Effector Mechanisms of Sunitinib-induced G1 Cell Cycle Arrest, Differentiation and Apoptosis in Human Acute Myeloid Leukaemia HL60 and KG-1 Cells
| Autor: | Teng, Chieh-Lin, 滕傑林 |
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| Rok vydání: | 2013 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 101 Acute myeloid leukaemia (AML) is a heterogeneous disease with dismal outcome. Sunitinib is an orally active inhibitor of multiple tyrosine kinase receptors approved for renal cell carcinoma and gastrointestinal stromal tumour that has also been studied for AML in several clinical trials. However, the precise mechanism of sunitinib action against AML remains unclear and requires further investigation. For this purpose, this study was conducted using human AML cell lines (HL60 and KG-1) and AML patients’ mononucleated cells. Sunitinib induced G1 phase arrest associated with decreased cyclin D1, cyclin D3, and Cdk2 and increased p27Kip1, pRb1, and p130/Rb2 expression. Moreover, sunitinib could induce AML monocytic differentiation which was characterized by morphological change and stimulating the expression levels of CD11b, CD11c, CD14, CD18 and CD54 monocytic surface markers. This event was accompanied by phosphorylated activation of protein kinase C alpha and beta (PKCα/b). Selective PKCα/b inhibitor treatment abolished sunitinib-elicited AML differentiation, suggesting that PKCα/b may underlie sunitinib-induced monocytic differentiation. Furthermore, sunitinib increased pro-apoptotic molecule expression (Bax, Bak, PUMA, Fas, FasL, DR4, and DR5) and decreased anti-apoptotic molecule expression (Bcl-2 and Mcl-1), resulting in caspase-2, 3, 8, and 9 activation and both death receptor and mitochondria-dependent apoptosis. Taken together, these findings provide evidence that sunitinib targets AML cells through both differentiation and apoptosis pathways. More clinical studies are urgently needed to demonstrate its optimal clinical applications in AML. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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