天然物cytoskyrin A於肺癌細胞中之抗癌研究

Abstract

肺癌位居全世界惡性腫瘤相關死因之首。其中又可分為兩種型態：一為小細胞肺癌，大約佔肺癌中15-20%，是極具侵略性的惡性腫瘤；另一個為非小細胞肺癌，大約佔80-85%，其對於化療藥物易產生抗藥性，且在近幾年使用化療治療肺癌患者之五年存活率依然維持在很低的百分比，所以，在肺癌治療中有必要去尋找或研發一個更有效的治療藥物。天然物是由自然界中發現的生物體所產生的一種化學化合物或物質。而植物一直都是天然物的主要來源，如洋地黃、奎寧、紫杉醇等，這些化合物常被用來製成藥物或作為藥物合成的基礎。臨床上已有多種從植物萃取分離出來具有抗癌等生物活性功能的抗癌藥。在本實驗中，我們與衛生福利部國家中醫藥研究所盧重光博士實驗室的合作，發現從日本琉球女貞果實內的共生菌所萃取出來的天然物cytoskyrin A，對於特定的肺癌細胞(A549, H460, H146 and H209)具有很好的抑制與抗癌效果。研究結果顯示cytoskyrin A能有效地抑制A549, H460, H146 與 H209細胞增生，並透過減少mTOR下游蛋白S6與MAPK下游蛋白ERK之磷酸化表現量進而導致細胞凋亡。除此之外，cytoskyrin A能促使NSCLC (A549 and H460)細胞週期停滯在G2/M，造成G0/G1之細胞數量顯著降低，亦能抑制NSCLC細胞轉移的能力。另外，我們也發現將cytoskyrin A與現有之化療藥物(etoposide)合併使用時，比cytoskyrin A單獨使用時對於非小細胞肺癌來的更具有毒殺性，能更強烈地減低非小細胞肺癌的細胞活性、抑制其增生、並更加促進癌細胞走向細胞凋亡。總結細胞毒殺性、細胞週期分析、細胞凋亡與訊息傳遞路徑之研究結果，我們建議cytoskyrin A很有潛力能成為治療特定肺癌之藥物。

Lung cancer is a leading cause of cancer mortality. Its five-year relative survival rate remains low and may relapse after initial chemotherapy. Therefore, the therapeutic strategies of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are urgently needed. Cytoskyrin A, a natural product isolated from symbiotic fungi inside the seed of Ligustrum liukuensis Koidz, is provided by a collaborative effect of Chung-Kuang Lu’s lab and has been distributed into a derivative of anthraquinone, which has been proved to have anticancer activity. However, the cytotoxicity effects of cytoskyrin A in lung cancer remain unelucidated. In this study, the anticancer activity of cytoskyrin A on various human lung cancer cell lines was investigated. Our results demonstrated that cytoskyrin A significantly inhibited cell viability, cell proliferation and induced apoptosis by the cleavage of apoptosis marker poly (ADP-ribosyl) polymerase (PARP) through suppressing the phosphorylation levels of apoptosis-related proteins like S6 and ERK on SCLC (H146 and H209) and NSCLC (A549 and H460) cells in a dose-dependent manner. Moreover, cytoskyrin A caused NSCLC cells accumulated mainly in G2/M phase after treated with indicated concentration for 24-hour and also suppressed the ability of migration in NSCLC cells with time- and dose- dependent treatment. In addition, cytoskyrin A co-treatment with current chemotherapeutic agent etoposide exerted enhanced cytotoxicity in NSCLC cells and induced cell apoptosis. Taken together, we have identified that cytoskyrin A exerts potent anticancer activity as a single agent and can further promote the anticancer efficacy when co-treatment with etoposide. Therefore, our results show that cytoskyrin A may be a promising chemotherapeutic strategy in lung cancer.