A targeted enzyme approach to sensitization of tyrosine kinase inhibitor-resistant breast cancer cells
| Autor: | Kelly L. Mueller, Courtney R. Giordano, Laura J. Terlecky, Kendra A. Krentz, Stanley R. Terlecky, Julie L. Boerner, Aliccia Bollig-Fischer |
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| Rok vydání: | 2012 |
| Předmět: |
Cell Membrane Permeability
medicine.drug_class Cell Survival Antineoplastic Agents Breast Neoplasms Biology Tyrosine-kinase inhibitor Article Breast cancer Gefitinib Cell Line Tumor medicine Humans Epidermal growth factor receptor Phosphorylation skin and connective tissue diseases Protein Kinase Inhibitors EGFR inhibitors Cancer Cell Biology medicine.disease Catalase respiratory tract diseases ErbB Receptors Gene Expression Regulation Neoplastic Drug Resistance Neoplasm Cancer research biology.protein Quinazolines Female Signal transduction Reactive Oxygen Species Tyrosine kinase medicine.drug Signal Transduction |
| Zdroj: | Experimental cell research. 318(16) |
| ISSN: | 1090-2422 |
| Popis: | Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) of potential use in patients with breast cancer. Unfortunately, in clinical studies, gefitinib is often ineffective indicating that resistance to EGFR inhibitors may be a common occurrence in cancer of the breast. EGFR has been shown to be overexpressed in breast cancer, and in particular remains hyperphosphorylated in cell lines such as MDA-MB-468 that are resistant to EGFR inhibitors. Here, we investigate the cause of this sustained phosphorylation and the molecular basis for the ineffectiveness of gefitinib. We show that reactive oxygen species (ROS), known to damage cellular macromolecules and to modulate signaling cascades in a variety of human diseases including cancers, appear to play a critical role in mediating EGFR TKI-resistance. Furthermore, elimination of these ROS through use of a cell-penetrating catalase derivative sensitizes the cells to gefitinib. These results suggest a new approach for the treatment of TKI-resistant breast cancer patients specifically, the targeting of ROS and attendant downstream oxidative stress and their effects on signaling cascades. |
| Databáze: | OpenAIRE |
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