Molecular characterization of sunitinib mediated cytotoxicity in human urothelial carcinoma cells
| Autor: | Shu-Ting Huang, 黃淑婷 |
|---|---|
| Rok vydání: | 2010 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 98 Urinary bladder cancer is one of the few cancers whose incidence has been increasing in Taiwan. Urinary bladder cancer arises from the cell lining in the interior surface of the bladder, and it is named urothelial carcinoma (UC). However, drug-resistance problems during chemotherapy lead to the failure of the therapy for many cancer patients. Therefore, an important clinical objective is to find an effective cytotoxic drug for drug-resistant bladder cancer cells.Sunitinib (known as SU11248) is an orally medicated multi-targeted receptor tyrosine kinase (RTK) selective inhibitor, and it also has anti-proliferation and anti-angiogenesis efficacy.In this study, we examined the sensitivity of the bladder cancer cell lines in response to the treatment of sunitinib by MTT assay, and found that N/P(14) cell line has the highest sensitivity to sunitinib. Further assessments using Western blotting, reali-time PCR, RT-PCR, flow cytometry and two-drug combination MTT assay show that the cytotoxicity of sunitinib toward UC cells is mainly through inhibition of receptor tyrosine kinase, including EGFR, PDGFRβ, and FGFR1, in which the following signal pathways MAPK and PI3K/Akt were inhibited. Our results showed resulted the following phenomenons: (1) down-regulated cell proliferation and cell growth, (2) induced cell pro-apoptosis related factors, such as p21, Bid, Bcl-2, cytchrome C, caspase 3 and caspase 8, (3) decreased angiogenesis molecules, such as STAT3 and VEGF, and (4) decreased drug-resistant molecules, such as XPF,GSTP1,GSTT2, GSTM4 andMRP1. Finally, combination of sunitinib with cisplatin showed synergistic effect on N/P(14) UC cell line and flow cytometry show high expression of ROS on N/P(14) UC cell line. In this study, sunitinib has been shown to have an excellent anti-cancer drug on UC cells, and it’s potential as a clinical drug is strongly suggested. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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