薑黃素結構類似物於體內抑制人前列腺癌之效果

Effect of curcumin analogs on anti-prostate cancer in vivo

張榮翔(Jung-Hsiang Chang)

指導教授 ： 侯文琪

共同指導教授 ： 蕭培文(Pei-Wen Hsiao)

臺北醫學大學/藥學院/生藥學研究所/碩士(2013年)

摘要

前列腺癌 (prostate cancer) 普遍發生在西方男性身上。近年來，根據行政院衛生署的統計，國人前列腺癌的發生率及死亡率逐年攀升，對男性造成嚴重的危機。許多文獻證實在薑黃 (turmeric) 中主要活性成分薑黃素 (curcumin) 具有抗氧化、抗發炎、抗腫瘤及轉移、誘導細胞計畫性死亡、及抗脂質過氧化等活性，但卻因生體可用率低及水溶性差等特性難以應用在生物體內，許多科學家陸續以薑黃素做為前驅物，期盼能找到具有臨床應用價值之類似物。本篇研究探討薑黃素類似物抑制前列腺癌之效果，經由雄性素受體調控冷光酵素活性試驗，篩選出其薑黃素結構類似物 No.2 具有顯著抑制雄性素受體的能力；同時也經由細胞存活率試驗，發現薑黃素結構類似物 No.2 具有濃度及時間依存性的抑制前列腺細胞增生。此外，利用細胞免疫染色及蛋白質表現量可證明薑黃素結構類似物 No.2 能誘導自體吞噬及細胞凋亡。在動物模式上，使用 PC-3 細胞原位接種之人類前列腺癌為對象，並以尾靜脈注射方式投予薑黃素結構類似物 No.2 於雄性裸鼠體內，實驗結果顯示薑黃素結構類似物 No.2 具有顯著抑制腫瘤生長之生物活性。

關鍵字

薑黃素 ； 前列腺癌

並列摘要

Prostate cancer is the most common disease that occurs in the male of western countries. It is also the seventh causes male cancer death in Taiwan. Mounting studies have revealed that curcumin is an active ingredient in turmeric through various biological effects, including anti-oxidation, anti-inflammation, cancer metastasis inhibition and proapoptosis. Despite of the remarkable anti-tumor effect of curcumin, bioavailability and aqueous solubility are major obstacles that hinder the clinical application of curcumin. Derivation of structural analogs is a frequently used strategy to improve the use of curcumin structure. Screening from a batch of curcumin analogs, we identified compound No.2 as a potent lead and studied its effect on prostate cancer. Cell culture of various prostate cancer cell lines and orthopotic xenograft of PC-3 cell line were used to study the in vitro and in vivo effects, respectively. The possible mechanisms were also evaluated. Our results reveal that No.2 exhibited dose- and time-dependent cytotoxicities and induced autophagy and apoptosis in treated PC-3 cells. Moreover, intravaneous No.2 significantly inhibited the tumor growth in a 10-week regimen in vivo. Overall, this study suggest No.2 is a promising candidate to treat prostate cancer.

並列關鍵字

Curcumin ； prostate cancer ； PC-3 cell

參考文獻

Adhami, F., Liao, G., Morozov, Y. M., Schloemer, A., Schmithorst, V. J., Lorenz, J. N., Kuan, C. Y. (2006). Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am J Pathol, 169(2), 566-583.

Aggarwal, B. B., Shishodia, S., Takada, Y., Banerjee, S., Newman, R. A., Bueso-Ramos, C. E., & Price, J. E. (2005). Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin Cancer Res, 11(20),

Aggarwal, B. B., & Sung, B. (2009). Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends in Pharmacological Sciences, 30(2), 85-94.

Aggarwal, S., Ichikawa, H., Takada, Y., Sandur, S. K., Shishodia, S., & Aggarwal, B. B. (2006). Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol, 69(1), 195-206.

Aksamitiene, E., Kiyatkin, A., & Kholodenko, B. N. (2012). Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochemical Society Transactions, 40, 139-146.