山竹黃酮誘發人類肝癌細胞凋亡之分子機制

本研究探討山竹果中的山竹黃酮(α-mangostin)對於人類肝癌細胞的抗癌能力。我們使用三株人類肝癌細胞當作模式，加入不同濃度的α-mangostin來進行肝癌細胞生長測試。MTT結果證實隨著α-mangostin的濃度和時間增加就會抑制肝癌細胞生長。為了瞭解α-mangostin抑制細胞生長是否誘導細胞凋亡。我們採用細胞群落實驗、DAPI染色、細胞週期分析和Annexin V/PI染色證實α-mangostin造成肝癌細胞核濃染、細胞週期停留subG1和細胞凋亡，同時西方墨點法證實α-mangostin誘導caspase-3、 -6、-7、-8、-9和PARP的活化。此外，α-mangostin也會抑制抗凋亡蛋白Bcl-xL, Bag-1, Intact-Bid and Bcl-2, 和增加凋亡蛋白Bak和tBid的表現，但不影響Mcl-1 and Bim 蛋白表現。α-mangostin誘導粒線體膜電位改變，造成粒線體蛋白Bax表現上升，Bcl-2表現下降和促進cytochrome C釋放。另外，α-mangostin也會增加細胞死亡接受器5(DR5)和TRAIL蛋白表現量增加，但不影響Fas、FasL、DR4蛋白表現. 最後採用裸鼠實驗證實α-mangostin會抑制裸鼠身上SK-Hep-1腫瘤的生長。綜合以上結果說明α-mangostin不但在細胞實驗誘導人類肝癌細胞走向細胞凋亡，同時動物實驗也能抑制肝癌細胞生長。我們期許α-mangostin未來可以當作抵抗肝癌的化學治療劑和新的治療策略。

關鍵字

山竹果；山竹黃酮；細胞凋亡

並列摘要

This study evaluated the anti-cancer effects of α-mangostin in human hepatocellular carcinoma (HCC) cells. In this study, three HCC cell lines were examined of their responses to α-mangostin, and the apoptotic mechanisms were elucidated. The results showed that α-mangostin induced apoptosis in a dose-and time-dependent manner, decreased the ability of colony formation, as evidenced by nuclear staining of DAPI, flow cytometry assay and the accumulation of positive cells for Annexin V/PI double-labeling. α-mangostin triggered the activations of caspases-3, -6, -7, -8, -9 and PARP, resulting in apoptosis induction. α-mangostin reduction in the protein levels of antiapoptotic Bcl-xL, Bag-1 and Intact-Bid, and an increase in the levels of proapoptotic Bak and tBid. α-mangostin did not affect the Mcl-1 and Bim protein levels. Moreover, α-mangostin also enhanced the permeability of the mitochondrial membrane, enhanced the up-regulated Bax and down-regulated the expression of Bcl-2, and induced the release of cytochrome C. Additionally, α-mangostin caused an increase in the protein levels of death receptor 5 (DR5), and TRAIL, but not affected the protein levels of Fas, FasL and DR4. The in vivo xenograft mice experiments revealed that α-mangostin signiﬁcantly reduced tumor growth in mice with SK-Hep-1 tumor xenografts. In conclusion, our data indicated that α-mangostin were effective in inhibiting the cell viability and induced cell apoptosis in HCC cells both in vitro and in vivo, possessing the potential to be a chemotherapeutic agent against human hepatocellular carcinoma.

並列關鍵字

Garcinia mangostana ； alpha-mangostin ； cell apoptosis

參考文獻

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山竹黃酮誘發人類肝癌細胞凋亡之分子機制

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