探討牡丹酚衍生物是否具有抗胰臟癌的作用

Abstract

胰臟癌是世界上最嚴重、預後最差的惡性腫瘤之一，雖然它的發病率僅排在第十一位，但是卻是第八大癌症死因。除此之外它的發病率及死亡率依舊逐漸增加，特別是在已開發國家，在過去二十年內它在台灣的癌症死因中從第十二位上升到第八位，而且五年存活率僅有五個百分點。儘管胰臟癌具有非常強的化療及放療抗性，但從1997至今傳統的化療藥物吉西他濱依舊是治療胰臟癌的標準藥物，也有許多研究發展了與吉西他濱或者5-氟尿嘧啶合併的治療方法，其中有四種合併療法可以顯著的延長病人的壽命，但是藥物的療效依然非常有限而且具有非常強烈的副作用，因此我們認為目前非常迫切需要新的治療胰臟癌的方法。 牡丹酚是一種傳統中藥的主要活性物質，有許多研究發現它具有抗癌的功效，但是卻也有藥物動力學的研究指出它的生物可利用性並不高。因此在本篇研究當中，我們合成了新的牡丹酚衍生物並且進行研究觀察這些衍生物是否具有抗胰臟癌的活性。為了這個目的我們使用了兩種人類的胰臟癌細胞分別是PANC-1以及BxPC-3。研究結果發現3k2以及3l1這兩個牡丹酚的衍生物具有毒殺胰臟癌細胞的效果，我們更進一步發現這兩種衍生物會導致胰臟癌細胞的細胞凋亡、細胞週期停滯並且降低XIAP蛋白的表現量，最後我們發現3k2以及3l1可以降低Akt以及ERK這兩個重要的訊號傳遞路徑蛋白的磷酸化。綜合所有實驗結果我們認為牡丹酚的衍生物3l2以及3l1可能是具有潛力的治療胰臟癌的藥物。

Pancreatic cancer is one of the most malignant cancers. The incident rate of pancreatic cancer is eleventh, but the cancer death is eighth in all cancers worldwide. Furthermore, the incidence is gradually elevated especially in developed countries. In Taiwan, it becomes the eighth leading causes of cancer death from twelfth in the past twenty years. The high propensity of invasion and metastasis leads to the worst outcome. The five-year survival rate of pancreatic cancer is only 5%. Despite the strong resistance to chemotherapy and radiotherapy of pancreatic cancer, gemcitabine is still considered as the standard therapeutic option since 1997. To improve the treatment, gemcitabine and 5-fu based combination therapy have been proposed. Four of the combination regimens can significantly prolong the survival of the patients. However, the efficacy is still finite and the excessive adverse effect can not be ignored. Hence, a novel therapeutic agent is urgently needed. Paeonol, a major ingredient of traditional Chinese medicinal herb Cortex moutan, has been found that exert anti-cancer efficacy, but it has a poor bioavailability. In the current study, we synthesized novel paeonol derivatives in order to identify a more effective anti-pancreatic cancer agent. To evaluate the anti-pancreatic cancer efficacy of these derivatives, two pancreatic cancer cell lines, PANC-1 and BxPC-3, were applied. Among these derivatives, we found that 3k2 and 3l1 posted significant cytotoxic effect to human pancreatic cancer cells. Both of them can induce apoptosis and cell cycle arrest. Our study revealed that 3k2 and 3l1 treatments inhibit the anti-apoptotic gene XIAP expression. Furthermore, 3k2 and 3l1 also downregulated the phosphorylation of Akt and ERK1/2. These results suggest that paeonol derivatives 3k2 and 3l1 might be potential therapeutic agents for the treatment of pancreatic cancer.