4β-Hydroxywithanolide E合併化療藥物抑制非小細胞肺癌作用探討

Inhibition of non-small lung cancer cells by combining 4β-hydroxywithanolide E with chemotherapeutic drugs

邱競儀(Ching-I Chiu)

指導教授 ： 吳志中

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

肺癌是發生率和致死率都極高的癌症，此外也是具有高侵略性及高轉移性的腫瘤，且對一般癌症治療較不敏感，因此醫界與學界皆致力於發展更有效的治療辦法。先前已有文獻指出，自茄科植物所分離出之withanolides類化合物具有抗癌潛力，而本研究使用的化合物4β-hydroxywithanolide E (4HW)，便是由茄科之祕魯酸漿果分離而得的withanolide類化合物。有研究指出，目前臨床使用的抗癌藥物 (例: mitomycin C) 可能會造成抗凋亡蛋白survivin的表現增加，進而使癌細胞產生抗藥性。因此在本實驗中，利用4HW合併使用臨床抗癌藥物，針對非小細胞肺癌細胞株H1299與A549作細胞毒性試驗，探究4HW是否可以藉由降低抗癌藥物引起之survivin表現，進而提升細胞對於抗癌藥物的敏感性，此外更進一步探討其可能之作用機轉。實驗結果顯示，利用4HW合併使用臨床抗癌藥物，可以提升其於H1299細胞株之細胞毒殺性；但同樣使用4HW合併臨床抗癌藥物作用於A549細胞株上，對於A549之細胞毒殺性就沒有明顯的影響。此外在H1299細胞中，4HW可以減少抗凋亡蛋白Bcl-2以及survivin的表現，同時也能抑制AKT路徑之活化。綜合以上實驗結果顯示在H1299細胞中，4HW可以降低抗癌藥物引起之survivin表現，提升H1299細胞對於抗癌藥物之敏感性。

關鍵字

非小細胞肺癌 ； 秘魯酸漿果 ； 抗癌藥物 ； 合併治療

並列摘要

Lung cancer is a common-occurring cancer worldwidely, and scientists put huge emphasis on discovering more effective and responsive therapeutic agents for lung cancer due to its high aggression and less response to standard chemotherapies. It has been reported that cancer cells may possess resistances against chemotherapeutic agents like mitomycin C due to the survivin expression. Withanilides, natural compounds found abundantly in Solaneace, have been known to possess anticancer potential. In our studies, we combined 4β-hydroxywithanolide E (4HW), a withanolide isolated from Physalis peruviana, with clinical chemotherapeutic agents for its ability to attenuate the surviving expression enhanced by chemotherapeutic agents and related protein expressions were examined by Western blot. Out results demonstrated that 4HW enhanced the cytotoxicity of doxorubicin (Dox) and mitomycin C (MMC) in H1299 lung cancer cells, but no obvious enhancement was observed in A549 lung cancer cells. We conducted Western blot and the results shown that 4HW inhibited protein level of survivin and Bcl-2, and the activation of AKT was inhibited after 4HW treatment, suggesting 4HW might attenuate the survivin expression arised by chemotherapeutic agents, enhanced the sensitivity of H1299 cells to chemotherapies, making it a promising anticancer compound for further studies.

並列關鍵字

non-small cell lung cancer ； 4β-Hydroxywithanolide E ； survivin ； AKT ； combination index

參考文獻

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