Silibinin對CT-26小鼠結腸腫瘤抗藥性醣蛋白P-glycoprotein之調節作用

The Modulatory Effect of Silibinin on P-glycoprotein Activity in Murine CT-26 Colon Carcinoma

郭馥華(Fu-Hua Kuo) ； 胡潔民(Chieh-Ming Hu) ； 吳欣穎(Hsin-Ying Wu) ； 廖美秀(Mei-Hsiu Liao) ； 許維倫(Wei-Lun Hsu) ； 詹東榮(Tong-Rong Jan)

《臺灣獸醫學雜誌》 35卷2期 (2009/06) Pp. 138-144

https://doi.org/10.7009/TVJ.200906.0138

摘要

癌症化學治療失敗和腫瘤細胞的多重藥物抗藥性(multidrug resistance; mdr)具高度相關性，多重藥物抗藥性基因mdr1的表現產物為P-glycoprotein (P-gp)，此蛋白能將化療藥物排出而使其無法達到有效的細胞內濃度。近幾年有研究報告指出中草藥天然物質具有抗癌和調節P-gp活性的作用，如類黃酮物質silibinin在某些離體及活體實驗模式中呈現抗癌效果。因此，本研究目的在應用小鼠結腸癌CT-26細胞及其活體腫瘤模式，探討silibinin對腫瘤Pgp活性是否具有調節作用。離體實驗結果顯示silibinin在不具細胞毒性的濃度下（低於50μM），和CT-26細胞(CT-26/WT)及其抗藥性細胞(CT-26/MDR)共同培養1小時後，具有抑制P-gp 活性的作用。在活體實驗方面，將CT-26/MDR細胞皮下接種於小鼠，並每日口服投予silibinin (200 mg/kg)， 於腫瘤大小約70-250立方公厘時，每週靜脈注射doxorubicin (DOX)1劑，劑量為10 mg/kg，共投與三劑，結果顯示silibinin單獨投予對腫瘤的生長並無作用，Silibinin與DOX合併亦沒有增強DOX的抗癌效果。綜合上述結果顯示，Silibinin雖然具有抑制離體CT-26細胞P-gp的活性，但是對活體腫瘤的生長則無顯著作用。

關鍵字

silibinin ； P-gp ； CT-26結腸癌 ； 多重藥物抗藥性

並列摘要

Multidrug resistance (MDR) is closely associated with the failure of cancer chemotherapy. P-glycoprotein (P-gp) is the protein product encoded by mdr1 gene. The function of P-gp is to efflux chemotherapeutic drugs, thereby reducing the intracellular drug concentrations. Recent studies have shown that natural phytochemicals exhibited anti-cancer and P-gp modulatory effects. For example, the anti-cancer activity of silibinin, a flavonoid compound, has been reported in several in vitro and in vivo models. The objective of the present study was to investigate the effect of silibinin on P-gp activity using the murine CT-26 colon carcinoma line and its animal tumor model. The cytotoxic effect of silibinin on CT-26 cells (CT-26NVT) and CT-26/MDR in vitro was evaluated by an MU assay. Treatment of cells with non-toxic concentrations (＜50 μM) of silibinin for 1 hr markedly inhibited the P-gp activity in CT-261WT and CCT-26/MDR cells, as measured by calcein accumulation. The effect of silibinin on the P-gp activity of CT-26/MDR tumor implants was also investigated. BALB/c mice bearing tumor implants were daily treated with silibinin (200 mg/kg) by gavage, and received ip injections of doxorubicin (DOX; 10 mg/kg/week for 3 weeks) when the tumor implants reached the size of 70-250 mm^3. The results showed that daily treatment of mice with silibinin did not affect the growth of tumor implants, as compared to the control group. In addition, silibinin treatment did not augment the anti-cancer effect of DCX. Taken together, our data demonstrated that the in vivo growth of CT-26/MDR tumor implants was unaffected by silibinin treatment, although the P-gp activity of the cells in vitro was suppressed by silibinin.

並列關鍵字

silibinin ； P-glycoprotein ； CT-26 colon carcinoma ； multidrug resistance