Tunghai University Institutional Repository:Item 310901/21031
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    Please use this identifier to cite or link to this item: http://140.128.103.80:8080/handle/310901/21031


    Title: Effector mechanisms of sunitinib-induced G1 cell cycle arrest, differentiation, and apoptosis in human acute myeloid leukaemia HL60 and KG-1 cells
    Authors: Teng, C.-L.J.abc, Yu, C.-T.R.d, Hwang, W.-L.a, Tsai, J.-R.e, Liu, H.-C.e, Hwang, G.-Y.b , Hsu, S.-L.
    Contributors: Department of Life Science, Tunghai University
    Keywords: Apoptosis;Bcl-2;Differentiation;PKC;Sunitinib
    Date: 2013
    Issue Date: 2013-05-14T09:00:05Z (UTC)
    Abstract: 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 cyclin-dependent kinase (Cdk)2 and increased p27Kip1, pRb1, and p130/Rb2 expression and phosphorylated activation of protein kinase C alpha and beta (PKCα/β). Selective PKCα/β inhibitor treatment abolished sunitinib-elicited AML differentiation, suggesting that PKCα/β 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, caspase-3, caspase-8, and caspase-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. ? 2012 Springer-Verlag Berlin Heidelberg.
    Relation: Annals of Hematology
    Volume 92, Issue 3, March 2013, Pages 301-313
    Appears in Collections:[Department of Life Sciences ] Periodical Articles

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