Natural Anthraquinone Compound Emodin as a Novel Inhibitor of Aurora A Kinase: a pilot study

Aurora kinase A (AURKA) carries out an essential role in proliferation and involves in cisplatin-resistance in various cancer cells. Overexpression of AURKA is associated with the poor prognosis of cancer patients. Thus, AURKA has been considered as a target for cancer therapy. Developing AURKA inhibitors became an important issue in cancer therapy. Taiwan Database of Extracts and Compounds (TDEC) is an academic and scientific platform through which investigators in different fields can share their research findings that includes information on the chemical structures, physicochemical properties, and biological activities of pure natural isolates, crude extracts, and synthesized compounds derived from plants, microbes, marine organisms, and Chinese herbal medicines. We found a natural product emodin is the candidate of AURKA inhibitor by utilized virtually screen from TDEC. Emodin is mainly isolated from rhubarbs possesses anti-cancer properties. However, the effect of emodin on AURKA has never been investigated. In the present study, molecular docking analysis indicated that emodin interacts with AURKA protein active site. We also found nine emodin analogues from Key Organic database by using ChemBioFinder software. Among that, one analogue 8L-902 showed a similar anti-cancer effect as emodin. The bindings of emodin and 8L-902 on AURKA protein were confirmed by cellular thermal shift assay. Furthermore, emodin inhibited the AURKA kinase activity in vitro and enhanced the cisplatin DNA adduct level in a resistant ovarian cancer cell line. It seems that emodin may have the potential to inhibit cancer cell growth and enhance cisplatin therapy in cancer with resistance. Collectively, our finding reveals a novel AURKA inhibitor, emodin, which may be vulnerable to ovarian cancer therapy in the future.

極光激酶 A (AURKA) 在增殖中發揮重要作用，並參與各種癌細胞的順鉑耐藥性。 AURKA 的過度表達與癌症患者的不良預後有關。因此，AURKA 被認為是癌症治療的靶點。開發 AURKA 抑製劑成為癌症治療中的一個重要問題。台灣萃取物及化合物數據庫 (TDEC) 是一個學術和科學平台，不同領域的研究人員可以通過該平台分享他們的研究成果，包括從植物、微生物、海洋生物和中草藥中提取的純天然分離化合物、粗萃物和合成物的化學結構、理化性質和生物活性信息。我們通過TDEC的虛擬篩選發現一個天然產物大黃素是AURKA抑製劑的候選者。大黃素主要從中藥大黃萃取，具有抗癌特性。然而，從未研究過大黃素對 AURKA 的影響。在本研究中，分子對接分析顯示大黃素與 AURKA 蛋白活性位點相互作用。我們還使用 ChemBioFinder 軟件從 Key Organic 數據庫中發現了九種大黃素類似物。其中，一種類似物 8L-902 顯示出與大黃素相似的抗癌作用。大黃素和 8L-902 與 AURKA 蛋白的結合通過細胞熱位移測定得到證實。此外，大黃素在體外抑制 AURKA 激酶活性，並提高抗性卵巢癌細胞系中順鉑 DNA 加合物的水平。研究

證實大黃素可能具有抑制癌細胞生長和增強耐藥癌症的順鉑治療的潛力，揭示了一種新的 AURKA 抑製劑-大黃素，可以提供新的卵巢癌治療方法。