臺灣博碩士論文加值系統

第一部分
Cisplatin（CIS）是目前廣泛用於癌症治療的第一線化療藥物，雖然CIS有良好的抗癌能力，但其副作用限制了使用劑量。Quercetin（Q）是一種在植物中含量豐富的類黃酮，研究顯示quercetin可能會增加某些抗癌藥物的抗腫瘤效果並減少藥物的有害影響。本研究首先利用異種移植的模式探討quercetin對cisplatin的抗腫瘤效果以及副作用的影響。A549細胞（人類非小細胞肺癌細胞株）皮下注射至雄性裸鼠右後側背部，四週後隨機分成六組，分別為control組以及單獨給予cisplatin （2或5 mg/kg，腹腔注射一週一次：CIS2及CIS5），或CIS2合併Q處理，Q有經口（飼料內含1%及0.1% quercetin；HQ及LQ）或經腹腔注射（10 mg/kg，一週三次；IQ）給予。結果顯示CIS2+HQ及CIS2+IQ顯著的抑制腫瘤生長，CIS2單獨與CIS2+LQ則否，且CIS2+IQ及CIS2+HQ的效果與CIS5相當。我們發現CIS2合併HQ能顯降低血漿TBARs、腓腸肌IL-6、血漿TNF-α及腫瘤組織促發炎激素（TNF-α、IL-1β、IL-6）的含量，而合併IQ會使血漿、腫瘤組織及腓腸肌的促發炎激素、血漿TBARs有顯著下降。給予含quercetin之飲食以及腹腔注射quercetin也會使腫瘤組織內總quercetin含量顯著增加，其含量高低為：HQ > LQ及IQ。此外，與CIS2相比，IQ能顯著增加腓腸肌、副睾脂肪的重量（p<0.05），但在HQ方面僅對副睾脂肪有增加的趨勢。骨髓細胞數量方面，IQ及HQ皆能顯著提升（p<0.05）。在全血計數方面，我們發現CIS2會降低嗜中性球以及增加淋巴球數量，而quercetin有抑制這些作用的趨勢。另外在cisplatin合併quercetin中血小板的數量是有顯著增加的，雖然在給予cisplatin的組別並沒有誘發血小板低下。在紅血球計數中以cisplatin處理會顯著降低紅血球數目，但給予Q沒有回復的效果。本研究的結果顯示，quercetin不僅能增加cisplatin的抗腫瘤效果，也改善某些cisplatin所帶來的副作用。
第二部分
在體內實驗中我們發現IQ的抗腫瘤效果比攝取含quercetin之飲食來的好。接著我們比較quercetin及其代謝物－quercetin-3-glucuronide（G）在濃度2 μM和5 μM下對cisplatin （1 μM）抑制A549細胞生長效應之影響，並探討可能的機制。結果顯示，在A549細胞中quercetin和quercetin-3-glucuronide會增強cisplatin誘導的生長抑制作用，且具劑量和時間效應性。在相同劑量中CIS+Q的抑制效果會較CIS+G來的好。我們進一步發現CIS會誘導細胞停滯於G2 / M期，而CIS+G會顯著增加cisplatin此一效應，CIS+Q則否。然而，CIS+Q顯著增加於sub-G1的細胞數，這意味著CIS+Q會誘導細胞凋亡，我們證實CIS+Q也顯著的增加caspase-3的活性，而CIS或是CIS+G則沒有顯著的影響。接著我們測定與細胞停滯與凋亡相關之蛋白－p21及p53蛋白的表現量，結果顯示CIS+Q及CIS+G會比CIS單獨顯著較早增加p21及p53蛋白表現，且CIS+Q的效果比CIS+G好。以上結果顯示quercetin比quercetin-3-glucuronide更能加強cisplatin對A549細胞的生長抑制作用，這與我們的體內研究結果一致。結果也顯示quercetin和quercetin-3-glucuronide的促進效果可能與增加p21和p53表現，進而增加細胞週期停滯和細胞凋亡有關。

Part 1.
Cisplatin (CIS) is a widely used chemotherapy drug for human cancers, including lung cancer. Despite its significant antitumor activity, the side effects limit its use. Quercetin (Q), a flavonoid present abundantly in plants, has been shown to may increase the antitumor effects of some anti-cancer drugs and to decrease their harmful effects. In this study, we first used a xenograft model to investigate the effects of quercetin on the antitumor and side effects of CIS. Male nude mice were injected with A549 cells (human lung cancer cell line) into the flank. After 4 weeks, the tumor-bearing mice were randomly treated with cisplatin (2 or 5 mg/kg, once a week; CIS2 and CIS5, respectively) alone, or CIS2 in combination with quercetin for 12 weeks. Quercetin was given by a quercetin containing diet (0.1% or 1% quercetin diet; LQ and HQ, respectively) or by intraperitoneal injection (10 mg/kg, 3 times a week; IQ). The results showed that CIS2+HQ and CIS2+IQ rather than CIS2 alone or CIS2+LQ significantly inhibited tumor growth. The effects of CIS2+IQ and CIS2+HQ were similar to that of CIS5. We found that CIS2 in combination a Q containing diet or IQ tended to decrease plasma TBARs levels as well as proinflammatory cytokines in plasma and in tumors, especially IQ. Quercetin containing diets and IQ also significantly increased the total quercetin concentration in tumor tissues in an order HQ>LQ and IQ. In addition, quercetin containing diets and IQ tended to increase gastrocnemius muscle, epididymal fat weight and bone marrow cell number compared to CIS2. Most the efficiencies of IQ were the best. CIS2 decreased the neutrophil count and increased the lymphocyte count. Quercetin tended to suppress these effects of cisplatin. In addition, CIS in combination with quercetin treatment significantly increase the platelet count, while CIS alone had no effect. However, CIS significantly reduced the red blood cell count and quercetin did not recover such an effect of CIS. The results of the present study demonstrated that quercetin not only increase the antitumor effect of cisplatin, but also reduce some of the side effects of cisplatin in vivo.
Part 2.
We found that the enhancing effect of IQ on the antitumor effect of CIS was better than that of quercetin from diet. We then compared the effect of quercetin and its metabolites, quercetin-3-glucuronide (G), at 2 μM and 5 μM on the anti-growth effect of CIS (1 μM) in A549 cells and explored the possible mechanisms. The results showed that CIS+Q and CIS+G enhanced CIS-induced cells growth arrest in A549 cells in a dose- and time-dependent manner. The combined inhibition efficiency of CIS+Q on cell growth was greater than that of the CIS+G at the same dose. Furthermore, we found that CIS induced cell cycle arrest in G2/M phase, and quercetin-3-glucuronide rather than quercetin significantly increased such an effect of CIS. However, CIS+Q significantly increased the cells in sub-G1 phase, indicating CIS+Q inducing apoptosis. CIS+Q also significantly increase caspase-3 activity, while cisplatin or CIS+G had no significant effect. We determined the expression of p21 and p53, which are associated with cell cycle arrest and apoptosis, in treated cells. The result showed that CIS in combination with Q quercetin or quercetin-3-glucuronide significantly increased p21 and p53 protein expression earlier than CIS alone. The effect of CIS+Q was better than that of CIS+G. In conclusion, quercetin has a better efficiency than quercetin-3-glucuronide to enhance the suppressed effect of CIS on the growth of A549 cells, which is in agreement with our in vivo findings. The results also suggest that quercetin and quercetin-3-glucuronide exert their effect may through increasing the expression of p21 and p53, which in turn inducing cell cycle arrest and apoptosis.

圖目錄 iii
表目錄 v
縮寫表 vi
摘要 I
一、前言 1
（一、）緒論 1
（二、）文獻探討 3
1. 順鉑Cisplatin 3
2. Cisplatin與癌症惡病質 7
3. 槲皮酮Quercetin 9
4. Quercetin代謝產物－槲皮酮葡萄醣醛酸Quercetin-3-O-glucuronide 13
5. 細胞週期Cell cycle 17
6. 半胱胺酸蛋白酶Caspase 21
7. p21 蛋白及 p53 蛋白 22
8. 促發炎激素pro-inflammatory cytokines 25
9. 血液學毒性 28
（三、） 研究目標 31
二、材料與方法 32
（一、）材料 32
1. 儀器 32
2. 藥品 33
（二、）實驗架構 36
1. 動物實驗 36
2. 細胞實驗 38
（三、）研究方法 39
1. 動物實驗研究方法 39
1-1. 實驗動物飼育及處理 39
1-2. 脂質過氧化分析（Thiobarbituric acid reactive substances, TBARS） 40
1-3. DNA傷害分析（Comet assay） 41
1-4. 腫瘤組織總quercetin含量分析 42
1-5. 骨髓細胞計數 43
1-6. 全血細胞計數 44
2. 細胞實驗研究方法 44
2-1. 細胞株及培養條件 44
2-2. 冷凍保存細胞 45
2-3. 解凍細胞 46
2-4. 細胞處理 46
2-5. 細胞生長分析（MTT assay） 46
2-6. 流式細胞儀測定細胞週期及apoptosis 47
2-7. caspase-3 活性測試 48
3. 細胞及動物研究方法 48
3-1. 促發炎激素（TNF-α、IL-1β、IL-6）分析 48
3-2. 西方墨點法（Western blot assay） 49
4. 統計分析 53
三、結果與討論 54
（一、）動物實驗結果 54
（二、）動物實驗討論 58
（三、）動物實驗圖表 63
（四、）細胞實驗結果 83
（五、）細胞實驗討論 86
（六、）細胞實驗圖表 89
四、結論 102
五、參考文獻 103
附錄一、預備實驗 127
附錄二、正式動物實驗 139
附錄三、細胞實驗 142

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