丹皮酚抑制人類口腔癌細胞移行與侵犯作用之機轉研究

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Title:	丹皮酚抑制人類口腔癌細胞移行與侵犯作用之機轉研究 Paeonol inhibits the migration and invasion of human oral squamous cell carcinoma CAL-27 cells by suppressing the activities of matrix metalloproteinases (MMPs)
Authors:	鍾雄光;Chung, Hsiung-Kwang
Contributors:	臨床醫學研究所碩士班
Keywords:	丹皮酚;抗侵犯;口腔癌;CAL-27 細胞株;基質金屬??;paeonol;anti-invasion;oral cavity cancer;CAL-27 cell lines;matrix metalloproteinases (MMP)
Date:	2012-07-27
Issue Date:	2012-08-31 16:35:17 (UTC+8)
Publisher:	中國醫藥大學
Abstract:	口腔癌佔民國一百年台灣地區男性癌症死因第四名, 且並未有下降的趨勢。治療以手術與放射線治療, 化學治療為主, 然而局部復發與頸部淋巴腺轉移常常導致治療失敗。丹皮酚是中草藥牡丹皮的萃取物, 已被證實有抗發炎, 抗氧化, 保護神經細胞等功效。近年來丹皮酚在抑制癌細胞株的相關實驗也越來越多, 本研究的目地在探討丹皮酚對於人類口腔癌細胞株 CAL-27 的抑制效果。分別以細胞存活率, 細胞週期評估, 活性氧化物質, 粒線體膜電位, 細胞傷口癒合, 細胞移行, 細胞侵犯, 明膠?電泳, 西方墨點, 即時聚合?鍊反應, 與激化?活性實驗來驗證丹皮酚對於 CAL-27 的抗癌效果。隨著丹皮酚的濃度增加與作用時間增長, CAL-27 的細胞存活率下降, 細胞週期被侷限在 G0 / G1 期。活性氧化物質上升, 粒線體膜電位下降而造成細胞凋亡。細胞傷口癒合, 細胞移行與侵犯結果發現丹皮酚有明顯的抑制效果。明膠?電泳,西方墨點近一步證實基質金屬??與其他導致細胞複製分裂的蛋白質如 GRB2, Ras, Rho A 等皆下降。即時聚合?鍊反應確立了只有第二型基質金屬??有在 mRNA 的層級受到丹皮酚的抑制。激化?活性實驗結果證明此傳導路徑是經由 PI3K 調控。丹皮酚可引發人類口腔癌細胞株 CAL-27 細胞凋亡與抑制移行侵犯而達到抗癌的效果。本研究團隊認為它有潛力成為治療口腔癌轉移的新興藥物。 The incidence of oral cavity cancer is increasing worldwide, and its prognosis remains poor, particularly in cases of advanced-stage cancer. The main causes of therapeutic failure are cervical nodal metastasis and regional recurrence. Paeonol, a compound found in Paeonia suffruticosa (moutan cortex), is a potent antitumor agent. The aim of this study was to investigate the effects of paeonol on the human oral cavity cancer cell line CAL-27. We found that paeonol decreased cell viability, induced cell cycle arrest in the sub-G1 phase, led to the production of reactive oxygen species (ROS), and decreased mitochondrial membrane potential. The anti-invasion effects of paeonol were confirmed on the basis of wound healing, invasion, and results of migration assays. Downregulation of the activities of matrix metalloproteinases at both the mRNA and protein levels was demonstrated using gelatin zymography, western blotting, and real-time PCR. Kinase assays revealed the suppression of phosphorylated mitogen-activated protein kinases, such as extracellular signal-regulated kinases (ERK) 1/2, p38, phosphoinositide 3-kinase (PI3K), and c-jun N-terminal kinase (JNK). Taken together, our results elucidate the potent signaling pathways involved in paeonol-induced anti-invasion activities in CAL-27 cells. The theoretical basis underlying the effects of paeonol was shown to involve reduction in the activity of protein kinases followed by inhibition of matrix metalloproteinases (MMP), particularly MMP-2.
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