研究α-mangostin誘發人類子宮頸癌細胞凋亡之分子機制

山竹果中富含氧雜蔥酮，許多研究顯示具有抗氧化和抗腫瘤的特性，而其衍生物α-mangostin的相關研究已經被證實在不同的腫瘤細胞中扮演抗癌、抗轉移和凋亡功能。但是，目前α-mangostin在子宮頸癌之研究尚不清楚。本研究目的證實α-mangostin對人類子宮頸癌細胞所誘導的細胞凋亡機制。本研究利用α-mangostin處理人類子宮頸癌細胞，以MTT、DAPI和annexin V雙染方式證實α-mangostin誘導子宮頸癌細胞凋亡。同時α-mangostin也會誘導caspase-3、-9和PARP(poly(ADP-ribose) polymerase)活化。α-mangostin也會誘導粒腺體膜電位改變，造成增加Bax和抑制Bcl-2蛋白表現。另外我們發現α-mangostin也會誘導ROS(Reactive oxygen species)產生，加入ROS抑制劑(NAC)會減緩α-mangostin誘導細胞凋亡、粒腺體膜電位改變和細胞凋亡相關蛋白活化。此外，我們也發現α-mangostin會誘導p38磷酸化，反之，加入p38抑制劑(SB203580)和siRNA-p38就會減緩α-mangostin誘導細胞凋亡、粒腺體膜電位改變和caspase-3/-9活化路徑，最後以裸鼠模式證實α-mangostin會抑制子宮頸腫瘤形成。綜合以上實驗結果證實α-mangostin誘導細胞凋亡是經由ROS的產生並活化p38蛋白，以及通過粒腺體凋亡途徑所執行。我們的研究結果說明，α-mangostin在子宮頸癌方面當作抗癌藥物的發展上深具潛力。

The mangosteen is a xanthone derivative shown to have antioxidant and anticarcinogen properties. α-mangostin is a flavonoid that has been shown to have anticancer, antiinvasive and apoptosis properties in various types of human cancer cells. The aim of this study was to investigate the mechanism of apoptosis induced by α-mangostin on human cervical carcinoma cells. In this study, HeLa and SiHa cell lines were treated with α-mangostin to suggest that α-mangostin induces apoptosis and by MTT assay, DAPI stain, annexin-V assay, α-mangostin triggered the activations of caspases-3, -9, and PARP, resulting in apoptosis induction. Furthermore, treatment with α-mangostin resulted in a loss of mitochondrial membrane potential (MMP), and augmented the Bax/Bcl-2 ratio. We also found that α-mangostin induces ROS release, added the ROS inhibitor (NAC) significantly abolished the α-mangostin-induced apoptosis, loss of MMP and apoptosis related-protein activation. Moreover, treatment of HeLa cells with α-mangostin induced a sustained activation of the phosphorylation of p38, and inhibition of p38 by SB203580 or transfection with the siRNA-p38 significantly abolished the α-mangostin-induced apoptosis through induction of apoptosis, loss of MMP and apoptosis related-protein activation. Finally, in vivo xenograft mice experiments revealed that α-mangostin significantly reduced tumor growth in mice with HeLa tumor xenografts. Taken together , that α-mangostin induces cell death by generation of ROS, and activation of p38 MAPK, and executed through mitochondrial mediated caspase pathway. Our results suggest that α-mangostin may be potentially used as anti-cancer agents in human cervical cancer.