Fatal pulmonary fibrosis associated with BCNU: the relative role of platelet-derived growth factor-B, insulin-like growth factor I, transforming growth factor-beta 1 and cyclooxygenase-2

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Title:	Fatal pulmonary fibrosis associated with BCNU: the relative role of platelet-derived growth factor-B, insulin-like growth factor I, transforming growth factor-beta 1 and cyclooxygenase-2
Authors:	Shen, YC;Chiu, CF;Chow, KC;Chen, CL;Liaw, YC;Yeh, SP
Contributors:	附設醫院內科部血液腫瘤科;China Med Univ Hosp, Dept Internal Med, Div Hematol & Oncol, Taichung 404, Taiwan;China Med Univ Hosp, Dept Med Res, Canc Res Ctr, Taichung, Taiwan;China Med Univ Hosp, Dept Pathol, Taichung, Taiwan;China Med Univ Hosp, Dept Med Res, Stem Cell Res Lab, Taichung, Taiwan;China Med Univ, Taichung, Taiwan
Date:	2004
Issue Date:	2010-09-24 14:20:03 (UTC+8)
Publisher:	NATURE PUBLISHING GROUP
Abstract:	Epithelial growth factor receptor (EGFR) has been proposed as a target for anticancer therapy. ZD1839 (Iressa) is a quinazoline derivative that selectively inhibits the EGFR tyrosine kinase activity and is under clinical use in cancer patients. However, the molecular mechanisms involved in ZD1839-mediated anticancer effects remain largely uncharacterized. In this study, exposure of human lung adenocarcinoma A549 cells to ZD1839 caused G1 arrest, and subsequently induced apoptosis. Moreover, ZD1839 increased the protein levels of p27(KIP1) and retinoblastoma-related Rb2/p130 while decreased the expression of cyclin-dependent kinase-2 (CDK2), CDK4, CDK6 and cyclin-D1, cyclin-D3. In vitro kinase assay showed that ZD1839 decreased these CDKs expression in A549 cells, leading to significantly reduce their kinase activities. In addition, ZD1839-induced death of A549 cells with characteristics of apoptosis including apoptotic morphological changes, DNA fragmentation and enhancement of TUNEL-positive cell. These events were accompanied by a marked increase of Fas protein expression, and activation of caspase-2, -3, -8. Co-treatment of cells with Fas antagonist antibody significantly blocked ZD1839-induced apoptosis. Caspase-8 and caspase-3 inhibitors, but not a caspase-9 inhibitor, were also capable of restoring cell viability. Our results indicate that downregulation of the expression and function of CDK2, CDK4, CDK6, cyclin-D1 and cyclin-D3, as well as upregulation of p27(KIP1) and pRb2/p130, are strong candidates for the cell cycle regulator that arrests ZD1839-treated A549 cells at G1 phase. Furthermore, upregulation of Fas appears to play a major role in the initiation of ZD1839-induced apoptosis, activation of caspase-8/caspase-3 cascade is involved in the execution phase of this death program. (C) 2004 Elsevier Inc. All rights reserved.
Relation:	BONE MARROW TRANSPLANTATION 34(7):609-614
Appears in Collections:	[China Medical University Hospital] Jurnal articles

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