肉桂酸衍生物對肺癌侵入轉移性抑制功效之細胞試驗與機轉探討

肺癌患者往往會被診斷出癌細胞有轉移的症狀，而死於早期及遠端轉移發生。轉移是由一連串步驟所串聯組成，包括細胞黏著、細胞外基質降解、細胞移行和侵入。因此，能對抗轉移相關步驟的物質，就可能可以用來防止腫瘤細胞發生轉移，並增加癌症患者生存的機會。肉桂酸 (3-phenyl-2-propenoic acid, cinnamic acid, CA) 已被證實可作為預防人類肺癌細胞發生侵入轉移的物質，但肉桂酸相關衍生物是否同樣對肺癌細胞侵入轉移性具有抑制效果仍不清楚。因此本研究目的在試驗並探討數種肉桂酸衍生物對肺癌 A549 細胞侵入轉移的抑制功效及其作用機轉。研究結果顯示，咖啡酸 (caffeic acid, CAA)、綠原酸 (chlorogenic acid, CHA) 和阿魏酸 (ferulic acid, FA) 在濃度≧100 µM 可抑制 phorbol-12-myristate-13-acetate (PMA) 所誘發 A549 細胞的侵入作用。此三種化合物可透過調控 urokinase-type plasminogen activator (uPA)、tissue inhibitor of metalloproteinase (TIMP)-1、plasminogen activator inhibitor (PAI) -1 & -2 抑制 MMP-9 活性；但只有 CAA 有降低細胞基質黏附力的效果。這些抑制作用牽涉的分子機轉除了降低 MAPK 和 PI3K/Akt 訊息傳遞蛋白外，也抑制了 NF-κB、AP-1 和 STAT3 轉錄因子的活化。本研究選擇肉桂酸相關衍生物-CAA、CHA 和 FA，證實其可抑制人類肺癌細胞發生侵入轉移的相關步驟，並探討其可能機制，至於化合物的結構特徵與抗侵入活性的關聯性則需再進行其他實驗驗證。

關鍵字

肉桂酸衍生物；咖啡酸；綠原酸；阿魏酸；侵入；肺癌細胞

並列摘要

Patients with lung adenocarcinoma are often diagnosed with metastasizing symptom and die of early and distal metastasis. Metastasis is made up of a cascade of interrelated and sequential steps, including cell adhesion, extracellular matrix degradation, cell movement, and invasion. Hence, substances carry the ability against one of the metastasis-associated steps could be a potential candidate for preventing tumor cells from metastasizing and prolonging life of cancer patients. Cinnamic acid (CA) was demonstrated to be such a candidate for human lung adenocarcinoma cells. Nevertheless, the effectiveness of CA derivatives on invasion of lung cancer cells is still unclear. The aims of this study were to explore the mechanisms underlying several select CA derivatives against invasion of human lung adenocarcinoma A549 cells. The results revealed that caffeic acid (CAA), chlorogenic acid (CHA), and ferulic acid (FA) can inhibit phorbol-12-myristate-13-acetate (PMA)-stimulated invasion of A549 cells at a concentration of ≧ 100 µM. The MMP-9 activity was suppressed by these compounds through regulating urokinase-type plasminogen activator (uPA), tissue inhibitor of metalloproteinase (TIMP)-1, plasminogen activator inhibitor (PAI)-1, and PAI-2; the cell-matrix adhesion was decreased by CAA only. The proposed molecular mechanism involved not only decreasing the signaling of MAPK and PI3K/Akt but also inactivating NF-κB, AP-1, and STAT3. In the present study, we selected CAA, CHA, and FA as potential inhibitors for invasive behaviors of human lung adenocarcinoma cells and disclosed the possible mechanisms. As for the association between structural feature and anti-invasive activity of these compounds cannot be determined here and needs to be further verified.

並列關鍵字

caffeic acid ； chlorogenic acid ； cinnamic acid derivatives ； ferulic acid ； invasion ； lung adenocarcinoma cells

參考文獻

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肉桂酸衍生物對肺癌侵入轉移性抑制功效之細胞試驗與機轉探討

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