探討蟛蜞菊萃取物及立普能的抗癌作用和機轉

Study of antitumor potentials of Wedelia chinensis extract and escitalopram oxalate

陳俐礽(Li-Jeng Chen)

指導教授 ： 曾博修

中山醫學大學/醫學院/醫學研究所 (原生化微生物免疫研究所)/博士(2023年)

https://doi.org/10.6834/csmu202000273

摘要

癌症是全世界的主要死因，肝細胞癌 (hepatocellular carcinoma, HCC) 和多型性神經膠母細胞瘤 (glioblastoma multiforme, GBM) 都惡性程度最高的原發性癌症。外科手術是癌症治療最常見且有效的方法之一，在肝臟中的血流豐富，而腦部中具各種重要功能區域，因此肝臟和腦部手術是具較高危險性及較高難度，而且術後的高復發率及預後不良，導致總體生存率低。因此尋找有效的抗癌藥物是迫在眉睫之事。細胞程序性死亡在體內平衡中起重要作用，當細胞受到環境刺激 並接收特定訊息後，由細胞內部主動執行的死亡。近年來許多研究指出在治療癌症過程中，癌細胞會造成程序性死亡，而抑制癌細胞生長、轉移及惡化。
蟛蜞菊 (Wedelia chinensis) 屬於草本菊科植物，傳統醫學上被認為具有止咳化痰、清熱解毒及祛瘀消腫等功效。立普能屬於選擇性血 清素再攝取抑制劑 (selective serotonin reuptake inhibitors, SSRIs) 的抗憂鬱劑，主要用於治療重度憂鬱症和焦慮症。先前研究指出，蟛蜞菊萃取物及立普能具有抗癌之功效。因此本篇論文將分為兩個部分，第一部分為探討蟛蜞菊萃取物對多型性神經膠母細胞瘤的抗癌作用;第二部分為探討立普能對肝細胞癌的抗癌作用。
第一部分，將人類神經膠質母細胞株 (GBM8401 和 U-87MG) 處理不同濃度的蟛蜞菊萃取物，結果發現能有效抑制細胞存活和細胞遷移的能力，並觀察到 GBM8401 細胞株的細胞週期中 sub-G1 期比 例增加。進一步結果發現蟛蜞菊萃取物誘導 GBM8401 細胞株的細胞凋亡作用和 U-87MG 細胞株的細胞自噬作用。此外，蟛蜞菊萃取物與木樨草素合併芹菜素的組合相比具顯著抑制細胞存活和細胞遷移的 能力。綜合以上研究，蟛蜞菊萃取物具有治療多型性神經膠母細胞瘤的潛力。
第二部分，將人類肝癌細胞株 (HepG2、Huh-7) 處理不同濃度的立普能，結果發現能有效抑制細胞存活，且通過增加 LC3-II/LC3-I 比 率和 ATG-3、ATG-5、ATG-7 和 Beclin-1 蛋白質的表達誘導細胞自噬作用。另外，立普能抑制腫瘤異種移植 Huh-7 細胞株的 SCID 小鼠腫瘤的生長。在全國人口基礎資料調查研究中分析結果發現使用立普能的個案肝癌累積發病率顯著減少。綜合以上研究，立普能對肝細胞癌具有發展抗癌藥物的潛力。

關鍵字

蟛蜞菊 ； 立普能 ； 多型性神經膠母細胞瘤 ； 肝細胞癌 ； 細胞凋亡 ； 細胞自噬

並列摘要

Cancer is among the world’s leading causes of death, with hepatocellular carcinoma (HCC) and glioblastoma multiforme (GBM) being primary cancers with the highest levels of malignancy. Surgery, one of the most common and effective treatments for cancer, is particularly risky and difficult in the liver and brain due to the rich blood flow in the liver and the various critical functional regions of the brain. In addition, HCC and GBM have high postoperative recurrence rates and unfavorable prognosis, leading to poor overall survival rates. This reveals an urgent need to identify effective anticancer drugs for these cancers. Programmed cell death is crucial to maintaining a balance within the body and refers to death initiated by the cell itself upon receipt of environmental stimuli and certain messages. Recent studies have shown that cancer treatment leads to programmed death of cancer cells, which inhibits the growth, metastasis, and progression of cancer cells.
Wedelia chinensis (Asteraceae) are applied as folk medicine to have effects including eliminating sputum, relieving cough, detoxifying, removing blood stasis, and antiinflammation. Escitalopram oxalate is a selective serotonin reuptake inhibitor antidepressant used to treat major depressive disorder and anxiety disorder. The anticancer effects of Wedelia chinensis extract and escitalopram oxalate have both been verified in research. There are two parts in this study, first is investigated the anticancer effects of WCE on GBM, second is determined the antitumor potentials of escitalopram oxalate against HCC.
In the first part, the GBM8401 and U-87MG cells were treated with varying concentrations of Wedelia chinensis extract. The results showed that Wedelia chinensis extract significantly inhibited the cell survival and invasive capability of both GBM8401 and U-87MG cells and that increased sub-G1 proportion was detected in GBM8401 cells. A further investigation revealed that Wedelia chinensis extract induced apoptosis of the GBM8401 cells and autophagy of the U-87MG cells. Moreover, Wedelia chinensis extract had significant effects in inhibiting proliferation and invasive ability than the combination of Luteolin and Apigenin on GBM8401 and U-87MG cells. In summary, Wedelia chinensis extract show potential in treating GBM.
In the second part, HepG2 and Huh-7 cells were treated with escitalopram oxalate at varying concentrations. Escitalopram oxalate significantly inhibited the proliferation and induced autophagy by increasing the LC3-II/LC3-I ratio and the expression of ATG-3, ATG-5, ATG-7, and Beclin-1 proteins in HepG2 and Huh-7 cells. In addition, escitalopram oxalate attenuated the growth of xenografted Huh-7 cells in SCID mice. A nationwide population-based cohort study revealed that the cumulative incidence of liver cancer was reduced significantly with patients used escitalopram oxalate. In conclusion, escitalopram oxalate demonstrates potential as an anticancer drug for treating HCC.

並列關鍵字

Wedelia chinensis ； escitalopram oxalate ； glioblastoma multiforme ； hepatocellular carcinoma ； apoptosis ； autophagy

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