4-hydroxy-2-methoxy-6-tridecylphenyl acetate在胰臟癌中的作用機制

The mechanism of 4-hydroxy-2-methoxy-6-tridecylphenyl acetate in pancreatic cancer

魏伶容(Ling-Rung Wei)

指導教授 ： 蔡婉琪

高雄醫學大學/健康科學院/醫學檢驗生物技術學系碩士班/碩士(2017年)

摘要

胰臟癌是全球最致命的癌症之一，具有高度的侵略性及致死率。雖然gemcitabine是臨床上治療胰臟癌的標準化療用藥，但卻有愈來愈多患者對gemcitabine產生抗藥性，因此尋找有效抑制胰臟癌細胞生長的新穎藥物是為當務之急。4-hydroxy-2-methoxy-6-tridecylphenyl acetate (HMTA) 是由黑星紫金牛 (Ardisia virens Kurz)所分離出來。本實驗室先前的研究指出，HMTA會造成PANC-1和BxPC-3胰臟癌細胞毒性，藉由annexin Ⅴ/PI與caspase-3活化證明該藥物會使細胞走向凋亡，另外，也會引起ROS產生造成DNA損傷。接續先前的研究，我們發現，在細胞實驗中，HMTA會毒殺胰臟癌細胞並降低癌細胞增生、抑制細胞移動以及侵襲的能力，並且引起粒線體膜電位下降而誘導細胞凋亡。細胞自噬指標LC3-II的上升則暗示了HMTA可誘導細胞自噬。而這些現象，有可能是透過HMTA抑制了STAT3活性而導致。在動物實驗中，HMTA能夠抑制癌細胞生長且無明顯副作用。綜合以上結果，HMTA具有發展為抗胰臟癌生長及轉移之潛力新穎藥物。

關鍵字

HMTA ； 胰臟癌 ； 移行 ； 侵襲

並列摘要

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the world, with characteristics of extremely high mortality and aggressiveness. Gemcitabine is the standard chemotherapy drug for pancreatic cancer. However, the emerging problem of gemcitabine-resistance is hard to conquer. Search for the novel therapeutic strategy is urgent. 4-hydroxy-2-methoxy-6-tridecylphenyl acetate (HMTA) is the pure compound isolated from Ardisia virens Kurz. Previous data in our lab has shown that HMTA could induce apoptosis in 2 pancreatic cancer cell lines, PANC-1 and BxPC-3. In addition, HMTA could induce ROS production and the consequent DNA damage in pancreatic cancer cells. In this study, we found that the proliferation of both PANC-1 and BxPC-3 cells were decreased by HMTA in a dose-dependent manner. The migration and invasiveness of PANC-1 and BxPC-3 cells were also inhibited by HMTA. We further found that the apoptosis induced by HMTA might be partly due to the decrease of mitochondria membrane potential. In addition, the increase level of LC3-II with treatment implied the involvement of autophagy in HMTA-induced cell death. The inactivation of STAT3 by HMTA might be responsive for above cellular phenomenon. Moreover, HMTA showed the promising therapeutic effects in vivo. Taken together, these results showed that HMTA might be an effective anti-proliferation and anti-metastasis reagent for pancreatic cancer treatment.

並列關鍵字

HMTA ； pancreatic cancer ； migration ； invasion

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