Protoapigenone衍生物抑制乳癌細胞化學治療引起的DNA損傷反應

Protoapigenone derivatives inhibit chemotherapeutic agents-induced DNA damage response in breast cancer cells

張雅婷(Ya-Ting Chang)

指導教授 ： 王惠君

高雄醫學大學/藥學院/天然藥物研究所碩士班/碩士(2017年)

摘要

乳癌在全球是最常被診斷的癌症之一，在台灣，乳癌高居女性癌症發生率之首。儘管目前已有多種乳癌的治療藥物，開發新的乳癌藥物仍相當重要，特別是對於化療後復發的乳癌患者。DNA損傷反應 (DDR) 和與其有關的修復機制在導致癌症扮演很重要的角色。或許是由於無法有效的修復DNA所造成的基因損傷，當癌細胞受到會造成DNA損傷的化療藥物作用時，會啟動一連串的DDR訊息傳遞網絡來保護自身的基因體。DDR的結果可能會造成細胞凋亡、細胞進行修復、細胞週期停止等。在先前的研究中，自大金星蕨的protoapigenone可經由抑制UV和cisplatin誘導產生的DDR而抑制乳癌細胞的存活性。本研究則主要比較protoapigenone和其化學合成衍生物738-5和738-7對DDR影響的差異。738-5與738-7對於MCF-7乳癌細胞的IC50分別為11.04和9.78 μM，也具有抑制MCF-7乳癌細胞形成球體的能力。Protoapigenone、738-5和738-7皆可抑制由hydroxyurea與doxorubicin誘導的ATM、Chk2及Chk1磷酸化，但只有738-5和738-7可抑制ATM蛋白質表現，且此現象具有劑量與時間依賴性。由實驗結果得知，738-5和738-7抑制MCF-7乳癌細胞的作用機轉與protoapigenone不盡相同，且可能是與氧化壓力的作用有關。

關鍵字

乳癌 ； protoapigenone ； DNA損傷反應 (DDR)

並列摘要

Breast cancer is one of the most common diagnosed malignancies among women worldwide. In Taiwan, women have the highest rate of getting breast cancer than other types of cancer. As a result, developing new treatment options is required for some particular situations, such as refractory to chemotherapy. Cancer receives DNA damage-based chemotherapy will activate DNA damage response (DDR) pathway to protect genomic stability. Either by arresting cell-cycle for DNA repair or inducing apoptosis, DDR can prevent damaged DNA propagates into daughter cells. In the previous research, plant-derived protoapigenone showed potent activity against breast cancer cell lines via inhibiting UV- and cisplatin-induced DDR. In the present study, we tested new synthetic protoapigenone derivatives, named 738-5 and 738-7, on DDR in MCF-7 breast cancer cell line. We demonstrated 738-5 and 738-7 suppressed MCF-7 breast cancer cell line with IC50 of 11.04 and 9.78 μM, respectively. 738-5 and 738-7 also inhibited the sphere forming ability of MCF-7 cells. Probed precisely into their effect on DDR showed both 738-5 and 738-7 had a similar ability to inhibit doxorubicin- and hydroxyurea-induced ATR, Chk1, and Chk2 phosphorylation. Differently, 738-5 and 738-7, but not protoapigenone, could decrease ATM and Chk2 phosphorylation which in parallel with reducing ATM protein expression. In MCF-7 cells, 738-5 and 738-7 could reduce ATM protein expression in a dose- and time-dependent manner. Our results showed the mechanism of action for 738-5 and 738-7 is different from protoapigenone and it may be related to oxidative stress.

並列關鍵字

Breast cancer ； protoapigenone ； DNA damage response (DDR)

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