探討白藜蘆醇抑制肺癌細胞對表皮生長因子受體之酪胺酸激酶抑制劑的抗藥性

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Title:	探討白藜蘆醇抑制肺癌細胞對表皮生長因子受體之酪胺酸激酶抑制劑的抗藥性 Resveratrol Decreases the Resistance of Lung Cancer Cells to EGFR Tyrosine Kinase Inhibitor
Authors:	彭竺英;Chu-Ying Peng
Contributors:	醫學院癌症生物學研究所
Keywords:	肺癌;表皮生長因子受體;Gifitinib;酪胺酸激酶抑制劑;抗藥性;白藜蘆醇;敏感化;lung cancer;EGFR;Gefitinib;tyrosine kinase inhibitor;drug resistance;resveratrol;sensitize
Date:	2010
Issue Date:	2010-09-29 12:15:02 (UTC+8)
Abstract:	肺癌在許多國家皆為一常見的惡性腫瘤，包括台灣在內，並且位居癌症死因之首。表皮生長因子受體（epidermal growth factor receptor, EGFR）調控細胞許多的生理功能，包括細胞的增生、分化、移動以及代謝，其過度表現或活化與許多癌症的發生有所關聯。Gifitinib (Iressa, 艾瑞莎) 為表皮生長因子受體之酪胺酸激酶的抑制劑，已有效的運用在非小細胞肺癌患者的治療，但其功效卻往往受到爾後抗藥性發生的抑制。白藜蘆醇 (resveratrol) 是一種天然的植物抗菌素 (phytoalexin)，主要存在於葡萄、花生以及桑椹中，亦存在於中草藥厚朴、虎杖之中。在科學文獻的記載中具有抗癌活性，能防止細胞癌變，阻止惡性腫瘤擴散，對腫瘤發生的起始、促進和發展三個階段都有抑制作用，並且在許多的實驗模式下也被證實具有化學增敏與化學預防的功效，因此具有成為重要的抗癌藥物之潛力。為了研究白藜蘆醇對肺癌細胞的標靶治療之影響，我們建立Iressa-resistance 的肺癌細胞株 (PC-9/IR)，當作我們的實驗模式。在功能分析上，我們發現在 PC-9/IR 細胞中，先給予無毒性劑量之白藜蘆醇 (1.25, 2.5, 5, 10 μM) 可敏感化艾瑞莎的毒殺效果。持續給予艾瑞莎48小時，在 PC-9/WT 細胞中可誘發55.37% ± 0.37%的細胞死亡，但在 PC-9/IR 細胞中只有8.76% ± 1.56%的比例。在合併治療上，我們觀察到在PC-9/IR中先給予白藜蘆醇可增強艾瑞莎所誘導的細胞死亡(單獨處理艾瑞莎的細胞死亡比例為8.76% ± 1.56%，合併白藜蘆醇與艾瑞莎的處理，細胞死亡比例則為48.71%±3.12%)。這些結果顯示，在具有抗藥性的肺癌細胞中，白藜蘆醇可能可以敏感化表皮生長因子受體之酪胺酸激酶的抑制劑。為了進一步了解其中所調控的分子機制，我們預測一些調控可能的下游目標，例如，上皮-間質轉化 (epithelial-mesenchymal transition, EMT) 相關分子與microRNAs。藉由二維電泳分析法與microRNA矩陣分析法，我們發現一些可能參與在肺癌細胞對表皮生長因子受體之酪胺酸激酶的抑制劑之抗藥性。 Lung cancer is one of the most common malignancies in many countries, including Taiwan, and also is the first leading cause of cancer-induced death. EGFR (epidermal growth factor receptor) regulated a lot of biological functions of cells including proliferation, differentiation, motility and metabolism; its overexpression or activate mutation are associated with a number of cancers. Gefitinib (Iressa), a specific EGFR tyrosine kinase inhibitor, has been used in treatment of non-small lung cancer patients. However, its therapeutic activity is limited by the development of drug resistance. Resveratrol (trans-3, 4’, 5-trihydroxystilbene) is a polyphenolic compound found in various plants and some Chinese herbs. Resveratrol has the ability to inhibit cancer formation at initiation, promotion and progression; also it has been shown to receive chemosensitive and chemopreventive effects in different experimental systems. To define the effects of resveratrol on target therapy of lung cancer cells, we used Iressa-resistance (PC-9/IR) lung cancer cells as our experimental models. In the functional assay, we found that pre-treatment with non-toxic dosages of resveratrol (1.25, 2.5, 5, 10 μM) sensitized the toxic effect of Iressa (2.5 μM) in Iressa-resistant PC-9/IR cells. Treatment with Iressa for 48 hrs induced 55.37% ± 0.37% cell death in PC-9/WT cells, but only 8.76% ± 1.56% in PC-9/IR cells. Pre-treatment with resveratrol increased Iressa-induced cell death in PC-9/IR cells (8.76% ± 1.56% cell death in vehicle + Iressa group; 48.71% ± 3.12% cell death in resveratrol + Iressa group). These results indicate that resveratrol may sensitize EGFR tyrosine kinase inhibitor in resistant lung cancer cells. To further evaluate the molecular mechanisms, we define the potential down-stream targets, such as epithelial-mesechymal transition (EMT)-related proteins and microRNAs, involved in resveratrol-induced de-resistance of EGFR tyrosine kinase inhibitor in lung cancer cells. By two-dimensional gel electrophoresis and microRNA microarray assay, we found some potential downstream targets which may involve in the resistance of lung cancer cells to EGFR tyrosine kinase inhibitor.
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