薏苡種皮乙醇萃取物結合doxorubicin抑制人類子宮惡性肉瘤細胞生長之探討

癌症從民國71年以來一直位居十大死因之首，目前治療方式中化學治療是其中一種。然而，在化學治療期間會產生大小不等的副作用及多重藥物阻抗性(Multi-drug resistance, MDR)，造成化療效果不佳。MDR 目前產生機制尚未完全明瞭，但有許多研究顯示，在腫瘤細胞內會有大量抗藥性蛋白P-醣蛋白(P-glycoprotein, P-gp)表現，因而產生抗藥性，而且P-gp 表現的癌細胞會對凋亡作用產生阻抗，也會造成藥物阻抗性。另外，化療效果不佳和腫瘤細胞轉移(tumor metastasis)也有密切關係。過去研究指出薏苡籽實萃取物具有抑癌作用，因此，本研究擬探討薏苡種皮乙醇萃取物結合抗癌藥物doxorubicin 對子宮惡性肉瘤細胞生長抑制之影響。結果顯示，(1)在薏苡種皮乙醇萃取物中以hexane 區分層(ATE-Hex)的抑制效果最佳，並且結合doxorubicin 後計算combination index (CI) ，顯示具有相乘作用；(2)給予ATE-Hex 有減少P-gp 之表現及減少轉移(migration) 之作用；(3)兩者結合在細胞週期結果可看到在48、72小時sub G1上升及western blot 結果顯示PARP 被截切；(4)抑癌活性分析部分：植物固醇抑制效果較脂肪酸好，其中又以campesterol 與β-sitosterol 的抑制效果最好。根據以上結果推測，薏苡種皮乙醇萃取物可抑制人類子宮惡性肉瘤細胞生長，若結合抗癌藥物doxorubicin 可減少藥物阻抗性，且具相乘作用。

關鍵字

薏苡種皮；多重藥物阻抗性；凋亡；轉移；植物固醇

並列摘要

Cancer has been the top ten causes of death in Taiwan from 1982. Chemotherapy is one of the cancer treatments. However, chemotherapy will cause many side effects and multiple drug resistance (MDR). These are the main poor effects of chemotherapy. MDR can be the result of a variety of mechanisms that are not completely understood, but many studies have shown P-glycoprotein expression was higher in tumor cells, and it induced MDR. On the other hand, there are evidences that P-gp positive cells are resistant to apoptosis. In addition, it’s also closely related between the poor effects of chemotherapy and tumor metastasis. Previous studies revealed that adlay seed extracts could have anti-cancer activity. Thus, this study will investigate that combination of adlay testa ethanolic extracts (ATE) and doxorubicin has on the growth inhibition of human uterine sarcoma cells. Results demonstrated that (1) ATE-Hex had the best effects of inhibition on MES-SA and MES-SA/Dx5 cells. Co-treatment of ATE-Hex and sub-toxic doxorubicin could synergistically or additively inhibit cancer cells proliferation. (2) ATE-Hex reduced the rhodamine efflux in MES-SA/Dx5 cells, indicated that ATE-Hex could reduce P-gp expression. ATE-Hex also could inhibit migration of MES-SA and MES-SA/Dx5 cancer cells. (3) Combination of ATE-Hex and doxorubicin induced apoptosis by increasing sub G1 phase and PARP being cleaved. (4) Analysis of anti-cancer activity, phytosterols had better inhibition on cancer cells growth than fatty acids, especially campesterol and β-sitosterol. These present findings showed that ATE could inhibit on the growth of human uterine sarcoma cancer cells. Furthermore, the combination of ATE and doxorubicin could decrease drug resistance and increase synergistic effect.