Combined crizotinib and endocrine drugs inhibit proliferation, migration, and colony formation of breast cancer cells via downregulation of MET and estrogen receptor
| Autor: | Nehad M. Ayoub, Ahmed Alhusban, Dalia R Ibrahim, Amer E. Alkhalifa |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Antineoplastic Agents Hormonal medicine.drug_class Estrogen receptor Breast Neoplasms Tyrosine-kinase inhibitor Receptor tyrosine kinase 03 medical and health sciences Inhibitory Concentration 50 0302 clinical medicine Growth factor receptor Crizotinib Cell Movement Cell Line Tumor Medicine Humans Protein kinase B Fulvestrant Protein Kinase Inhibitors Cell Proliferation biology business.industry Estrogen Receptor alpha Drug Synergism Hematology General Medicine Proto-Oncogene Proteins c-met Tamoxifen Ki-67 Antigen Oncology Hepatocyte Growth Factor Receptor 030220 oncology & carcinogenesis Cancer research biology.protein business medicine.drug |
| Zdroj: | Medical oncology (Northwood, London, England). 38(1) |
| ISSN: | 1559-131X |
| Popis: | Hormone-dependent breast cancer is the most abundant molecular subtype of the disease. Despite the availability of endocrine treatments, the use of these drugs is limited by their serious adverse reactions and development of acquired resistance often mediated by growth factor receptors. The hepatocyte growth factor receptor, MET, is a receptor tyrosine kinase known for its oncogenic activity and mediating resistance to targeted therapies. Crizotinib is a small-molecule tyrosine kinase inhibitor of MET. In this study, the anticancer effects of combined crizotinib and endocrine drugs were investigated in breast cancer cells in vitro along with the molecular mechanisms associated with these effects. Results showed that crizotinib inhibited growth of MCF7 and T-47D breast cancer cells in a dose-dependent manner with IC50 values of 2.88 μM and 0.93 μM, respectively. Combined treatment of crizotinib and 4-hydroxytamoxifen resulted in synergistic growth inhibition of MCF7 and T-47D cells with combination index values of 0.39 and 0.8, respectively. The combined treatment significantly suppressed migration and colony formation of MCF7 and T-47D cells. Immunofluorescence showed a significant reduction of the expression of the nuclear protein Ki-67 with the combination of crizotinib and 4-hydroxytamoxifen in both cell lines. Western blotting indicated that the combination treatment reduced the levels of active and total MET, estrogen receptor α (ERα), total and active levels of AKT, ERK, c-SRC, NFĸB p65, GSK-3β, and the anti-apoptotic BCL-2 protein. Findings from this study suggest a potential role of MET inhibitors in breast cancer treatment as monotherapy or combination with endocrine drugs. |
| Databáze: | OpenAIRE |
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