| Abstract: | 研究目的: 癌症幹細胞（CSC）表現出特定的特徵，包括去控制的自我更新，腫瘤起始，促進和轉移潛能，異常訊息傳遞和化學療物抗性。因此，針對治療癌幹細胞是目前治療腫瘤的新興癌症治療方法。α-山竹酮素已被證明具有多種抗癌和抗轉移的特性及功能。因此，我們假設α-山竹酮素可能會降低子宮頸癌幹細胞的特性和化學抗性的功能。
研究結果: SiHa和HeLa癌幹細胞具備高度表達癌幹細胞的標記Sox2，Oct4，Nanog和CD49f表現。同時也發現α山竹酮素顯著降低癌幹細胞細胞球體形成能力以及癌幹細胞標誌蛋白表現。進一步研究表明，α-山竹酮素誘導線粒體去極化和線粒體凋亡途徑，包括增加Bax蛋白表現和抑制Mcl-1和Bcl-2蛋白表現，以及活化caspase-9/3途徑。此外，α-山竹酮素促進線粒體凋亡和抑制癌幹細胞蛋白表達，同時協同增強順鉑對SiHa癌幹細胞的細胞毒性及更加強誘導粒線體凋亡路徑。利用活體外研究證實α-山竹酮素顯著抑制子宮頸癌SiHa幹細胞的腫瘤生長，同時協同增強順鉑的抗子宮頸癌腫瘤形成作用
結論:α山竹酮素可以降低SiHa和HeLa癌幹細胞增殖，並顯著增強順鉑產生的細胞毒性，這些現象可能是透過線粒體凋亡途徑。因此，此項研究說明α-山竹酮素可能具有抑制子宮頸癌幹細胞的特性來改善子宮頸癌化療的臨床潛力。
Purpose: Cancer stem cells (CSCs) exhibit specific characteristics including decontrolled self?renewal, tumor?initiating, promoting, and metastatic potential, abnormal stemness signaling, and chemotherapy resistance. Thus, targeting CSC is becoming an emerging cancer treatment. α?Mangostin has been shown to have potent and multiple anticancer activities. Accordingly, we hypothesized that α?mangostin may diminish the stemness and proliferation of CSC?like cervical cancer cells.
Result: In our results, comparing to the parent cells, CSC?like SiHa and HeLa cells highly expressed CSC marker Sox2, Oct4, Nanog, CK?17, and CD49f.α?Mangostin significantly reduced the cell viability, sphere?forming ability, and expression of the CSC stemness makers of CSC?like cervical cancer cells. Further investigation showed thatα?mangostin induced mitochondrial depolarization and mitochondrial apoptosis signaling, including upregulation of Bax, downregulation of Mcl?1 and Bcl?2, and activation of caspase?9/3. Moreover,α?mangostin synergically enhanced the cytotoxicity of cisplatin on CSC?like SiHa cells by promoting mitochondrial apoptosis and inhibiting the expression of CSC markers.
Consistent with in vitro findings, in vivo tumor growth assay revealed thatα?mangostin administration significantly inhibited the growth of inoculated CSC?like SiHa cells and synergically enhanced the antitumor effect of cisplatin.
Conclusion: Our findings indicate that α?mangostin can reduce the stemness and proliferation of CSC?like SiHa and HeLa cells and promote the cy cisplatin, which may attribute to the mitochondrial apoptosis activation. Thus, it suggests that α?mangostin may have clinical potential to improve chemotherapy for cervical cancer by targeting cervical CSC. |
