臺灣博碩士論文加值系統

化學治療為目前癌症最普遍的療法，然而，癌細胞同時對不同藥物產生抗藥性的現象是造成化療無法成功的一大原因，而藥物外排通道P-醣蛋白在這方面扮演了重要的角色。為了解決抗藥性的問題，P-醣蛋白的抑制劑已經經歷了三代的研發，但在臨床試驗的結果總是不如預期。在第四代P-醣蛋白抑制劑的開發上，已將目標轉向從天然物中尋找有效且相對無毒性的物質。本篇研究探討了牛樟芝子實體乙醇粗萃取物、去二甲氧基薑黃素、去甲氧基薑黃素及薑黃素對P-醣蛋白的抑制效果及機轉，也評估了ABCB1基因多型性對此抑制情況的影響。

首先建立帶有人類ABCB1基因上常見多型性位點變異組合的HEK293細胞株。藉由real-time RT-PCR來確認P-醣蛋白的表現，而P-醣蛋白的功能則由rhodamine 123 累積和排除實驗以及calcein-AM攝取實驗來檢測。牛樟芝子實體乙醇粗萃取物、去二甲氧基薑黃素、去甲氧基薑黃素及薑黃素對P-醣蛋白在表現及功能上的影響也由以上的實驗來評估。MDR1 shift assay和ATPase assay則用來釐清P-醣蛋白和待測物質之間的交互作用。

在檢測後，確認我們所建立的表現野生型和變異型P-醣蛋白細胞株之基礎ABCB1 mRNA表現和P-醣蛋白的外排功能皆正常。Rhodamine 123 排除實驗的結果顯示，牛樟芝子實體乙醇粗萃取物、去二甲氧基薑黃素、去甲氧基薑黃素及薑黃素能顯著地抑制野生型P-醣蛋白的外排功能，50%抑制濃度分別為1.51μg/ml, 3.08μM, 1.56μM 和 5.8μM。牛樟芝子實體乙醇粗萃取物是經由non-competitive之機轉來調控野生型P-醣蛋白，而類薑黃素則是藉由uncompetitive之機轉來抑制。然而，在經過72小時待測物質的處理後，並不會影響P-醣蛋白mRNA的表現。待測物質對由ABCB1位點變異所建立的變異型P-醣蛋白的影響，則呈現了和野生型P-醣蛋白不同的抑制強度及機轉。此外，ATPase assay的結果指出此四項物質會影響P-醣蛋白ATPase的功能，可能會與P-醣蛋白的受質有交互作用。

本篇研究成功地確立從蕈類及植物中取得的牛樟芝子實體乙醇粗萃取物、去二甲氧基薑黃素、去甲氧基薑黃素及薑黃素為具有潛力的P-醣蛋白功能調節劑。且證實了ABCB1基因上常見變異位點的組合型會影響這些P-醣蛋白功能調節劑的抑制強度及機轉。從天然物中尋找新穎抑制劑的任務仍屬於早期發展階段，本篇研究提供了充滿希望的開端及詳盡的機轉探討，將可在未來體內研究及臨床應用上有所幫助。

Chemotherapy is the most common treatment for cancer. However, the ability of cancer cells simultaneously becoming resistant to different drugs, a phenomenon called multidrug resistance (MDR), remains a big difficulty to successful chemotherapy and the drug efflux transporter, P-glycoprotein (P-gp), is reported to play an important role in this field. Although three generations of P-gp inhibitors have been developed to overcome this problem, the outcome of clinical trials among these agents has been negative. The discovering of “fourth generation inhibitors” aims at exploring potent and relative non-toxic substances from natural products. In the present study, we investigated the P-gp inhibitory effect and mechanism of ethanol extracts from Antrodia cinnamomea fruiting bodies (EEAC), bisdemethoxycurcumin (BDMC), demethoxycurcumin (DMC), and curcumin, the influence of common polymorphisms in ABCB1 gene was also evaluated.

HEK293 cell lines harbored some combinations of the common polymorphisms in human ABCB1 gene were established. Real-time RT-PCR was conducted to confirm the expression while rhodamine 123 accumulation and efflux assay and calcein-AM uptake assay were carried out to examine the function of P-gp. Influence of EEAC, BDMC, DMC and curcumin on P-gp expression and function was also evaluated by the above experiments. MDR1 shift assay and ATPase assay were conducted to figure out the interaction between P-gp and the tested substances.

The basal ABCB1 mRNA expression and P-gp efflux function of the established wild-type and variant-types P-gp expressing cell lines were confirmed. Results from rhodamine 123 efflux assay clearly demonstrated that EEAC, BDMC, DMC, and curcumin significantly inhibited wild-type P-gp efflux function with IC50 1.51μg/ml, 3.08μM, 1.56μM and 5.8μM, respectively. EEAC modulated wild-type P-gp through non-competitive inhibition while curcuminoids inhibited wild-type P-gp by uncompetitive kinetic. However, the P-gp mRNA expression was not changed after incubating the cells with the tested substances for 72 hours. Variant-type P-gp caused by ABCB1 gene mutations showed varied potency and distinct mechanism from wild-type P-gp inhibition. Moreover, results of ATPase assay revealed that these four substances influenced the P-gp ATPase function and may have interaction with other P-gp substrates.

This study successfully characterized EEAC, BDMC, DMC and curcumin, sourced from natural fungi and plants, as potential P-gp function modulators. The common polymorphism haplotypes in ABCB1 gene were demonstrated to affect the potency and mechanism of these candidate P-gp inhibitors. As the exploring of novel inhibitors from natural products is still in the early stages, the promising beginning and detailed mechanism investigation provided by this study will be helpful in the future in vivo studies and clinical practice.

目錄 I
圖目錄 III
表目錄 VIII
縮寫表 IX
中文摘要 X
英文摘要 XII
第一章 緒論 1
第一節 癌症藥物多重抗藥性與P-醣蛋白 1
第二節 牛樟芝之抗癌效用及對P-醣蛋白之影響 7
第三節 類薑黃素之抗癌效用及對P-醣蛋白之影響 9
第二章 研究目的 12
第三章 材料與方法 14
第一節 研究設計 14
第二節 研究材料 16
第三節 實驗方法 19
第四章 研究結果 31
第一節 P-醣蛋白的基礎表現量及功能 31
第二節 牛樟芝子實體乙醇粗萃取物與P-醣蛋白間交互作用及機轉之探討 33
第三節 去二甲氧基薑黃素與P-醣蛋白間交互作用及機轉之探討 38
第四節 去甲氧基薑黃素與P-醣蛋白間交互作用及機轉之探討 43
第五節 薑黃素與P-醣蛋白間交互作用及機轉之探討 48
第五章 研究討論 52
第六章 結論、研究限制與未來展望 63
第七章 圖表與說明 65
參考文獻 135

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