplastic Agents Digitonin Biology Tritium Sensitivity and Specificity Biochemistry Flow cytometry chemistry.chemical_compound Tumor Cells Cultured medicine Humans Cytotoxicity Ovarian Neoplasms Pharmacology Cisplatin Cell Death medicine.diagnostic_test Cell Membrane Drug Synergism DNA Neoplasm respiratory system Flow Cytometry Molecular biology In vitro medicine.anatomical_structure Membrane chemistry Toxicity Female medicine.drug |
| Zdroj: | Biochemical Pharmacology. 45:2079-2085 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/0006-2952(93)90019-s |
| Popis: | Killing of human ovarian carcinoma 2008 cells by cisplatin (DDP) is in direct proportion to the amount of drug entering the cell. DDP and its analogue [3H]dichloro(ethylenediamine)platinum[II] ([3H]-DEP) enter cells relatively slowly. We found that the uptake of [3H]DEP into 2008 cells could be increased by treating the cells briefly with the plasma membrane-selective detergent digitonin. A similar effect was observed in an 11-fold DDP-resistant subline of 2008 cells, designated 2008/C13*5.25. A measurable effect was produced by concentrations as low as 5 microM, and 40 microM digitonin increased [3H]DEP accumulation at 1 hr by 4.4 +/- 0.2- and 6.5 +/- 0.7-fold (means +/- SD) in 2008 and 2008/C13*5.25 cells, respectively. The effect was rapid, occurring within 1 min. Increased [3H]DEP uptake was accompanied by increased platination of DNA (8.5-fold in 2008 cells and 18.5-fold in 2008/C13*5.25 cells), and by enhanced killing of both the DDP-sensitive and -resistant cells that was shown to be synergistic by median effect analysis. The combination index at 50% cell kill was 0.64 +/- 0.14 (values < 1 indicate synergy). We conclude that a brief exposure to digitonin can increase [3H]DEP uptake in vitro, and can overcome the impaired [3H]DEP accumulation associated with acquired DDP resistance. DDP and digitonin interact synergistically to increase tumor cell kill in vitro. |
| Databáze: | OpenAIRE |
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