Sunitinib 抑制急性骨髓性白血病細胞生長與誘發細胞分化及凋亡之分子作用機制

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Title:	Sunitinib 抑制急性骨髓性白血病細胞生長與誘發細胞分化及凋亡之分子作用機制
Other Titles:	Effector Mechanisms of Sunitinib-induced G1 Cell Cycle Arrest, Differentiation and Apoptosis in Human Acute Myeloid Leukaemia HL60 and KG-1 Cells
Authors:	滕傑林 Teng, Chieh-Lin
Contributors:	黃光裕;徐士蘭 Hwang, Guang-Yuh;Hsu, Shih-Lan 生命科學系
Keywords:	急性骨髓性白血病;細胞分化;細胞凋亡;PKC;Bcl-2;DR4 Acute myeloid leukaemia;Differentiation;Apoptosis;PKC;Bcl-2;DR4
Date:	2013
Issue Date:	2014-02-14T01:18:25Z (UTC)
Abstract:	急性骨髓性白血病 (Acute Myeloid Leukaemia, AML) 是成年人最常見的血癌。但是完全治癒率僅有30%。Sunitinib 是目前臨床使用於腸道基質瘤以及轉移性腎癌的多標靶化療藥物。事實上，已有臨床相關的研究顯示，特定對於化學治療無效的急性骨髓性白血病病患使用 sunitinib 後，部分的病患也能達到一定的緩解。但是有關 sunitinib 作用於急性骨髓性白血病之分子機轉，目前並不清楚。本論文之研究在探討sunitinib對抗急性骨髓性白血病之作用及其分子機轉。實驗的結果發現，以sunitinib 處理急性骨髓性白血病HL60及KG-1細胞株，可以抑制細胞生長，促進細胞分化，造成細胞凋亡。在細胞週期方面，sunitinib 會造成 G1 期的停滯，並伴隨著cyclin D1，cyclin D3，以及 Cdk2 的蛋白質表現量下降。同時亦會造成p27kip1，pRb1，p130/Rb2 表現量增加。同時，sunitinib 處理增加 monocyte 分化指標性分子 CD14，CD11b，CD11c，CD18，及 CD54 的表現，以及protein kinase C α和β磷酸化的上升。處理protein kinase C α和β的抑制劑可降低sunitinib誘發之血癌細胞分化。更進一步的研究結果顯示，sunitinib 不但會增加急性骨髓性白血病HL60及KG-1細胞之凋亡分子的表現 (Bax，Bak，PUMA，Fas，FasL，DR4，以及DR5)，亦會降低抑制細胞凋亡分子 Bcl-2 以及 Mcl-1 的表現。最終誘發了 caspase-2，-3，-8，以及 -9 的活化，啟動了細胞死亡受體以及粒線體相關之細胞凋亡路徑。本研究亦分離急性骨髓性白血症病人的癌細胞處理sunitinib，發現亦可促進血癌細胞的分化及死亡。綜合以上結果，本研究之結果，提供了sunitinib 誘使血癌細胞細胞分化以及凋亡作用之分子層次的證據。但 sunitinib 對急性骨髓性白血病臨床應用之可行性，則需要更多的研究數據來確認。 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.
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